4. Locoregional primary disease – Breast Cancer
4.1 General diagnostic and therapeutic concepts
The incidence of breast cancer increased in Germany until the end of the 1980s and has only decreased significantly in recent years. Since 1990, the mortality rate has also been declining. In the USA and England a decrease in mortality of more than 20% is also observed, which is associated with consistent early detection and adjuvant systemic therapy. It is to be hoped that the mammography screening now implemented throughout Germany on the basis of the Cancer Early Detection Guidelines (KFÜ) and the federal mammography contracts created for this purpose, in which asymptomatic women between the ages of 50 and 69 are personally invited to mammography screening, will lead to the earlier detection of breast carcinomas and a further reduction in mortality in the medium term.
Decisive progress has been made in imaging diagnostics both for palpable as well as clinically unclear or suspicious findings and the establishment of interventional methods in preoperative diagnostic clarification.
For patients with breast carcinoma, unclear or suspicious findings and precancerous lesions, in addition to careful clinical examination
- Mammography including additional mammographic images (e.g. enlargement mammography),
- Mammary sonography with radiofrequency probes (7.5-12 MHz analogous to the DEGUM recommendation),
- the interventional methods such as punch biopsy and vacuum biopsy,
- magnetic resonance imaging (MRT) with the administration of contrast medium,
- the galactography,
- the rarely used pneumocystography (largely replaced by high-frequency sonography technology) and
- fine needle puncture only in special individual cases (e.g. lymph node puncture axilla).
at your disposal. The arsenal of these non-invasive and invasive diagnostic methods, in combination with the histological processing of the preoperatively removed punches including the immunohistochemical findings obtained there (estrogen and progesterone receptor, HER2 status), allows targeted surgical planning within the framework of a pretherapeutic consultation. Here, the extent of the surgery, taking into account the oncological safety margins, any oncoplastic surgeries that may be necessary to reconstruct the surgical defect and the patient's wishes can be brought together to form an overall surgical concept.
In addition to this early, comprehensive surgical planning, the introduction of sentinel node biopsy in particular has led to progress in the surgical treatment of primary breast cancer. The restriction of conventional axillary lymphonodectomy to cases with clinically or sonographically affected axilla allows for a limitation of surgical radicality in the axilla with a significant reduction of short and long-term morbidity for almost 70-80% of our patients. Here the surgical standard has changed substantially.
The same applies to the oncoplastic surgical techniques. The increased use of intramammary reconstructions using the glandular rotational flap technique to avoid larger tissue defects and defect coverage using local flap techniques, in particular thoracoepigastric displacement flaps, today make it possible to preserve breasts with acceptable cosmetic results and restored body integrity with maximum oncological safety even in the case of larger tissue resections.
The diagnostic and surgical advances in the therapy of primary breast cancer are complemented by the success of primary systemic therapy. Here, chemotherapy - for receptor-negative tumors - has led to remarkable histopathological complete remission rates. With the help of this primary systemic therapy, breast carcinomas that were previously considered inoperable can be operated on and the rate of breast-conserving surgeries can be increased.
Postoperative radiotherapy leads to an improvement in local tumor control. Meta-analyses have shown that mortality is also significantly reduced. The effects are largely independent of the patient's age. This applies to percutaneous radiotherapy after breast-conserving surgery as well as after mastectomy. The effects of radiotherapy on regional lymph drainage have not been conclusively clarified.
The adjuvant systemic therapy has gained a new significance, especially due to the consensus meetings in St. Gallen as a result of the renaissance of adjuvant endocrine therapy in post-menopausal women with hormone receptor positive tumors. Especially in post-menopausal patients with endocrine sensitive tumours, the use of aromatase inhibitors as upfront therapy, as sequence therapy ("switch"), i.e. the use of aromatase inhibitors following a shortened tamoxifen therapy of 2-3 years and a total therapy duration of 5 years, as well as in the form of an extended adjuvant therapy with aromatase inhibitors after regular 5-year tamoxifen therapy have proven to be promising.
The data available to date from large, multi-centre prospective randomised studies must be supported by the long-term results, especially in order to better sound out previously unrecognised late effects of long-term treatment with aromatase inhibitors.
In adjuvant systemic chemotherapy, too, further therapeutic successes can be expected in the short and medium term if the taxanes or the dose-dense and dose-intensified chemotherapy are used optimally. The results of adjuvant therapy with trastuzumab (Herceptin®) have received particular attention. US studies show a significant prolongation of the absence of relapse and a reduction in the rate of metastasis as well as an improvement in overall survival through the use of this antibody.
Overall, the treating physicians have a large arsenal of diagnostic and therapeutic options at their disposal for their patients. It is certainly crucial for the improvement of the overall results that our patients are treated according to the recommendations of these guidelines. Under- or over-therapy, i.e. therapy that does not comply with the guidelines, reduces the quality of results (disease-free survival, overall survival).
4.2 Diagnostics on abnormal findings and pretherapeutic diagnosis of spread in confirmed breast cancer
4.2.1 Basic diagnostic workup
Basic diagnostics as described in Recommendation 4.1 are recommended for the clarification of abnormal findings and as part of the pretherapeutic diagnosis of confirmed breast cancer. An algorithm for the diagnostic procedure for women with abnormal findings of the breast can be found in Appendix 11.1 (Algorithm: Diagnostics of women with abnormal or suspicious findings of the breast from early detection) and also applies to women whose suspicious findings were collected outside of screening programmes.
The following are considered basic tests:
- Medical history and clinical breast examination: inspection, palpation of breast and lymph drainage areas
- Mammography
- Ultrasound
If the clinical breast examination reveals abnormal findings, the diagnosis should be completed by appropriate imaging procedures and, if necessary, a histological examination.
- Consensus
- Strong consensus
The effects of endogenous and exogenous hormones should be taken into account when performing and reporting diagnostic measures.
Background 4.1 and 4.2
If the assessability of the diagnostic procedures is only possible to a limited extent due to the effect of hormone treatment, an individual decision must be made on how to proceed. The following measures must be taken into account [175], [176], [177], [178], [179], [180]:
- Modification, discontinuation or interruption of hormone intake (taking into account the histological result)
- Adapted choice of imaging methods
- Education about hormone-related limitations of diagnostic safety (increased false positive and false negative rates) of all methods. In particular, the use of MRI is to be examined under consideration of increased false-positive rates [181], [182].
4.2.2 Imaging methods
Mammography
Women over 40 years of age should be given a mammography if the findings are abnormal.
- Consensus
- Strong consensus
In women under 40 years of age, mammography should be used where a suspected malignancy cannot be ruled out with sufficient certainty on the basis of clinical examination, sonography and - if indicated - percutaneous biopsy.
- Consensus
- Strong consensus
Suitable additional images should be considered for mammographic clarification.
- Consensus
- Strong consensus
In the case of currently detected malignant tumours, a mammography should be performed pre-therapeutically.
- Consensus
- Strong consensus
In cases of high mammographic density or limited mammographic assessability, a sonography should be performed as a supplement.
Background 4.3 to 4.7
Mammography in symptomatic and pre-therapeutic patients serves to assess the original findings as correctly as possible (with regard to dignity and extent) and thus to ensure optimal therapy planning and to exclude further changes requiring clarification.
Good sensitivity and high accuracy for mammography are comprehensively documented for women over 40 years of age [45], [64], [92]. The pre-test probability increases by a factor of 2 or more even in asymptomatic women if there is a familial risk or a breast carcinoma already detected on the opposite side. In the case of clinical suspicion this increase is usually even significantly higher depending on the type of clinical findings.
Thus, in symptomatic women > 40 years of age, the risk of overlooking or misjudging a carcinoma far exceeds the risk of carcinoma initiation through exposure to X-rays in quality-assured mammography [51], [184]. Therefore, mammography should be used in symptomatic patients from the age of 40 onwards. Pretherapeutically, the mutual breast should also be completely examined mammographically if a mammary carcinoma has already been found on one side [28], [185].
In order to exploit the full potential of mammography, suitable additional images (individually or anatomically adapted projections, so-called rolled images, spot and magnification images or, if available, tomosynthesis) should be used in addition to standard images if necessary to clarify unclear findings.
For the targeted use of tomosynthesis in the diagnostic situation, there is now sufficient evidence for at least equivalent results for the differentiation of soft tissue changes compared to additional mammographic images before [186], [187], [188], [189], [190], [191].
There is insufficient data for the primary use of tomosynthesis in the symptomatic situation. However, results from studies on the use of tomosynthesis in the screening situation suggest an increase in sensitivity even in combination with synthetic mammography. The extent to which these can be transferred from the screening situation to the curative situation has not been conclusively clarified [74], [192].
If a reliable exclusion of malignant tumours is not possible with the above mentioned procedures including sonography, interventional clarification (punch biopsy) is primarily indicated.
In cases in which no reliable diagnosis can be made with the above techniques or in which a biopsy is problematic (multiple findings, pronounced scarring, extreme localization), the use of contrast medium MRI can be considered.
If MRI is not feasible (e.g. pacemaker, cochlear implant, claustrophobia), studies are available for contrast agent mammography that demonstrate an improvement in detection, especially in dense glandular tissue. These studies show a comparable diagnostic accuracy for contrast medium mammography as for contrast medium MRI with regard to detection and expansion assessment [193], [194], [195], [196], [197], [198], [199].
The preparation and reporting of mammography images should be restricted to equipment and persons who are subject to appropriate quality assurance (as part of the screening programme or existing quality assurance agreements).
Like any imaging method, mammography does not achieve 100% sensitivity. In women ≥ 40, it is usually between 85-90% [92]. Therefore, depending on the findings and glandular tissue in symptomatic women ≥ 40, mammography must be supplemented with suitable additional imaging or interventional methods (usually sonography and percutaneous biopsy) until a definite clarification is achieved with the highest possible certainty.
In women below the age of 40, benign changes and tumours are far more common than malignancies. In total, less than 5% of all breast cancer cases occur before the age of 40 (Tumor Register Munich 2016). In addition, in the glandular tissue which is often denser in adolescents the accuracy of mammography decreases [200] and the risk of X-ray radiation increases with younger age. Nevertheless, about 50% of breast carcinomas can be reliably detected with mammography.
These changed conditions have to be taken into account in the indexing of mammography examinations. Screening mammograms are not recommended before the age of 40 for women without risk. In symptomatic patients, clinical and sonographic examination should be performed first. If sonography (and possibly percutaneous biopsy) cannot exclude breast cancer with sufficient certainty, the use of mammography should be considered depending on the clinical suspicion or remaining uncertainty, individual risk and age of the patient. (For the use of early detection mammography before the age of 40 at high risk, see Chapter 3.3).
Sonography
Sonography is to be used for the clarification of clinically unclear and mammographic as well as MR-tomographic findings of evaluation categories 0, III, IV and V.
The aim of standardized mammary sonography is the systematic and reproducible examination of the mammary gland and axilla. The findings should be reproducibly documented.
- Consensus
- Strong consensus
Structural, process and result quality should also be demonstrated as a basic requirement for the application of mammary sonography.
- Consensus
- Strong consensus
Background 4.8 to 4.10
Sonography should be used for clarification of clinically unclear and mammographic as well as MR-tomographic findings of evaluation categories 0, III, IV and V. The examination should be performed systematically and reproducibly. Additional criteria to the B-image such as Doppler sonography, 3D sonography and elastography can be helpful in differentiating between malignant and benign findings [205], [206], [207]. Automated 3D chest ultrasound can be performed using a system positioned by assistant personnel. The images are automatically generated and forwarded to a workstation. Image interpretation and reporting by the physician takes place at the workstation. The diagnostic indices are essentially identical to the hand-held ultrasound [208], [209], [210].
The intraoperative use of ultrasound in the context of carcinoma surgery (direct visualization of the incision boundaries) can reduce the postoperative resection rate [211], [212], [213]. It may be helpful to use ultrasound for postoperative quality control of residual glandular tissue after prophylactic mastectomy in high-risk patients.
Regular participation in certified advanced training courses on breast diagnostics (e.g. via DEGUM) is generally recommended [214].
Contrast medium MRI
In the diagnostic situation, KM-MRI should be limited to those cases that cannot be resolved with sufficient certainty using conventional diagnostics (MG, US) and percutaneous biopsy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus
- References
- [215]
The performance of a pre-therapeutic KM-MRI for a diagnosed breast carcinoma only makes sense in justified cases. The indication for this should be made in a multidisciplinary conference.
A KM-MRI of the breast should only be performed where the possibility of an MRI-supported intervention exists or is bindingly regulated and the histological results of the MRI intervention are presented in a multidisciplinary conference in the sense of documenting the quality of results.
- Consensus
- Strong consensus
Background 4.11 to 4.13
In the majority of cases in the diagnostic situation, the confirmation or exclusion of a breast carcinoma can be achieved with sufficient certainty by a combination of clinical examination, mammography, sonography and percutaneous biopsy. In the following situations, however, the complementary performance of a KM-MRI can help to solve the problem:
- Currently percutaneous biopsy with benign result but insufficient radiological-pathological correlation
- Suspicious palpation findings without sufficient correlation in mammography and sonography
- Suspicious findings in mammography or sonography in which a percutaneous biopsy is not feasible (e.g. focus can only be defined in one plane, focus not accessible due to the location of a percutaneous biopsy, multiple suspicious foci of the same type)
In these cases, KM-MRI enables a relevant increase of the positive and especially the negative predictive value [215].
The available data on the use of KM-MRT for preoperative tumor staging do not justify the routine use of this procedure in all patients with a newly diagnosed breast carcinoma [216], [217], [218]
In selected cases, however, the use of complementary KM-MRI can optimize locoregional propagation diagnostics and improve therapeutic decision making [219], [220], [221], [222]. These cases include
- unclear locoregional spread after conventional diagnostics
- lobular carcinoma
- high genetic or familial risk of disease
- young, premenopausal patients
- planned partial breast irradiation
Whenever possible, additional findings in preoperative CMM MRI that lead to a change in the therapeutic procedure should be histologically confirmed preoperatively. This requires a sufficient time interval between preoperative MRI and the planned surgery appointment as well as the existence of the professional and technical prerequisites for performing an MRI-guided biopsy at the treating breast centre. The determination of the indication for preoperative KM-MRI in a multidisciplinary conference enables the optimal consideration of all relevant diagnostic and therapeutic aspects.
4.2.3 Diagnostic confirmation
Imaging guided minimally invasive biopsy
The histological clarification of findings should be carried out by punch biopsy, vacuum biopsy and, in exceptional cases which must be justified, by open excision biopsy.
The biopsy should be controlled by means of imaging that clearly shows the findings.
When selecting the collection method, diagnostic certainty and the risk of side effects should be taken into account.
The examiner should take suitable measures to ensure that the localisation of the finding can be found again (e.g. by clip insertion).
- Consensus
- Strong consensus
Even if the findings are primarily detected by mammography or MRI, the sonographically controlled punch biopsy should be performed if the sonographic correlate is reliable.
- Consensus
- Strong consensus
If microcalcification is present without accompanying focal findings, stereotactically controlled vacuum biopsy should be used.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2b
- Consensus
- Strong consensus
- References
- [223]
Vacuum biopsy should be used for mammographic or MRI-guided tissue collection.
- Consensus
- Strong consensus
For all biopsies, the correlation between the histological result and the suspected clinical diagnosis shall be checked and documented.
- Consensus
- Strong consensus
In case of histopathologically benign findings of imaging category 4 or 5, which have been biopsied representatively, an imaging control with the appropriate examination method should be performed once after 6 months.
- Consensus
- Consent
For interventional, preferably sonographically guided punch biopsy, ≥ 3 samples should be taken at ≤ 14 G with verifiable target detection of the punch needle.
For vacuum biopsies, ≥ 12 samples should be obtained using a 10 G needle. For other calibres (between 8-G and 11-G), the number of samples taken should provide an equivalent sample volume.
- Consensus
- Strong consensus
Open excision biopsy
Pre-operative or intraoperative marking should be carried out using the method that allows the findings to be clearly visualized, especially in the case of non-palpable changes.
Proof of adequate resection must be provided intraoperatively by means of specimen radiography or specimen sonography. If MR-guided marking has been performed, an MR control should be performed within 6 months in case of histologically unspecific benign findings.
- Consensus
- Strong consensus
In the case of preoperative wire marking of non-palpable findings, the wire should lie in the focus and protrude less than 1 cm beyond it. If the wire does not penetrate the focus, the distance between the wire and the edge of the focus ≤ should be 1 cm. In the case of extensive findings, marking the surgically relevant target volume with several markings can be useful.
The surgical material should be clearly marked topographically and sent to the pathologist without incision on the tissue material obtained.
- Consensus
- Strong consensus
Background 4.14 to 4.26
Histological clarification should be performed minimally invasive by punch or vacuum biopsy. Punch and vacuum biopsies are used to determine tumor biological factors that are necessary for pretherapeutic treatment planning (tumor type, grading, hormone receptor status, HER2neu, Ki-67, etc.). In exceptional cases where minimally invasive intervention is not possible, open excision biopsy can be used. Independent of the preoperative needle marking, direct intraoperative sonographic targeting can optimize the resection volume [211], [212], [213]. After open excision biopsy a primary systemic therapy is no longer possible. A biopsy should always be performed with the imaging technique that allows the findings to be clearly displayed. If the findings can be displayed with several methods, the gentlest method should be selected. When a biopsy is performed, the correlation between the histological result and the suspected imaging diagnosis should always be checked. If a biopsy has not been performed representatively, another biopsy must be performed to obtain a representative result. A tumor cell dissection in the punch channel takes place. The puncture channel does not have to be removed during breast-conserving therapy with radiotherapy [232], [233].
Punch biopsy should be primarily used for the fine tissue clarification of suspect lymph nodes, since current comparative studies show a higher sensitivity for CNB than for FNB with the same specificity [224], [225], [226], [227]. FNA should be reserved for centers with extensive experience in cytological punctures as well as in the evaluation of cytology.
Staging
In the case of newly diagnosed breast carcinoma from UICC stage II with increased risk and III and IV without symptoms of metastasis, staging (lung, liver, skeleton) should be performed.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Consent
- References
- [234]
In case of newly diagnosed breast cancer and the clinical suspicion of metastases, imaging staging should be performed.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2a
- Consensus
- Consent
- References
- [235]
Whole body staging should only be performed in women with a higher risk of metastasis (N+, > T2) and/or aggressive tumor biology (e.g.: HER2+, triple-negative), clinical signs, symptoms and if a planned decision on systemic chemo/antibody therapy is planned. Whole body staging should be performed using CT thorax/abdomen and skeletal scintigraphy.
- Consensus
- Consent
Background 4.27 to 4.29
Current international guidelines [28], [234] do not recommend general whole-body staging at the time of diagnosis of early breast cancer. The prevalence of distant metastases is given as 0.2% for stage I and 1.2% for stage II. The lack of recommendation for staging in the early stage serves to avoid unnecessary further examinations and stress due to false positive incidence findings in imaging staging. The prevalence of distant metastases is increased in N+ [236]. In addition, this guideline contains a consensus recommendation for staging in aggressive tumor biology if this has a decisive influence on the therapeutic procedure.
The available evidence on the selection of staging methods is limited. Studies have shown sensitivities and specificities of the individual methods. However, there are no studies on the influence of the selected methods on the actual outcome (survival as a function of any resulting changes in therapy or quality of life).
Due to better sensitivity and specificity, CT thorax/abdomen and skeletal scinitgram have replaced the earlier staging with thoracic x-ray and abdominal ultrasound as basic staging examinations (ESMO 2015/17).
A general recommendation for PET or PET-CT is not given based on the NCCN 2014, ESMO and NCGBCI Ireland 2015 guidelines, since even here false negative findings (for slower growing metastases and metastases
The question of when further imaging examinations are useful, there is a layman's understanding "Make smart decisions together" -Recommendation based on this guideline.
4.3 DCIS and high-risk lesions
4.3.1 Preliminary remarks
DCIS and risk lesions are usually clinically occult changes that are detected during early clinical diagnosis or mammography screening. This chapter deals with ductal carcinoma in situ (DCIS), atypical ductal epithelial hyperplasia (ADH), lobular neoplasia (LN), flat epithelial epidermis (FEA) and intraductal papilloma. These changes have the character of a neoplasia in common, but with quite different risk of progression. The aim of diagnostic and therapeutic measures, especially excision, is on the one hand to avoid progression into invasive carcinoma and the associated morbidity and mortality. Since it is not only a question of precursor but also indicator changes, the aim is also to reduce the risk of ipsi- or contralateral carcinoma not directly associated with the lesion.
4.3.2 DCIS
4.3.2.1 Clinical presentation, risk and course in DCIS
DCIS - General
In the treatment of a patient with ductal carcinoma in situ (DCIS) without invasive components, the advantages and disadvantages of available forms of therapy or their combination will be explained. The relative and absolute effects of adjuvant therapy measures in relation to the local recurrence probability and overall survival will be presented.
- Consensus
- Strong consensus
Background 4.30
The incidence of DCIS has increased significantly in the last decades and amounts to approximately 5,500 per year [43] in Germany. Clinically, about 80% of DCIS behave asymptomatically and only 20% of DCIS manifest themselves as symptom-related disease [237].
Recently, studies have shown a low breast-cancer-specific long-term mortality of pure DCIS in the US population [238] of 3.3% after 20 years (and 1.7% if cases with contralateral second carcinoma are excluded [eTable 5 in the supplement]), thus triggering a discussion about the importance of early detection of DCIS and its treatment [239]. The mortality rate after diagnosis of DCIS is partly due to cases with undiscovered occult invasion or microinvasion [240], and partly to invasive tumor recurrence or ipsilateral second cancers which may occur many years after diagnosis of DCIS [241]. The overall low mortality rate can be regarded as an expression of an adequate therapy for patients with DCIS according to current standards. The epidemiological data do not allow the conclusion that DCIS generally takes an indolent natural course of the disease. Rather, case series with overlooked DCIS indicate a long-term mortality of breast cancer which can be attributed to tumor progression [242], whereas the mean time interval between overlooked DCIS and the occurrence of invasive breast cancer in the Nurses Health Study was about 9.0 years [243]. As these were low risk cases, the time interval for the untreated DCIS until the occurrence of an invasive carcinoma should be altogether shorter, however, concrete data are not available in the literature. For the DCIS discovered in the screening a connection with the avoidance of an invasive interval carcinoma could be proven [55].
With regard to the risk factors for an unfavorable course, i.e. for the occurrence of an intramammary tumor recurrence, clinical factors play a role, in particular the age of the patient and the findings of a clinically manifest disease compared to a disease detected in screening, as well as radiological factors such as the density of glandular tissue, and last but not least histological and tumor biological factors. The age of the patient was a significant risk factor for tumor recurrence in several prospective-randomized and retrospective clinical studies [244], [245], and in patients
Much of the uncertainty regarding the clinical management of DCIS is due to the fact that DCIS histologically and biologically represents a heterogeneous disease with varying malignancy potential, and that an invasive disease can only be excluded when the lesion has been pathomorphologically fully examined [246]. Pathomorphological factors which reflect the malignancy potential of the DCIS are the grading and subtype of the DCIS [247], the size of the lesion and (to a certain extent) the immunohistological phenotype. Recently, gene expression analysis has also been discussed to better estimate the aggressiveness of the DCIS [248]. Among these parameters, grading is the most important risk factor [244], followed by lesion size and detection of comedotype necrosis [249]. It could be shown that the group of patients with high-grade DCIS and extensive comedotype necroses in > 50 % of ductuli has a significantly increased risk of both ipsilateral invasive and non-invasive tumor recurrence [250]. The role of gene expression analysis in this context has not yet been conclusively clarified. In a low-risk collective defined by means of a DCIS-specific multiassay the 10-year local recurrence rate after breast-conserving surgery without radiotherapy was still 10.8% [251], which is similar or worse compared to collectives with breast-conserving surgery without radiotherapy defined by conventional risk factors [252], [253].
The determination of the size of the DCIS is not necessary for the assessment of the T/pT category according to TNM, but nevertheless important for the pathological-radiological correlation and for the management of the patient [254]. The larger the DCIS, the more probable the presence of multifocality and marginal infestation as well as tumor residuals, and thus the probability of a local recurrence with the possibility of a metachronous tumor invasion [255], [256], [257], [258], [259], [260]. In addition, the risk of an occult invasion increases with an increase in tumor size [261]. A threshold value for a critical size of the DCIS, up to which breast-conserving therapy is possible, cannot be given. The DCIS size is often underestimated due to mammographic evaluation or preparation radiography, but can also be overestimated in cases with well differentiated DCIS at the base of a mastopathy with benign calcifications. A relatively accurate estimation of the total extent of the DCIS is possible by serial, lamellar processing with an accuracy of 3 - 5 mm. Small DCIS of 1 cm or less can be measured directly histologically in the sectional preparation [262]. It should be noted that, especially with low-grade DCIS, the propagation of the DCIS can be discontinuous. It is therefore recommended to indicate the total size including these gaps and not the size of the individual foci in the case of a supposed multifocality [262]. When resecting a DCIS in several parts, the pathologist should try to reconstruct the size of the DCIS taking into account the topography of the individual sub-preparations [263].
4.3.2.2 Surgical therapy of DCIS
Complete excision is the therapeutic basis for the treatment of DCIS. The resection limits should be at least 2 mm for pure DCIS when adjuvant radiotherapy is connected.
Background 4.31
Just as in invasive breast cancer, breast-conserving therapy can be considered standard today in DCIS, especially when there is a favourable relation between the extent of the lesion and the breast size. However, in contrast to invasive carcinoma, there is no randomized controlled trial for DCIS that has compared the outcome after breast conservation therapy with that after mastectomy. Histopathological studies on the spread pattern of DCIS show that DCIS is a usually (90%) unicentric, but potentially multifocal lesion, which can theoretically be rehabilitated by surgery alone, provided that a targeted (segmentally oriented) surgery with sufficient resection limits is performed [269], [270].
The question of which resection limits have to be adhered to in the breast-conserving therapy of DCIS is directly related to the implementation or the renunciation of postoperative radiotherapy. With a resection margin of 10 mm or more, the benefit of radiotherapy is only slight [271], [272]. A 2 mm wide safety margin is associated with a lower risk of recurrence than a 1 mm wide margin, but does not differ statistically from a 5 mm wide resection margin if breast-conserving surgery is performed with subsequent whole breast radiation [273]. In case of mastectomy and affected resection margin or narrow resection of
Taking into account careful pathological work-up and radiological-pathological correlation with respect to the topography and the size of the DCIS, a minimum resection margin of at least 2 mm therefore appears to be sufficient if adjuvant radiotherapy is performed [264], [265], [266], [268], [274]. If radiotherapy is not performed, wider safety margins should be aimed for, although no optimum margin can be given here. Here, further risk factors should be taken into account, especially whether the DCIS extends over a wide area or only with an extension close to the edge [271] as well as size and grading of the DCIS [259]. If a complete excision cannot be achieved by resection(s), a secondary mastectomy should be considered. In the case of a marginal margin of less than 2 mm, the necessity of a follow-up resection should be discussed as an individual case decision in the interdisciplinary team, taking into account the clinical situation (topography of the marginal situation, size and grading of the DCIS, age of the patient, etc.).
Radiotherapy of DCIS
An axillary dissection should not be performed in DCIS. A sentinel node biopsy should only be performed if a secondary sentinel node biopsy is not possible for technical reasons, e.g. in the case of a mammary ablatio.
Background 4.32
Since DCIS is by definition a non-metastatic lesion, no staging examination is required, and usually no sentinel lymph node (SN) biopsy is needed. However, an SN biopsy can be performed in the case of primary mastectomy or very peripheral tumour site, as the morbidity of the SN intervention is low and the SN biopsy cannot be performed in this constellation for technical reasons if an invasive carcinoma has been subsequently identified [185], [275], [276], [277]. When a DCIS is diagnosed by means of punch or vacuum biopsy, an invasive carcinoma is found in about 20% of the surgical specimens subsequently obtained [278], [279], [280]. There is an increased risk in palpable lesions and DCIS with a radiological size of > 4 cm [279], [281], [282]. However, even in this situation, the probability of a clinically relevant, positive sentinel lymph node being present in the case of occult tumor invasion is low and can be clinically neglected [279], [283], [284]. An SN biopsy should therefore be performed secondarily in BET because of DCIS, if necessary.
4.3.2.3 Radiotherapy of the DCIS
Adjuvant radiotherapy reduces the risk of local recurrence after breast-conserving therapy by up to 50%, but at low risk the benefit for the patient is small. The possibility of radiotherapy should be offered to the patient depending on the individual risk profile.
Background 4.33
The radiotherapy of DCIS aims to reduce the intramammary recurrence risk and the associated morbidity [285], [289]. However, it is not an obligatory component of the breast-conserving therapy of DCIS, but an individual therapy decision which depends on clinical, radiological and pathological criteria. In the EBCTCG meta-analysis the 10-year in-breast recurrence rate with negative resection margin was 26.0% without radiotherapy compared to 12.0% with postoperative whole breast irradiation (p 3 mm 6.7% and 0.9% (p = 0.0003) for the sole excision compared to excision plus whole breast irradiation (p = 0.0003) in the RTOG-9804 study [252]. The risk of an intramammary recurrence after 10 years is currently given as 11% for patients with postoperative follow-up irradiation and 19% without follow-up irradiation. Thus, the risk of recurrence has been significantly reduced compared to older data [290]. This can be attributed to improvements in diagnosis and therapy of DCIS. These include the radiological diagnosis and early detection of the DCIS, the pathomorphological processing and evaluation of the tissue samples [291] and last but not least the surgical treatment of the DCIS. In a low risk collective (G1/G2 to 2.5 cm) the intramammary recurrence rate after 12 years without radiotherapy was 12.5% and thus approx. 1% per year [252], and in a further prospective-retrospective analysis of 209 low risk patients without radiotherapy (size 2 cm or less, age 50 years or more, grade 1 or 2) the 12-year intramammary recurrence rate was only 7.8% and thus 0.65% per year [253]. These recurrence rates are lower than the 15% after 10 years considered acceptable by EUSOMA for invasive carcinomas [292].
Although half of the tumor recurrences after DCIS are invasive tumor recurrences, no survival benefit from postoperative radiotherapy of DCIS has been shown in several prospective randomized studies and a follow-up of up to 20 years [285], [286]. In a retrospective analysis, however, the hazard ratio for the mortality probability after breast cancer for the invasive intramammary recurrence was 18.1 (95% AI: 14.0 - 23.6) [238]. There are indications for the association of breast cancer mortality in DCIS with pathological risk factors (grading, size, comedotype necroses of DCIS) [287]. In low-grade DCIS no significant mortality could be detected in this cohort, independent of the performance of surgical intervention [293]. The possible reduction of the intramammary recurrence risk by radiotherapy must therefore be seen together with the unclear effect on mortality and requires an individual therapy decision taking into account the risk factors for an intramammary recurrence.
According to the available data, the number needed to treat (NNT) to prevent a local recurrence by follow-up irradiation is 7 [Early Breast Cancer Trialists' Collaborative, Group%A Correa, C.%A McGale, P.%A Taylor, C.%A Wang, Y.%A Clarke, M.%A Davies, C.%A Peto, R.%A Bijker, N.%A Solin, L.%A Darby, S. et al. 2010] for all DCIS and 17 for a low-risk collective ( 50 years). The patient should be informed about the personal (absolute) benefit as well as the possible risks of irradiation on the basis of an individual risk assessment. There is evidence that hypofractionation, similar to invasive carcinoma, can reduce radiotherapy-associated morbidity in DCIS and is similarly effective in preventing intramammary recurrence [294], [295].
4.3.2.4 Antihormone therapy in DCIS
Similar to radiotherapy the risk of intramammary recurrence after BET due to DCIS can be reduced by adjuvant antihormonal therapy [289]. This also applies to the contralateral risk of an invasive second carcinoma [296]. However, the effect on the intramammary risk of recurrence is less than for adjuvant radiotherapy, and likewise without a detectable influence on survival [296], [297], [298], [299]. The number of patients to be treated (NNT), for the detection of a locally protective effect by the administration of tamoxifen over 5 years is 15 patients [297]. The NNT rate for subgroups is: ipsilateral DCIS 47; contralateral DCIS 93; ipsilateral invasive carcinoma 63 and contralateral invasive carcinoma 54 patients [297]. Aromatase inhibitors have a similar protective effect in DCIS as tamoxifen [300]. Due to the relatively low benefit for the individual patient with DCIS, [301] is recommended as a cautious indication for adjuvant antihormonal therapy in DCIS. This shows a higher benefit in postmenopause than in premenopause [302]. If an indication for antihormonal therapy is given, the determination of the estrogen receptor in DCIS is necessary [296].
4.3.3 Risk lesions
4.3.3.1 Preliminary remarks
The therapeutic concept for high-risk lesions should be developed on an interdisciplinary basis (radiodiagnostics, surgeon, pathology) after the histological findings from a punch/vacuum biopsy are available.
- Consensus
- Strong consensus
Background 4.34
Clinical screening and mammography screening programs are increasingly detecting clinically occult risk lesions of the mamma, which may be associated with microcalcifications or architectural defects. The risk of progression of these lesions [57], grouped together as "benign lesions with uncertain malignant potential (B3)", is quite heterogeneous and generally lower than in DCIS. The recommendations for excision of risk lesions refer to the natural course, subtype and extent of the lesions. In recent years the literature base for recommendations for the management of occult risk lesions has broadened significantly and this has led to a more conservative approach [303]. However, the literature on risk lesions is mainly based on non-randomized, retrospective case series of individual institutions, where information on the radiological-pathological correlation is often missing as well as information on the indication for surgery, if the lesions caused excision in only a part of the patients. This could at least partly explain the range of variation in the published upgrade risk with open biopsy. In principle, the procedure for risk lesions should be decided individually in an interdisciplinary conference, taking into account pathological-radiological correlation diagnostics.
4.3.3.2 Atypical ductal hyperplasia (ADH) in punch or vacuum biopsy
If ADH is diagnosed, an open PE should be performed to exclude a higher grade lesion.
- Consensus
- Strong consensus
Background 4.35
Atypical ductal epithelial hyperplasia (ADH) is a proliferation of isomorphic ductal epithelia of terminal ductuli or duktulo-lobular units (TDLUs) with cytological and structural features of a well differentiated DCIS. ADH is morphologically similar to a small, well differentiated DCIS and is only differentiated by quantitative criteria. A well-differentiated DCIS can only be diagnosed if the change in a TDLU exceeds a size of 2 mm or at least two separate duct structures are homogeneously affected [247], [304]. Even in the WHO expert group there is no agreement on which of the two quantitative criteria is to be preferred [247], [304]. In the punch biopsy, the diagnosis of a well differentiated DCIS should be made with caution due to the problematic differential diagnosis. In most cases it is sufficient to describe an alteration as atypical ductal epithelial proliferation to induce an excision [303]. However, it can be assumed that an ADH is usually small and extends over less than 2 - 3 mm [305] (http://www.euref.org/european-guidelines). If no further changes are found in the resectate, the therapy should be based on the diagnosis of ADH [247], [304]. The risk of breast carcinoma in the long-term course of ADH is 3 - 5 times higher [306], [307], [308] and the cumulative risk of invasive or insitu carcinoma is indicated with 21% (95% CI 14-28%) [309] or with 20% for a median follow-up of 17 years [310].
In clinical studies in which ADH was diagnosed by punch biopsy, the upgrade rate to DCIS or invasive carcinoma in open biopsy is 28% to 56% [311], [312], [313], [314], [315], but is lower if there is concordance between radiological and pathological findings [316]. In a meta-analysis, the upgrade rate for Z. n. vacuum biopsy and diagnosis of ADH was significantly lower and was 20.9% [317]. There are different approaches to achieve a better estimation of the risk in ADH. These include, for example, a postinterventional mammogram and close monitoring [313], the number of affected TDLUs [318], [319], [320] or cytological atypes or necroses [320], [321]. Suggestions to avoid an open biopsy try to define subgroups by combining these criteria or by complete removal of microcalcifications [322], [323]. This may help in individual cases to plan the therapy. However, the predictive criteria cannot be regarded as sufficiently validated due to the small number of cases in the available studies. Therefore, open PE is currently recommended for diagnosis of ADH in punch or vacuum biopsy [303], [324].
4.3.3.3 Lobular neoplasia (LN) in punch or vacuum biopsy
In case of isolated or incidential findings of an LN (classic variant) in punch or vacuum biopsy and concordance with imaging, further bioptical clarification is not necessary. In the case of LN with increased risk (pleomorphic LN, florid or tumorous LN, LN with comedotype necroses) an excision of the change should be performed, as well as in the case of discordance with the radiological findings.
- Consensus
- Strong consensus
Background 4.36
Lobular neoplasia (LN) is characterized by an atypical proliferation of loosely cohesive or discohesive and generally small, uniform epithelia within a terminal ducto-lobular unit with or without pagetoid spread into the ducts. It includes both atypical lobular hyperplasia (ALH) with distension and distortion of less than 50% of the azini in the affected terminal dukto-lobular unit (TDLU) [325], and lobular carcinoma in situ (LCIS). The LN is considered a non-obligate precursor lesion for breast carcinoma [326] and at the same time a risk lesion with increased tumor risk ipsi- and contralateral. The risk for invasive carcinoma is given as about 1 - 2% per year and the lifetime risk is calculated at 30 - 40% [327], [328]. The risk for pleomorphic LCIS is possibly higher [329].
The management of diagnosing an LN in punch biopsy depends on whether the LN is the only pathological change, on the subtype of the LN and on any associated pathological changes. In case of an incidence of a classic LN in punch biopsy (ultrasound or vacuum biopsy) there is no definite indication for an open biopsy for further clarification and the further procedure should be determined in the interdisciplinary findings conference. A wait-and-see approach with follow-up is acceptable in this situation, since the risk of carcinoma at the biopsy site within 3 - 5 years (i.e. the probability of an overlooked carcinoma) is indicated with ≤ 2% [303]. In contrast, in the case of radiological-pathological discordance of the findings, i.e. if the pathological findings do not explain the radiological index lesion (e.g. focal findings or malignoma-typical microcalcifications), there is a higher risk. In this situation further clarification should be carried out by means of a representative open biopsy [247], [330], [331].
Among the variants of the LN and at the same time lobular intraepithelial neoplasias with increased risk of later invasive carcinoma are the LCIS with comedotype necroses, the pleomorphic LCIS and the florid LCIS. These special forms of LCIS can be clinically associated with a focal finding or radiologically extensive microcalcifications, as in DCIS, and are frequently associated with a (micro-)invasion [332], [333]. In pleomorphic LCIS, higher grade cellular atypia are found, sometimes accompanied by massively distended lobules and infestation of the ducts as well as formation of comedotype necroses and microcalcifications. The pleomorphic LCIS differs from a ductal carcinoma in situ by the cellular morphology and the loss of the E-cadherin expression [334]. If these variants of an LN with increased risk are present (pleomorphic LN, florid or tumor-like LN, LN with comedotype necroses) an excision of the alteration should be performed [303], [330], [335], [336]. The B classification of the classic LN is B3, unless the criteria for a pleomorphic LN or an LN with comedotype necroses are present which justify classification as in the B5a category [337].
4.3.3.4 Flat epithelial atype (FEA) in punch or vacuum biopsy
In the case of diagnosis of FEA, an open PE can be dispensed with if the suspicious calcifications have already been completely or almost completely removed by means of vacuum biopsy imaging. In the case of radiologically extensive calcifications or in case of discordance with the radiological findings, a representative open PE should be performed.
- Consensus
- Strong consensus
Background 4.37
The term flat epithelia (FEA) is the term preferred by the WHO for columnar cell hyperplasia with nuclear atypes [247], [338]. In a typical case, intraluminal microcalcifications, which represent secretion calcium, are associated with FEA and lead to the clarification and diagnosis of FEA. Morphologically and on the molecular level there are multiple relationships and similarities of FEA with atypical ductal epithelial hyperplasia (ADH) and lobular neoplasia [339]. Not infrequently, these changes occur together on [340] and are considered early, non-obligatory precursor lesions in the low-grade pathway for multistep carcinogenesis of breast cancer [341], [342], [343].
The risk of a higher grade lesion (DCIS or invasive carcinoma) in a subsequent open biopsy is less than 10% [344], [345], [346], [347] in more recent studies and taking into account the pathological-histological correlation. In case of complete or largely complete removal of microcalcifications, further clarification by means of open biopsy is therefore not necessary [303], [348], [349]. This concerns the removal of microcalcifications by means of 9G or 11G vacuum biopsy [350].
4.3.3.5 ADH, LN, FEA in open biopsy
Bei Vorliegen einer klassischen LN oder einer FEA (alleine oder in Kombination mit einem invasiven Karzinom) am Resektionsrand ist keine Nachresektion erforderlich. Bei Vorliegen einer isolierten ADH am Resektionsrand sollte eine Nachresektion erfolgen. Ebenso sollte bei Vorliegen einer LN mit erhöhtem Risiko am Resektionsrand (alleine oder in Kombination mit einem invasiven Karzinom) eine Nachresektion erfolgen.
- Consensus
- Strong consensus
Background 4.38
For the procedure in the diagnosis of a risk lesion (ADH, LN, FEA) in open biopsy, a distinction must be made as to whether it is an accompanying finding associated with an invasive carcinoma or ductal carcinoma in situ or an isolated change. In the low-risk lesions (classic LN or FEA) at the resection margin, no resection is necessary [330], [351]. On the other hand, in the case of an LN with increased risk at the resection margin (alone or in combination with an invasive carcinoma), resection is recommended because this change spreads intraductally and is biologically similar to a low-grade DCIS [330], [335], [351], [352]. In the case of isolated atypical ductal hyperplasia (ADH) at the resection margin in the open biopsy, similar to ADH in the punch biopsy, it must be taken into account that the findings may not be representative. Since ADH is only differentiated from a well differentiated DCIS on the basis of quantitative criteria, a resection should be performed here if necessary to exclude higher grade changes.
4.3.3.6 Papilloma in the punch or vacuum biopsy
In the case of histological diagnosis of a lactiferous papilloma detected by imaging or a papilloma with ADH, an excision should be performed; this can also be performed as a vacuum biopsy, provided that no atypia are present.
- Consensus
- Strong consensus
Background 4.39
The diagnosis of a lactiferous papilloma in the punch biopsy (ultrasound-guided or vacuum biopsy) means, similar to the other B3 lesions, a risk of a higher grade lesion in a subsequent open biopsy. This applies less to the histological differential diagnosis compared with a papillary DCIS or a papillary or solid-papillary carcinoma, which can be made without further ado at the punch biopsy. Rather, there is the problem of the heterogeneity of the lactiferous papilloma and the possibility of association of the lesion with a DCIS or an invasive carcinoma. The background is the question of the representativeness of the punch biopsy. Therefore, it must first be considered whether the finding is an incident lesion, i.e. a small papilloma or micropapilloma that is only histologically detectable (with negligible risk), or an imaging finding that is only partially recorded in the punch biopsy. Furthermore, the upgrade risk depends on whether atypical papilloma is present, i.e. whether it is a papilloma with ADH or an atypical papilloma.
In a recent meta-analysis of 34 studies, the upgrade rate for papilloma was 7.0% compared to 36.9% for atypical papilloma. Furthermore, a lower tendency to upgrade was found in the newer studies after 2005 [353]. Despite the relatively low risk of upgrade in benign papilloma, the literature predominantly recommends post-excision in punch biopsy diagnosis of papilloma [354], [355], [356], [357]. An exclusively radiological evaluation of the course of the disease is justifiable in the case of small or incident papillomas, also if the papilloma has already been completely excised by the punch biopsies or vacuum biopsies and the mamma can be easily monitored by imaging [303], [358]. As an alternative to open biopsy, completion can also be carried out by vacuum biopsy [359].
4.3.3.7 Papilloma in open PE
If a papilloma or papilloma with ADH is detected in an open biopsy, no further intervention is necessary. If atypia are present at the edge of the resection, a follow-up resection should be performed.
- Consensus
- Strong consensus
Background 4.40
The further procedure in case of a benign lactiferous papilloma or a papilloma with ADH in an open biopsy depends on the question of possibly accompanying atypical changes, for example a DCIS in the surrounding parenchyma. In the absence of such changes, no further intervention is required. The recommendation to complete the excision of an atypical papilloma in the resection margin is based on the possible association with a well differentiated DCIS, which otherwise would not be completely excised [360], [361].
4.4 Surgical therapy of invasive carcinoma
4.4.1 General recommendation
Background 4.41 and 4.42
The complete removal of the tumor with free resection limits is a prerequisite for a low local recurrence risk. The local recurrence risk is decisively determined by the tumor biology. The extension of the resection limits in biologically aggressive tumours (e.g. triple-negative, HER2-positive) does not lead to a reduction in local recurrence. Therefore, for all intrinsic subtypes, including concomitant DCIS, resection is considered sufficient if no tumour tissue is detectable at the edge of the incision ("no ink on tumour"). A metrically defined minimum distance between tumour tissue and the edge of the incision is not required [365]. However, these statements are only valid under the condition that the indicated adjuvant therapy measures (systemic therapy, radiotherapy including boost) are performed [364].
Retrospective resection is not indicated for R0 resection, even in the case of narrow free cut margins. In the case of extensive intraductal components, a larger safety margin may be appropriate (see chapter 4.3.2 DCIS).
Adjuvant radiation and systemic therapy also have an influence on the local recurrence rate. However, R0 resection is a prerequisite for its optimal local effectiveness. Thus, the effects of boost irradiation after breast-conserving surgery can only be recognized with regard to the local recurrence rate if R0 resection has been performed [366]. The influence of adjuvant therapy and biological factors such as age of the patient and degree of differentiation of the tumor on the local recurrence rate is unclear, especially in the case of R1-resection. So far available data come from mainly retrospective studies with small collectives.
Basically, the macroscopic and microscopic assessment of the resection margins as well as the specification of the minimum safety distance, taking into account the topography and tumor type (DCIS or invasive), are an indispensable prerequisite for quality assurance of breast-conserving therapy. For this purpose, the resection margins must be clearly marked (e.g. suture marking) in order to enable targeted resection if necessary. The tumour bed should be marked intraoperatively with (titanium) clips to enable a targeted boost irradiation (avoidance of "geographic miss").
4.4.2 Breast conserving therapy
Randomized clinical studies have shown that, taking into account certain clinical and histological parameters, breast-conserving therapy achieves identical survival rates as mastectomy.
The aim of surgical therapy is the removal of tumours in healthy people. Thereby, a breast-conserving therapy (BET) with subsequent radiotherapy of the entire breast is equivalent to a mastectomy alone in terms of survival.
All corresponding patients with or without previous primary systemic therapy should be informed about the possibility of breast conservation therapy (BET) and mastectomy with the option of primary or secondary reconstruction.
- Consensus
- Consent
Background 4.43 and 4.44
Indications for the breast-conserving therapy of the breast carcinoma are:
- locally limited non-invasive carcinomas of the breast (DCIS, see Chapter 4.3)
- invasive carcinomas with a favourable relation of tumour size to breast volume
- invasive carcinomas with intraductal accompanying component as long as the resection margins run in healthy tissue
The resection margins should be tumor free (R0) during histopathological examination, no tumor at the ink margin [362]. A resection is not indicated for R0 resection even if the free incision margins are narrow. In the case of extensive intraductal components, a larger safety margin may be useful (see chapter 4.3.2 DCIS).
Breast-conserving therapy should be avoided for (see Chapter 4.4.3 Mastectomy) [185], [374], [375], [376]:
- Incomplete removal of the tumor (incl. intraductal component), even after resection
- Inflammatory breast carcinoma (as a rule also in pathological complete remission)
- in case of contraindications for post-irradiation after breast-conserving therapy in case of absolute indication for irradiation
- wish of the informed patient
It should be noted that patients under 40 years of age with a slightly differentiated breast carcinoma and insufficient adjuvant systemic and radiation therapy have an increased risk of local recurrence after BET [377].
In the presence of a multicenter carcinoma, a breast-conserving therapy can be considered in individual cases if the edges of the incision are tumor-free (see Chapter 4.4.3 Mastectomy) [378], [379], [380], [381], [382], [383], [384], [385].
If the lesion is not palpable preoperatively, it must be localized by an imaging guided marking, such as a wire marker, and extirpated according to this marking [386], [387], [O'Higgins, N. et al. 1998] The harvested tissue must be checked for completeness by the same imaging procedure that was used for marking. An additional postoperative mammographic or sonographic check can confirm the completeness of the extirpated findings.
The removed breast tissue must be marked so that the pathologist can orientate it.
The tumor bed should be fitted with clips for the subsequent boost radiation in order to enable correct application of the boost radiation even after intramammary displacement plasty [366], [389].
For defect coverage with local tissue after breast-conserving surgery, various surgical methods can be used within the scope of oncoplastic therapy concepts (e.g. local glandular flap plasty, tumor position-adapted reduction or rotational flaps) [390].
4.4.3 Mastectomy
A mastectomy should be performed for the following indications:
- Incomplete removal of the tumour (incl. intraductal component), even after resection
- inflammatory breast carcinoma (usually also in pathological complete remission)
- in case of contraindications for post-irradiation after breast-conserving therapy in case of absolute indication for irradiation
- wish of the informed patient
Taking into account tumour-free resection margins, the mastectomy can also be performed as a skin-saving procedure with or without preservation of the MAK.
Unter Berücksichtigung der Tumorlokalisation und Tumorgröße kann bei multizentrischem Sitz im Einzelfall auf eine Mastektomie verzichtet werden.
A contralateral prophylactic mastectomy should not be performed in non-mutation carriers or in patients without evidence of a familial high-risk situation to reduce the risk of contralateral breast cancer.
Background 4.45 to 4.48
Modified radical mastectomy is always performed when a breast-conserving procedure is not possible or the tumour size expansion and thus the risk of recurrence is increased. This also applies to inflammatory breast carcinoma, even after neoadjuvant chemotherapy, for incomplete removal of the tumour even after resection, and in principle always due to the patient's wishes. Which cosmetic result is achievable and expected in view of the oncologically possible procedure even after reconstructive measures must be realistically assessed in dialogue with the patient. The incision should take into account later reconstruction possibilities. The entire mammary gland tissue, the skin and the nipple-areola complex and the pectoralis fascia are removed. The pectoralis muscles are preserved.
Skin-saving mastectomy forms have not yet been compared with modified radical mastectomy in prospective randomized studies, but show comparable recurrence rates in long-term studies and meta-analyses. A prerequisite is the histopathologically proven tumor resection in sano, i.e. the removal of the entire glandular body (as far as possible).
In recent years, modified radical mastectomy has increasingly been abandoned in favour of skin-sparing mastectomy (SSM) with or without preservation of the nipple-areola complex (MAK). Numerous cohort studies and meta-analyses confirm that these techniques do not lead to an increased local redictivity rate compared to modified radical mastectomy [393], [394]. Prerequisite for this is an adequate adjuvant therapy according to the guidelines and, if the MAK is maintained, an areolaferous tumor and histologically tumor-free retroareolar tissue [391]. Patients with advanced tumor size also do not show an increased local recurrence rate due to SSM, but suffer more often a recurrence due to metastasis.
Several retrospective cohort studies indicate that breast-conserving therapy is not associated with an increased local recurrence rate compared to mastectomy even in the presence of multifocality or multicentricity under the condition of adjuvant therapy according to guidelines and under the assurance of histologically free resection margins. The limited data available does not justify a general recommendation for a BET. However, a breast-conserving surgery can be considered individually with the patient while informing her about the advantages and disadvantages, provided that a cosmetically satisfactory result can be achieved.
At this time there is no evidence that prophylactic mastectomy of the opposite side in patients with breast cancer and without a familial high-risk situation or without BRCA1/2 mutation improves the prognosis with regard to survival [164], [174], [395]. For patients with a familial high-risk situation or with a proven mutation, the decision for prophylactic contralateral mastectomy should be made after detailed discussion with the patient in an interdisciplinary team.
4.4.4 Plastic reconstructive surgeries
Every patient undergoing a mastectomy should be informed about the possibility of immediate or later breast reconstruction or the possibility of refraining from reconstructive measures; contact should be offered to those affected or to self-help groups or self-help organisations.
Background 4.49
Breast reconstruction seems to have no influence on the oncological course of the disease or the detection of local recurrence [393], [396], [397]. However, due to the lack of randomized studies, the data available is not sufficient. The decision whether breast reconstruction is performed immediately or at a later time depends on the individual situation of the patient and her wishes [398]. An immediate reconstruction can be associated with less psychological stress for the patient. However, some women wish to have a time lag after the diagnosis and primary therapy of breast cancer in order to be able to take time to consider the possibilities of plastic surgery in peace. The possibilities of breast reconstruction include implants, autologous tissue or a combination of both. Which procedure is suitable for the individual patient depends not only on the patient's personal ideas but also on the physical conditions (size of the breast, own tissue available) and whether radiotherapy is planned or has been carried out earlier. After previous radiation therapy, breast reconstruction with autologous tissue is preferable to the use of expanders or implants, since irradiated tissue can only be stretched and shaped to a limited extent [399]. If radiotherapy is planned, an expander or an implant in the sense of a spacer should be inserted first and the tissue reaction after irradiation should be waited for to decide on the optimal reconstruction technique (autologous/alloplastic) [400], [401], [402]. An approximating surgery of the mutual breast may be necessary to achieve a symmetrical image. The reconstruction of the nipple is performed by reconstruction of the nipple-areola complex and/or by tattooing [390]. The possibilities and indications for plastic reconstruction are shown in Appendix 11.2. : Figure 6, the classification of procedures in Figure 7 [390].
4.4.5 Surgical therapy of the axilla
The axillary staging is intended to be a component of the surgical therapy of invasive breast cancer.
- Consensus
- Consent
This is to be carried out with the help of sentinel lymph node removal (SLNB) for lymph node status that is inconspicuous on palpation and sonography.
In patients with pT1-pT2/cN0 tumors who undergo breast-conserving surgery followed by percutaneous irradiation via tangential counterfields (tangential irradiation) and who have one or two positive sentinel lymph nodes, axilla dissection should be avoided.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1b
- Consensus
- Consent
- References
- [275]
Patients who are having a mastectomy or who do not meet the criteria mentioned under d. should receive axillary dissection or radiotherapy of the axilla.
In the case of exclusive micrometastasis, a targeted therapy of the lymph drainage areas (surgery, radiotherapy) should be avoided.
In patients receiving primary systemic therapy (PST) and who have a pretherapeutically and sonographically negative lymph node status, the SLN should be performed after PST.
In patients who receive primary systemic therapy (PST) and have a punch biopsy positive (cN1) and a clinically negative nodal status after PST (ycN0), an axilla dissection should be performed.
In patients who receive primary systemic therapy (PST) and have a positive nodal status before and after PST, an axilla dissection should be performed.
- Consensus
- Strong consensus
In the case of evidence of distant metastasis, axial staging should be avoided.
- Consensus
- Strong consensus
Background 4.50 to 4.59
The sentinel node biopsy (SLNB) is a targeted surgical procedure for determining the nodal status of breast cancer. The procedure is used to identify patients with increased systemic and local risk and to plan adjuvant therapy.
Provided that the procedure is standardized and quality-assured, the SLNB has a high staging accuracy and a significantly reduced shoulder-arm morbidity. The SLNB goes with a safe local control (axillary recurrence
The SLNB is indicated in all patients with a clinically negative lymph node status and for whom axillary staging is necessary [275].
The SLNB is not indicated in cases of clinical suspicion of advanced lymph node involvement and tumour-transmitted lymph nodes [275]. To clarify preoperatively whether lymph node metastasis is actually present in clinically and/or sonographically suspicious lymph nodes, an ultrasound-guided FNA or a biopsy of the suspicious lymph nodes may be helpful. Histological evidence of lymph node metastasis precludes the use of sentinel node biopsy.
In patients with histologically proven tumor involvement of the axilla, surgical removal of the axillary lymph nodes may be indicated. In patients with positive nodal status, the number of affected lymph nodes or the ratio of affected to examined lymph nodes may provide information for the selection of subsequent antineoplastic systemic therapy and adjuvant radiotherapy.
A randomized study of the American College of Surgeons Oncology Group (ASOG Z0011-study) examined the significance of axilla dissection in patients with T1 and T2 tumors and 1-2 positive SLN, in whom a breast-conserving therapy with subsequent percutaneous radiotherapy of the entire affected breast via tangential radiation fields (WBI) had been performed, with regard to the locoregional recurrence rate and overall survival. No advantage for axilla dissection could be identified [406], [412]. Due to methodological limitations of the study, an evidence search was performed in which the probability of error of the study was classified as "unclear" [413].
In further randomized studies, the clinical value of a dissection of axillary or other regional lymph nodes was examined in different patient groups with a low risk profile [370], [414], [415], [416], [417]. In these studies, axillary dissection was not associated with a survival benefit either.
Apart from the NSABP-B-04 study, the above mentioned studies generally included tangential field irradiation of the breast and thus partial irradiation of the axilla (at least in Level I). The NSABP-B-04 study is thus the only available study in which no further therapy (i.e. no surgery, no systemic therapy, and no radiotherapy) was performed on positive axillas. In this study 38% of the patients in the axillary operated collective had histological lymph node metastases. In the non-treated group, 19% had follow-up surgery for axillary recurrence. This allows the conclusion that with untreated axilla tumour-affected lymph nodes become clinically apparent in only about 50% of cases. It is therefore not clear what influence radiotherapy has on the risk of axillary recurrence in affected sentinel lymph nodes and the absence of axillary dissection, and which therapeutic procedure is most suitable for reducing the regional risk of recurrence with the least side effects or late effects.
Based on the available data, there is a well-founded option to refrain from axilla dissection in the above-mentioned group of patients in the Z0011 study with a positive SLN. This is particularly relevant for patients in whom no further affected lymph nodes are expected and/or in whom the identification of additional lymph node metastases would not result in changes in adjuvant therapy. Patients with a T1 or T2 tumour and 1-2 positive SLN can thus be offered the option of foregoing axillary dissection with breast-conserving therapy, provided that they are made aware of the current data situation. A replacement of the axilla dissection by radiotherapy of the axilla can be considered as an alternative.
Patients with micrometastases in the SLN should not be recommended for axillary dissection because there is no evidence for an increased regional risk of local recurrence [407].
Patients who undergo a mastectomy or who do not undergo postoperative radiotherapy of the affected breast are usually not suitable patients for waiving axilla dissection.
In exceptional situations (e.g. old age, multimorbidity, etc.), a waiver of any axillary intervention may be considered [370], [414], [415], [417]. In Germany, the Insema Study (LKP: Prof. Dr. Th. Reimer, sponsored by the DKH) is currently being conducted to prospectively identify patients who can do without axillary staging. Axillary staging is not indicated in patients in the stage of distant metastasis (M1).
In patients treated with primary systemic therapy (PST), the optimal procedure in the area of lymphatic outflow pathways has not been conclusively clarified. A distinction must be made between women who primarily have clinically (palpatory and sonographic) inconspicuous lymph nodes and those whose nodal status is primarily classified as suspicious.
Women with a clinically unremarkable lymph node status benefit from axillary staging after PST. They avoid surgery (before PST) and possible follow-up therapies for clinically occult, positive lymph nodes that are successfully treated by systemic therapy [418]. In addition, histopathological complete remission (response of systemic therapy to the tumor in the breast and lymph nodes), an important endpoint in clinical trials, can only be determined if the lymph node status is recorded after systemic therapy. The feasibility (detection rate) as well as the accuracy (false negative rate) seem to be comparable in this collective with primarily operated patients [408].
In patients without clinical and/or imaging suspicion of axillary metastasis and in whom PST is planned, SLNB can therefore be performed either before or after PST. The decision depends on the weighing of the clinical relevance and the consequences for possible therapy decisions [418].
In patients with primarily suspect lymph node status, a minimally invasive clarification of the suspicious lymph node should be performed by punch biopsy or fine needle aspiration. In the case of a confirmed primary lymph node involvement, the success rates of SLNB (detection rate, false negative rate) after PST are clearly limited [410], [411]. Therefore, an axilla dissection after PST is recommended for these patients.
Newer procedures that could possibly lead to an improved detection and accuracy of SLNB (in primarily nodal-positive patients) after PST, such as the clip or seed marking [419], are currently still insufficiently evaluated and cannot be recommended for clinical routine.
Sufficient data regarding the locoregional risk of recurrence of an SLNB after PST are not yet available. In particular, it is not clear whether the unfavourable false negative rate of SLNB after PST in women with primary positive nodal status translates into an increased rate of locoregional recurrence or unfavourable overall survival.
In view of the insufficient information available, the conduct of clinical studies on this issue and the encouragement of suitable patients to participate in these studies are expressly supported.
4.5 Pathomorphological examination
4.5.1 Preliminary remarks
This chapter deals with the pathomorphological examination of the tissue samples. This is used to establish the diagnosis and to determine prognostic and predictive factors that are helpful in assessing the course of the disease and the response to therapy.
Recommendations from internationally recognized guidelines and published protocols [420], [421], [422], [423], [424], [425], [426], [427], [428] were used as a basis.
Preceded by "General Principles", which give general information on the qualitatively good performance of the pathomorphological examination and its prerequisites. Special aspects of examinations of "Percutaneous biopsies in the context of interventional diagnostics", "Excision biopsies", "Mastectomy preparations" and "Lymph nodes" are presented separately and are divided into the following topics:
- Macroscopic processing ("cutting") with removal of tissue for histological examination
- Microscopic processing (sectional planes, staining, special methods) and review (including criteria of classification)
These instructions are supplemented in the appendix (see Appendix 11.3) by the recommended classifications and grading systems as well as proposed forms for the "Begleitschein zur Einsendung" and the "Dokumentation der Gutachterlichen diagnostischen Beurteilung".
4.5.2 General principles
4.5.2.1 General patient data, preliminary findings, anamnestic information
The patient data, preliminary findings and further information to the pathologist are best communicated using a form (see Appendix 11.3: Form 1), which records the following information:
- Patient data (name, date of birth, gender, identification number, if available)
- Physician in charge
- day of collection
- Clinical diagnosis or indication for tissue sampling
- further clinical information:
- location of tissue sample collection (e.g. right breast, upper outer quadrant)
- Type of collection (e.g. high-speed punch biopsy, modified radical mastectomy)
- Clinical findings and imaging (e.g. findings palpable/non-palpable; microcalcification present/not present; if necessary with transmission of the preparation radiography)
- Possibly previous neoadjuvant therapy
- Preliminary findings and essential details of the medical history
General principles for surgical material
The surgical material should be clearly topographically marked with details of the problem and the clinical-radiological findings and sent in full to the pathologist.
- Consensus
- Strong consensus
Background 4.60
A well-organized cooperation between the disciplines involved is a prerequisite for pathomorphological diagnostics.
For the most accurate pathomorphological diagnosis possible, the biopsy or surgical material must meet certain conditions, which are listed below:
- All biopsy and surgical material should be sent to the pathologist.
- The excisate/mastectomy preparations must be clearly topographically marked by the surgeon (e.g. with different coloured sutures); the location of the markings must be noted on the clinical accompanying form (see Appendix 11.3: : : Form 1).
- If material is to be taken from the tumour (or other tissue) (e.g. for scientific investigations, tumour bank), this must be done under the control of the pathologist. For this purpose, the surgical specimens are to be sent to the pathologist immediately after removal, unfixed.
- In such a material removal it must be taken into account that necessary classifications of a tumor (especially R-classification, pTNM-classification, tumor heterogeneity) must not be affected.
- Tissue fixation is carried out in 10 % neutral buffered formalin in sufficient quantity. A fixation period between 6 h and 72 h [426] is recommended.
4.5.2.2 Documentation of the macroscopic processing
For documentation of the macroscopic processing, see the sections on the respective type of tissue sample.
4.5.2.3 Documentation of the microscopic processing and assessment
The following information is documented, possibly using a form (see Figure 9 and Figure 10):
- Type of tissue sample
- Page reference
- Major pathological changes (e.g. invasive carcinoma, intraductal carcinoma, atypical ductal hyperplasia, fibrocystic mastopathy, mastitis)
- Carcinoma:
- Histological type
- Grading (for invasive carcinomas and DCIS)
- Presence of an associated intraductal carcinoma/DCIS (for invasive carcinomas)
- tumour size*\footnote {not collected in percutaneous biopsies} (DCIS and invasive carcinomas; for invasive carcinomas with extensive intraductal component [Def. see extent of intra-ductal tumour component]: indication of the size of the invasive component and additionally indication of the size of the associated DCIS)
- If necessary, indication of additional, additional tumour foci, if present (multifocality/multicentricity)*
- resection margin*\footnote {not collected in percutaneous biopsies} (for invasive carcinomas and DCIS)
- Tumour directly at the edge of the resection ("border forming")
- tumour not directly at the edge of the resection; then minimum safety distance of the tumour from the edge of the resection in mm with indication of localisation (if necessary, separate for intraductal components)
- Peritumoral vascular invasion (if present under light microscopy)
- pTNM Classification*\footnote {not collected in percutaneous biopsies} [429] (if necessary including further tissue samples)
- Additional immunohistological tests:
- Estrogen receptor (ER) or progesterone receptor (PgR) status (for invasive carcinomas; for DCIS if therapeutically relevant)
- Human Epidermal Growth Factor Receptor (HER)2 and Ki-67 status (for invasive carcinomas)
- Microcalcifications, if available: Location or indication of association with benign or malignant lesion
- Comments:
- Reference to the intraoperatively communicated frozen section findings
- Reference to clinical/radiological findings (especially microcalcifications: e.g. "finding is compatible with" or "correlation not certain")
- Reference to findings on other tissue samples/preliminary examinations (in the case of findings on surgical specimens after percutaneous mammary biopsy: statement required whether or not biopsy cavity is included in the surgical specimen).
4.5.2.4 Clarification of mammographically detected microcalcification
In the clarification of mammographically suspect microcalcifications, the correlation of the histopathological findings with the findings of the imaging procedures is necessary (preparation radiography or disc radiography required).
It should be noted that mammography not only detects calcium phosphate (type II microcalcifications), which can be stained with hematoxylin-eosin, but also calcium oxalate (type I microcalcifications) in rare cases. The latter can be detected in polarized light or dark field.
If there is no evidence of radiologically relevant microcalcification (> 100 µm) in the initial sections, further sections should be made, possibly supplemented by special staining (Kossa), and any remaining material should be embedded.
Occasionally, radiography of the paraffin blocks or of the remaining tissue not yet embedded is also helpful for finding the radiologically relevant microcalcification in larger tissue samples.
When detecting radiologically relevant microcalcifications, their localization in relation to the histopathological change should be indicated.
4.5.2.5 frozen section examination
The intraoperative frozen section examination should only be performed if there is an immediate surgical consequence.
Fields of application are:
- Dignity assessment of palpable focal findings >10 mm, if a preoperative diagnosis by means of minimally invasive biopsy was not possible
- Determination of the resection margin status
- Assessment of the sentinel lymph nodes
- A frozen section examination should not be performed for non-palpable lesions and minimally invasive biopsies (punch biopsies, vacuum-assisted biopsies).
- Consensus
- Strong consensus
Background 4.61
The aim of the intraoperative frozen section examination on surgical preparations of the breast is to evaluate those criteria which directly influence the further surgical procedure:
- Dignity of the lesion: benign or malignant (DCIS or invasive carcinomas), if a preoperative diagnosis by means of minimally invasive biopsy was not possible,
- Size and extent of a tumour (if necessary, detection of multiple tumour foci),
- Tumor detection at the edge of the incision [430], [431].
The intraoperative examination of the sentinel lymph nodes (SLN) allows in positive cases a one-stage surgery of the axilla. However, if the result is negative, it must be taken into account that subsequent processing of the formalin-fixed and paraffin-embedded residual material will still find metastases in the sentinel lymph nodes in up to 21% of cases [432], [433]. An intraoperative work-up of the lymph nodes in sections is not justified in view of the limited assessability of frozen sections and the effort involved.
As an alternative to frozen section examination, a preoperative punch biopsy or fine needle aspiration can be performed to examine the lymph node status under certain conditions. With appropriate expertise, aspiration cytology can also be performed.
The material examined in the frozen section is to be processed using the paraffin technique.
4.5.2.6 Histological classification and grading
All invasive carcinomas should be histologically classified (according to the current WHO classification [119] ).
- Consensus
- Strong consensus
4.5.2.6.1 Histological classification
The WHO classification of breast tumours is the international basis for the classification and nomenclature of breast carcinomas [119]; see Annex 11.3: Table 24.
The histological classification is carried out both on the punch and vacuum biopsies and on the surgical specimens. In particular with the special types of breast carcinoma (e.g. tubular, mucinous) a final classification is only possible on the surgical specimen. Due to intratumoral heterogeneity, there may be differences between the punch/vacuum biopsy and the surgical specimen. The published agreement rates are between 65% and 100% [434].
4.5.2.6.2 Expansion of intraductal tumor component
If the invasive carcinoma is accompanied by an intraductal component that extends beyond the border of the invasive carcinoma, not only the distance of the invasive carcinoma but also the distance of the intraductal component to the nearest resection edges should be given in mm.
The evidence for the fact that with a negative resection margin ("no ink on tumor"/no color on the tumor), an extensive intraductal component (EIC) is associated with an increased risk of local recurrence is contradictory and depends on the definition of the EIC [435], [436], [437]. The presence of an EIC is associated with a significantly increased risk of local recurrence if the size of the intraductal tumor component in one dimension is at least twice the size of the invasive carcinoma [437]. It is therefore appropriate to apply this definition and to indicate the presence of such an EIC.
In addition, significant DCIS residuals are found more frequently in patients with EIC with positive or dense resection margins in post-resectates than in patients without EIC [438]. Therefore, the guidelines of the Society of Surgical Oncology (USA) and the American Society for Radiation Oncology also recommend that postoperative mammography should be considered in micro calcified EIC-positive carcinomas, as residual calcifications would justify a post-excision [435]. It is also pointed out that the characteristics of young age and several narrow resection margins in patients with EIC-positive carcinoma are associated with an increased local recurrence risk. Patients with these characteristics could benefit from a post-excision [365], [436].
Grading of invasive carcinomas
4.5.2.6.3 Histological grading
Histological grading is also carried out on the punch and vacuum biopsies as well as on the surgical specimens of the breast (see Appendix 11.3: Table 25). It should generally also be indicated numerically (G1, G2 or G3).
The agreement between the histological grading of punch biopsies and surgical specimens is moderate (kappa value: 0.35-0.65) [440], [441], [442], [443], [444], [445], [446], [447], [448], [449], [450]. The punch biopsies tend to show a lower grading, especially due to an underestimated mitosis number [440], [441], [442], [444], [445], [447], [448], [451]. Possibly the Ki-67 (Mib-1) proliferation index in the punch biopsies correlates better than the mitosis number with the low and high mitosis rates in the excidates [451].
For the decision for or against neoadjuvant therapy, the differentiation between grade 2 and grade 3 is of particular relevance preoperatively. In particular for carcinomas with minimal tubular differentiation (3 score points) and high nuclear pleomorphism (3 score points), there are various suggestions for modified mitosis scoring on punch biopsies for better assignment of the grade on the non-invasive biopsies. On the one hand, the halving of the limit values for the mitosis scores is recommended [O'Shea, A. M. et al. 2011], [453], on the other hand, the use of the Ki-67 index instead of the mitosis score is advocated [454], so that breast carcinomas with a Ki-67 index > 25% would receive a score of 3 for proliferative activity.
Neither of these two proposals has yet been sufficiently validated and generally accepted internationally. However, they can be helpful in borderline cases to achieve a better match of the grading of the punch biopsy and the surgical specimen.
4.5.2.6.4 DCIS-Grading
The grading is based on the grading scheme according to WH0 [119] (see Annex 11.3, Table 23).
For all DCIS, the following parameters should be listed in addition to the grading:
- Core degree according to "Consensus Conference on the Classification of DCIS in Philadelphia, 1997" [455] (see Annex 11.3 Table 22)
- Comedo-like necroses existing/not present
4.5.2.7 Multifocality/multicentricity
Currently there is no internationally uniform definition of the terms "multifocality" and "multicentricity" before [456], [457]. The following classification is recommended:
- Multifocality: Occurrence of macroscopically recognizable, separate carcinoma foci in one quadrant or according to Faverly [458] with a distance between the foci of less than 4 cm.
- Multicentricity: Occurrence of separate carcinoma foci in more than one quadrant or according to Faverly [458] at a distance of at least 4 cm between foci.
4.5.2.8 Peritumoral lymph vessel invasion
The presence of peritumoral (lymphatic) vascular invasion (LVI) should be reported, as LVI is an important independent prognostic factor [459], [460]. This is especially true for nodal-negative T1 tumors, where the detection of LVI means that the risk of recurrence and the development of distant metastases is significantly increased [461], [462].
In the diagnosis of peritumoral LVI, strict criteria must be applied to delimit tumor cell complexes located in artificially created tissue gaps (e.g. as a result of shrinkage artifacts) [119], [463], [464]:
- Detection in peritumoral tissue.
- The tumor cells are located in capillary vascular spaces that are lined by an endothelial border.
- The arrangement of the tumor cells often doesn't match the shape of the vascular space.
- Occurs at the site of normal lymphatic vessels:
- Associated with other vascular structures
- Periductal
- In the interlobular stroma
Occasionally, immunohistochemistry (e.g. D2-40 detection) can be helpful.
4.5.3 Determination of hormone receptor and HER2 status and the Ki-67 proliferation index of invasive carcinomas
In invasive breast carcinoma, the primary diagnosis of invasive breast cancer is to determine the estrogen and progesterone receptor status as well as the HER2 status, preferably already at the punch biopsy.
Additionally, the proliferation rate can be determined by immunohistochemical detection of Ki-67.
- Consensus
- Strong consensus
The determination of estrogen and progesterone receptor status will be performed immunohistochemically. The percentage of positive tumour cell nuclei and the average intensity of staining should be reported. In addition, scores can be obtained by stating the method (Allred (Quick) Score, Immunore according to Remmele and Stegner). The evaluation as ER- or PgR-positive requires at least 1 % positive tumour cell nuclei.
- Consensus
- Strong consensus
As a prerequisite for trastuzumab therapy, HER2 positivity is defined as immunohistochemically proven protein overexpression with a score of 3+ or gene amplification, preferably detected by in situ hybridization (ISH).
When determining the hormone receptor and HER2 status and the Ki-67 proliferation index, the reliability of the detection methods used should be ensured. This includes internal test validation, the use of standardized protocols, on slide and internal controls as well as regular successful participation in external quality assurance measures.
- Consensus
- Strong consensus
Background 4.64 to 4.68
The quality of the detection methods used, including pre-analytics (including fixation) and evaluation, should be ensured by the use of SOPs and regular internal and external quality controls. For external quality control, the regular, annual successful participation in interlaboratory comparisons is recommended, which is offered, for example, by the "Pathology Quality Assurance Initiative" (QuIP), a joint venture of the German Society of Pathology (DGP) and the Federal Association of German Pathologists (BDP).
In the guidelines of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) it is recommended that the ER/PgR determination is preferably performed on punch biopsies [421] because of the faster fixation of the tissue. The HER2 determination can be carried out primarily on punch biopsies as well as on surgical specimens [426]. The decisive factor is the time until fixation (cold ischemia time, /= 0.81 or concordance >/= 95%). It must also be ensured that artificially altered tissue (edge, retraction or squeezing artifacts) is excluded from the assessment.
The validity and reproducibility of the HER2 determination can be more easily ensured with standardized test kits, which is why the use of such test kits is recommended. For the detection of HER2 gene amplification, the various methods of in situ hybridization (fluorescence, chromogenic, silver-amplified) can be used, taking into account quality requirements. If test kits are used, the application follows exactly the manufacturer's instructions.
The expected HER2-positivity rate for invasive breast cancer is currently averaging 15%. Deviations from this average value can result from the composition of the examination collective. Potential influencing variables are the histological degree of differentiation, the hormone receptor status, the histological tumor type as well as the nodal status of the examined carcinomas and the age of the patients (all P<0.0001) [469]. Es wird empfohlen, die HER2-Positivitätsrate zur Qualitätssicherung kontinuierlich zu überwachen.
4.5.3.1 Interpretation Hormonrezeptorstatus
Die Interpretation der immunhistochemischen Reaktionsergebnisse sollte den Empfehlungen der ASCO/CAP-Leitlinien folgen [421]:
Die Bewertung als ER- bzw. PgR-positiv erfordert mindestens 1% positive Tumorzellkerne [421], [470], [471]. Als ER- oder PgR-negativ werden Tumoren dann bewertet, wenn bei positiver interner Kontrolle weniger als 1% der Tumorzellkerne immunreaktiv sind. Die Empfehlung des Grenzwertes von 1% basiert auf den Ergebnissen eines systematischen Reviews [472]. Allerdings basiert dieser Review ausschließlich auf retrospektiven Studien, in denen ein Grenzwert für die endokrine Therapie festgelegt wurde. Verschiedene Grenzwert-Level wurden in den Studien nicht gegeneinander getestet.
Es gibt mittlerweile Hinweise dafür, dass Tumoren mit niedriger ER-Positivität (1-9% positive Zellen) gesondert zu betrachten sind [470]. Verschiedene Studien haben gezeigt, dass sie ER-/PgR-negativen oder triple-negativen Mammakarzinomen (ER-, PgR- und HER2-negativ) tumorbiologisch und prognostisch näher stehen als ER-positiven (>10% positive Tumorzellen) [473], [474], [475], [476], [477].
Daher wird folgende Unterteilung empfohlen [472], [478]:
- ER-/PgR-positiv: >10% positive Tumorzellen
- ER-/PgR-gering positiv: 1%-9% positive Tumorzellen
- ER-/PgR-negativ: <1% positive Tumorzellen
Neben dem Prozentsatz positiver Tumorzellkerne ist gemäß den ASCO/CAP-Leitlinien auch die durchschnittliche Färbeintensität anzugeben [421]. Als Ergänzung kann der international akzeptierte Allred-Score [479] oder der Immunreaktive Score (IRS) nach Remmele und Stegner [480] mitgeteilt werden (s. Anhang 11.3 Tabelle 28).
Die Immunhistochemie ist nicht verwertbar und sollte eventuell an einer anderen Probe wiederholt werden, wenn
- externe oder On-slide-Kontrollen nicht das erwartete Ergebnis liefern,
- Artefakte den Großteil des Materials einnehmen,
- normale epitheliale Zellen innerhalb der Probe keine nukleäre Anfärbung zeigen,
- das Gewebe in starken Säuren entkalkt wurde,
- ein ER-negativer/PgR-positiver Phänotyp vorliegt (um eine falsch negative ER- oder falsch positive PgR-Testung auszuschließen),
die Fixation des Gewebes nicht optimal war (kalte Ischämiezeit > 1h, Fixati-on < 6h oder > 72h) und das Testergebnis bei fehlender interner Kontrolle negativ ist.
Auch bei Vorliegen eines histologischen Typs, der üblicherweise ER-/PgR-positiv ist (tubulär, muzinös), sollte vorsichtshalber die Testung (evtl. auch an einer anderen Gewebeprobe) bei ER-/PgR-negativem Ergebnis wiederholt werden.
The increase of the immunohistochemical cut-off for the score 3+ from 10% to 30% [481] recommended in the 2007 ASCO/CAP guidelines has been withdrawn. Thus, the prerequisites for an immunohistochemically HER2-positive test result again meet the criteria applied in the pivotal studies for anti-HER2 therapy (Fig. 1a). The update committee also cited as reasons for the reduction of the cut-off to the original level the fact that the increase affected only a few patients [0.15%; [482]] and that the analytical quality of HER2 testing had generally improved since 2007, [426].
A weak point of the ASCO/CAP guideline published in 2013 is the contradictory definition of the 2+score with unclear differentiation from the 1+-score [426]. This ambiguity was corrected in 2015 by revising the definition to reapply the original criteria from 2007 [468].
The threshold value for an ISH-positive test result was also readjusted to the criteria used in the approval studies for anti-HER2 therapy. Accordingly, a HER2/CEN17 ratio > 2.0 is considered HER2-positive (Fig. 1b).
However, the addition of the pericentromere region of chromosome 17 can lead to false negative results if only the ratio is taken into account as a criterion for distinguishing HER2-positive and negative cases. Therefore, according to the current update, a ratio of 4.0 and Fig. 1b). A test result in the borderline category should trigger re-testing as before (other validated method on the same material or re-testing on other material, for example on excidate if borderline result on needle biopsy). The ultimate goal is to achieve a clear HER2 test result (negative or positive) as a basis for clinical decision making. The "borderline" category is a subgroup that has not yet been adequately investigated and where it is uncertain how many of the affected patients will benefit from anti-HER2 therapy.
In the 2013 update, criteria for the evaluation of HER2-heterogeneous tumours were defined for the first time, i.e. for tumours containing cell populations with and without HER2 gene amplification. The experts assume that a HER2-amplified cell population is only clinically relevant if the HER2-amplified cells can be separated as aggregated complexes from HER2-negative cell assemblies. To identify areas with HER2-amplified cells, the preparation should be completely screened before at least 20 cell nuclei are evaluated. Alternatively, areas with potential HER2 amplification can be narrowed down using IHC. If a second contiguous cell population with elevated HER2 signaling levels exists, representing more than 10% of the cells on the section, it will be evaluated separately. In both populations the signals should be counted in at least 20 adjacent cells in at least 2 areas each and evaluated separately. Tumours that contain amplified and non-amplified areas under these conditions are considered HER2-positive. In the report of findings, the percentage of the tumour with HER2 gene amplification should be stated.
In summary, the 2013 update recommends that primary testing be performed on the punch biopsy. If the test result is clearly negative or positive according to the criteria in Fig. 1, no re-testing is usually required.
Exceptions are, among other things, test results that are discrepant to the histopathological findings or if the tumor in the excidate shows a different tumor type or histological grading than in the punch biopsy.
A new HER2 test on the excidate of the tumor should be requested if
- HER2 status at punch biopsy unclear (IHC and ISH in borderline area)
- heterogeneous HER2 status at the punch biopsy
- HER2 test positive for invasive carcinomas, G1, of the following histological types:
- ductal or lobular, ER- and PgR-positive
- tubular, mucinous, cribriform
- adenoid-cystic carcinoma (usually triple-negative)
- HER2 test negative and
- less invasive tumor contained in punch biopsy
- resectate G3 carcinoma, which is morphologically different from the carcinoma in the punch biopsy
- there are doubts about the sample handling of the punch biopsy (too long ischemia time, too short fixation, etc.)
A general retesting of G3 carcinomas on the resected tissue, whose testing on the needle biopsy showed a HER2 negative result, is not necessary [468], [483]
HER immunohistochemistry is not usable and should be repeated or replaced by ISH if
- controls do not deliver the expected result,
- artifacts take up most of the material,
- normal gangetic epithelia show a strong membrane coloration (internal control).
The HER-ISH is not usable and should be repeated if
- controls do not deliver the expected result,
- at least two tumour areas cannot be evaluated,
- > 25 % of the signals are too weak to be evaluated,
- > 10% of the signals appear in the cytoplasm,
- Core resolution is bad,
- autofluorescence is strong (FISH).
4.5.3.2 Evaluation Ki-67 proliferation index
For the determination of the Ki-67 proliferation index (PI), no generally accepted, comprehensive recommendation for standardisation is available to date. The background to this is that the methodological approach in the studies that have demonstrated a prognostic or predictive relevance of Ki-67 is very heterogeneous [484]. As a consequence of the lack of standardization, increased interobserver variability in the determination of Ki-67-PI was repeatedly observed in reproducibility studies, especially in the middle range or in G2 mammary carcinomas [484], [485], [486], [487]. Due to the heterogeneous approach in the studies, the consensus recommendation of an international working group on Ki-67 in breast cancer also focuses only on certain key points regarding the methodological procedure including evaluation and interpretation of the results [488]. The experts emphasized that it is not possible to give generally valid Ki-67 limits for prognosis, prediction and monitoring. Limit values defined in studies could only be applied locally if the local results were validated against the study results.
In the meantime, however, the above mentioned international working group and other study groups have shown that the reproducibility of the Ki-67 determination can be significantly improved by systematic training and application of uniform criteria [489], [490], [491]. However, an acceptable reliability of the determination can be achieved with different procedures (e.g. counting and semi-quantitative estimation). This means that it is currently not possible to favor a particular procedure, especially since different evaluation strategies were used in the recently published studies that prove the prognostic or predictive relevance of Ki-67-PI [492], [493], [494], [O'Shaughnessy, J. et al. 2015], [496].
Nevertheless, it is possible to define certain framework conditions on which there is general consensus in order to improve reproducibility:
- Application of a standardized staining protocol with internal and external quality control
- Evaluation preferably at the invasion front of at least 3 visual fields at high magnification, 400x (exception: needle biopsy, if the invasion front cannot be delimited or the extent of the infiltration
- Exclusive evaluation of the nuclear staining, which stands out from the nuclear counterstain (nucleoli alone are not counted, staining intensity is irrelevant)
- Indication of the percentage of Ki-67-positive tumour cells in relation to the total number of tumour cells
- Determination of percentage by single cell counting, semi-quantitative estimation in 5% steps or by image analysis possible [489], [492], [497], [498], [499]
The use of image analysis procedures requires that the result of each individual measurement is critically reviewed by the pathologist and the size of the measurement field is adjusted if necessary [500].
There is no uniform view on the question of which cell number should be analysed. The recommendations range from 100 to 2000 cells [488], [489], [497]. In the studies on the reproducibility of the Ki-67 determination, it was unanimously shown that - regardless of the number of cells analysed - the agreement<10%) und hoch proliferierenden Tumoren (> is good at low (<10%) und hoch proliferierenden Tumoren (> 25%). The deviations are most pronounced in the middle range (10-25%) [486], [487]. Recently published studies of various working groups unanimously show that the concordance, also in this middle range, can be improved by evaluating 4 or 5 different, randomly selected visual fields [489], [491]. It is therefore obvious, especially in the middle proliferation range, to evaluate several visual fields (> 3) in order to record the proliferation activity of the tumor in a representative manner.
4.5.4 Prognostic and predictive factors
To assess the course of the disease (prognosis), the pTNM status (locoregional tumor spread, locoregional lymph node involvement, distant metastasis) will be assessed according to the current TNM classification (currently 8th edition [508].
To assess the course of the disease (prognosis), the resection margin status (R-classification, according to current TNM-classification, currently 8th edition [508]) as well as safety margins are to be assessed.
To assess the course of the disease (prognosis), the histological type (according to current WHO classification) should be determined.
To assess the course of the disease (prognosis) the histological grading according to Elston and Ellis [510] is to be determined.
To assess the course of the disease (prognosis) the peritumoral lymph vessel invasion (according to the current TNM classification, currently 8th edition [508]) is to be assessed.
In order to assess the course of the disease (prognosis), age should be determined.
- Consensus
- Strong consensus
Ki-67
The addition of Ki-67 to the conventional prognostic factors (age, pT, pN, grade, ER, PR, HER2) improves the prognostic assessment in women with histologically confirmed ER/PR-positive and HER2-negative invasive breast cancer for the decision whether adjuvant chemotherapy should be given.
Ki-67 is a continuous marker of proliferation activity. With a Ki-67-positivity >/= 25% an increased risk can be assumed.
- Consensus
- Strong consensus
The reproducibility of the Ki-67 determination can be significantly improved by applying uniform criteria. The determination should therefore be standardised.
- Consensus
- Strong consensus
Multigenic tests for nodal-negative carcinomas
Only if the conventional prognostic parameters including Ki-67 do not allow a clear decision for or against adjuvant chemotherapy in women with ER/PR-positive, HER2-negative, nodal-negative invasive breast cancer, a methodologically standardized and clinically validated multigene test can be used for the decision.
However, there is a need for further research with regard to the benefit of multi-dimensional tests, as the study situation and follow-up times in the available studies are not yet sufficient.
When a multi-test is performed, no more than one test should be used for decision making.
- Consensus
- Consent
Background 4.69 to 4.79
The recommendation to collect the listed conventional pathomorphological and clinical parameters follows international guidelines [465], [466]. A recent meta-analysis also confirmed the importance of the resection margin status [364]. Retrospective analysis of SEER registry data including more than 100,000 patients supports the effect of grading on disease progression as well as the results of the PlanB study, where multivariate analysis confirmed that grading (locally and centrally determined) is an independent prognostic factor [492], [512]. In the current edition of the AJCC Cancer Staging Manual (8th ed.) for the new prognostic stage grouping to be implemented on January 1, 2018, in addition to the TNM classification also histological grade, ER, PgR and HER2 status and the Oncotype DX® Recurrence Score are considered [517]. The anatomical stage grouping remains unaffected.
4.5.4.1 uPA/PAI-1
Although the invasion factors uPA/PAI-1 according to the current ASCO guidelines can be used to decide for or against adjuvant systemic therapy in ER/PgR-positive and HER2-negative nodal-negative breast cancer [485], the majority of the guideline group has spoken out against a renewed recommendation in the current revision of the S3 guideline. The main reason for this is that the results of the prospective randomized chemo-N0 study in nodal-negative breast cancer are not transferable to current treatment standards. This is also the conclusion reached by the experts of the ASCO guideline in the explanatory text to the statement [485] - despite their open recommendation. The patients in the group with low uPA/PAI-1 did not receive any systemic treatment in the chemo-N0 study, i.e. also no endocrine therapy as is standard today for ER/PgR-positive tumors [518]. It is therefore not possible to say what the additional benefit of chemotherapy for high uPA/PAI-1 in ER/PgR-positive tumours would be under current conditions if the patients in the comparative arm received endocrine therapy. In addition, the HER2 status of the tumours analysed in the chemo-N0 trial is unknown. There are indications that there is a correlation between uPA/PAI-1 and intrinsic subtypes. HER2-positive or triple-negative carcinomas are significantly less likely to be uPA/PAI-1-negative than luminal A-type carcinomas [519]. The question therefore arises whether uPA/PAI-1 is actually an independent prognostic parameter. Furthermore, the prognostic value seems to be different for the individual subtypes and is not detectable in hormone receptor-positive breast carcinomas if the HER2-positive tumors are excluded [520]. The assessment of the S3 guideline group is therefore in line with that of the Institute for Quality and Efficiency in Health Care (IQWiG) in its final report on the evaluation of uPA/PAI-1 in primary breast cancer with intermediate risk of recurrence after R0 resection. It concludes that the patient-relevant benefit or harm of an uPA/PAI-1-supported therapy decision is unclear due to a lack of suitable studies [521].
4.5.4.2 Ki-67
The correlation between the immunohistochemically determined Ki-67 proliferation index and the prognosis of breast cancer has been shown in numerous clinical studies. Nevertheless, Ki-67 is not recommended in the current ASCO biomarker guidelines as a decision aid for or against adjuvant chemotherapy [485]. In the S3 guideline update, the question was raised whether more recent evidence is available to show that the addition of Ki-67 to conventional factors improves the prognosis estimate for invasive breast cancer. For this purpose, a systematic literature review was conducted for the period 2015-10/2016. A meta-analysis was identified that included more than 64,196 patients from 41 studies. The meta-analysis concludes that Ki-67 is an independent prognostic parameter for the overall survival of patients with breast cancer. The prognosis of tumours with high Ki-67-positivity is significantly worse than that of Ki-67-low-expressing tumours (hazard ratio, HR=1.57; 95% CI 1.33-1.87; p<0,00001). Dies gilt ebenso für die Subgruppe der ER-positiven Tumoren (HR=1,51; 95% CI 1,25-1,81; p<0,0001) [484]. In kürzlich publizierten prospektiven Studien wurde außerdem der stärkere Nutzen einer Chemotherapie bei Frauen mit hoch proliferierenden ER-/PgR-positiven, HER2-negativen invasiven Mammakarzinomen gezeigt [492], [493], [496]. Aus Sicht der Leitliniengruppe liegt daher ausreichende Evidenz vor, den Ki-67-Proliferationsindex bei Frauen mit histologisch gesichertem ER-/PgR-positivem, HER2-negativem invasiven Mammakarzinom bei der Entscheidung für oder gegen eine adjuvante Chemotherapie einzubeziehen.
Nevertheless, there are objections to the use of Ki-67 as a prognostic factor (Harris 2016). One of the points of criticism is that the studies use very different threshold values (1-30%) [484] and that there is no uniform threshold value to differentiate the risk groups. For daily practice it would be desirable to be able to clearly differentiate between different prognosis groups on the basis of defined limit values. However, it should be remembered that Ki-67 is to be understood as a continuous marker of the proliferation rate of a tumor. Ki-67 must probably also be understood in the context of subgroups of breast carcinoma (e.g. hormone receptor-positive versus negative tumours), which have different proliferation activity.
<=10% als niedrig. Gemäß der Metaanalyse von Petrelli et al. [484] ist der Grenzwert mit der höchsten prognostischen Signifikanz bislang noch nicht bekannt. Allerdings konnte anhand der Auswertung von 25 Studien, die hinsichtlich des Zusammenhangs zwischen Grenzwert und Überleben informativ waren, gezeigt werden, dass das Gesamtüberleben bei einer Ki-67-Positivität>The general consensus is that carcinomas can be divided into those with low, intermediate and high proliferation activity. In the case of hormone receptor-positive, HER2-negative breast carcinoma, Ki-67-positivity is generally valid /= 25% was significantly lower than Ki-67-positivity < 25% (HR=2,05; 95% CI 1,66-2,53, p<0,00001). Diese Schlussfolgerung der Meta-Analyse bildet die Grundlage für die offene Empfehlung der S3-Leitliniengruppe, dass bei einer Ki-67-Positivität >/= 25% an increased risk can be assumed. This is also supported by the multicenter data from one of the German clinical cancer registries [494]. In the intermediate range of more than 10% to 25% Ki-67 is not safe to use for therapy decisions in daily practice.
Another criticism of Ki-67 as a prognosis marker is the lack of reproducibility between laboratories and examiners [485].
The international working group on Ki-67 in breast cancer as well as other working groups have therefore carried out a number of studies and interlaboratory comparisons to improve the analytical validity of Ki-67, from which conclusions can be drawn for a standardised evaluation (see Section 4.5.3 Evaluation Ki-67). It can also be assumed that the variability of the determination has improved over the years due to increasing automation of immunohistochemistry, training and participation in interlaboratory comparisons. The data for the already mentioned study of a clinical cancer registry were collected multicenter in different pathologies [494] and prove the prognostic relevance of Ki-67.
Ki-67 can also provide useful information on the proliferation rate of hormone receptor negative tumors.
4.5.4.3 Intrinsic subtypes
By analyzing gene expression profiles, molecular subtypes of breast cancer were identified that differ significantly in their clinical course and treatment response: Luminal A and Luminal B, HER2-positive, basal-like [522], [523]. Since the array analyses required for this are not feasible in daily diagnostics, the commercially available PAM50 gene expression test was developed, which can reliably detect these intrinsic subtypes in clinical diagnostics and has prognostic significance [524]. Alternatively, a simplified classification was proposed in which the tumors are differentiated by an immunohistochemical algorithm [525], [526], [527]:
- Luminal A: ER and/or PgR positive and HER2 negative and Ki-67 low
- Luminal B:
- HER2 negative: ER and/or PgR positive and HER2 negative and Ki-67 high
- HER2-positive: ER- and/or PgR-positive and HER2-positive and Ki-67 high or low
- HER2 positive: ER and PgR negative and HER2 positive
- triple negative: ER, PgR and HER2 negative.
This stratification of breast carcinomas offers itself as a biological model for therapeutic strategies. Accordingly, the last St. Gallen Consensus recommendations were based on this biological model [470], [471], [528], [529]: For a tumor of the type Luminal A, a sole endocrine therapy is considered necessary, while for the other subtypes, chemotherapy is recommended in the majority of cases, in HER2-positive disease supplemented by anti-HER2 therapy. However, when transferring the molecularly defined subtypes into immunohistochemical categories, it should be borne in mind that these are not congruent. Thus, with 79% most but not all triple-negative tumors are basal-like and on the other hand 31% of basal-like tumors are not triple-negative [530]. The indication for chemotherapy in ER/PgR-positive tumors respectively the differentiation of Luminal A and Luminal B HER2-negative depends in the proposed immunohistological classification exclusively on the Ki-67 proliferation index. The question of the optimal threshold value for Ki-67 to differentiate Luminal A and B is not answered (see also section Ki-67). When stratifying luminal tumors for treatment planning, it must also be taken into account that their leading feature is ER expression. The PgR status can provide helpful additional information, especially if high positivity is present. If ER is highly expressed and Ki-67-PI is low, strong PgR expression confirms the presence of a luminal A type tumor. A low PgR expression (1-9% positive tumor cell nuclei) is not sufficient to classify ER-negative tumors into the group of luminal tumors. Like tumors with low ER-positivity, they are biologically more likely to be classified as ER/PgR-negative or triple-negative breast carcinomas (see also Section 4.5.3: Interpretation of hormone receptor status). In the meantime, other factors are also being considered to stratify the luminal tumors for treatment planning. In addition to the extent of ER/PgR positivity, these include grading and risk stratification based on gene expression profiles (multigene tests) [470], [471], [528]. However, a prospective validation of selectivity is also lacking for most of these parameters. The risk groups of the gene expression tests described in the following section can be helpful for clinical decisions in the borderline area.
4.5.4.4 Multigen tests
It is undisputed that patients with breast cancer benefit overall from adjuvant drug therapy [Early Breast Cancer Trialists' Collaborative, Group et al. 2012]. In addition to the acute toxicities (e.g. nausea, vomiting, alopecia), chemotherapy can also have a not inconsiderable rate of undesirable side effects, which can have a potentially long-term negative impact on quality of life (e.g. amenorrhoea, fatigue, sensory polyneuropathy, "chemobrain") or even life-threatening (e.g. heart failure, secondary leukemias) are [532], [533], [534], [535], [536]. Therefore, an accurate risk assessment plays a decisive role. In addition to the classic clinical-pathological prognostic factors, multi-test methods are playing an increasingly important role. Risk assessment is of great importance, since patients with a low absolute risk have only a low absolute benefit from adjuvant chemotherapy [Early Breast Cancer Trialists' Collaborative, Group et al. 2012]. For this reason it is crucial that predictive biomarkers in general and multi-test in breast cancer in particular are assessed according to clear and stringent criteria of evidence [537].
Different commercially available multigene tests for breast cancer
This compilation includes some of the most frequently used gene expression tests in Germany (EndoPredict®, MammaPrint®, Oncotype DX®, Pro-signa®), it does not claim to be complete.
Three of these multigene tests were extensively investigated prospectively and retrospectively in early hormone receptor-positive breast cancer. Both EndoPredict® (EP) [538], [539], [540], [541] as well as Oncotype DX® [542], [543], [544], [545], [546] and Prosigna® were evaluated. (PAM50) [547], [548], [549], [550] could consistently show in these studies that they were able to identify patients in a low-risk group with a 10-year risk of distant metastases below 10% with pure endocrine therapy and without adjuvant chemotherapy. The multivariate analysis showed the prognostic significance independent of classical clinical-pathological factors such as age, tumor size, nodal status [105].
For both Oncotype DX® and MammaPrint® prospective evidence is available in the meantime. In the prospective-randomized PlanB study, Gluz and collaborators were able to show that patients with a low recurrence score (RS) ≤11 with pure endocrine therapy had an excellent 3-year disease-free survival of 98% even without adjuvant chemotherapy [492]. The very good survival of patients with hormone receptor-positive, HER2-negative and nodal-negative tumors with a low RS (<11) unter rein endokriner Therapie wurde ebenfalls im Rahmen der prospektiv randomisierten TAILORx-Studie gezeigt [516]. Patientinnen, die als low-risk mit einem RS [Cardoso, F.,van't Veer, L. J.,Bogaerts, J.,Slaets, L.,Viale, G.,Delaloge, S.,Pierga, J. Y.,Brain, E.,Causeret, S.,DeLorenzi, M.,Glas, A. M.,Golfinopoulos, V.,Goulioti, T.,Knox, S.,Matos, E.,Meulemans, B.,Neijenhuis, P. A.,Nitz, U.,Passalacqua, R.,Ravdin, P.,Rubio, I. T.,Saghatchian, M.,Smilde, T. J.,Sotiriou, C.,Stork, L.,Straehle, C.,Thomas, G.,Thompson, A. M.,van der Hoeven, J. M.,Vuylsteke, P.,Bernards, R.,Tryfonidis, K.,Rutgers, E.,Piccart, M.,Investigators, Mindact 2016,#ID 205785]. 32% hatten diskordante Ergebnisse zwischen genomischer (G) und klinisch-pathologischer (C) Risikoeinteilung. C high-risk / G low-risk-Patientinnen hatten ein erkrankungsfreies Überleben von 90,3%, wenn sie zur genomischen Risikoeinteilung randomisiert wurden und dementsprechend keine Chemotherapie erhielten. In der Chemotherapiegruppe wurde für die Patientinnen eine Risikominderung von absolut etwa 3 Prozentpunkten beobachtet, die in der Per-Protokoll-Auswertung statistisch signifikant war (p=0,03; Hazard Ratio 0,64). Daraus ergibt sich, dass ein relevanter Effekt der Chemotherapie nicht ausgeschlossen werden kann.
Concordance of different gene expression tests
In the OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis) Prelim Feasibility Study, 313 patients with early ER-positive, HER2-negative breast cancer were randomised prospectively between chemotherapy followed by endocrine therapy and therapy after risk assessment using Oncotype DX® [551], [552]. In this study, the results of the risk assessments between Oncotype DX®, Prosigna®, MammaPrint®, MammaTyper®, NexCourse Breast® (IHC4-AQUA) and the classification into subtypes using Blueprint®, MammaTyper® and Prosigna® were then compared. The agreement between different tests was only moderate in terms of risk classification (kappa 0.33-0.60) and subtype determination (kappa 0.39-0.55). These results show that for the individual patient, different tests can result in different risk assessments and thus divergent recommendations for or against chemotherapy.
Comparison of prognostic significance between different multi-tests
A comparison of the prognostic significance between the two gene expression assays Oncotype DX® and PAM50 in the TransATAC study showed that the risk of recurrence (ROR) determined by PAM50 provided more prognostic information in ER-positive, endocrine treated patients than the recurrence score (RS) [553] calculated by Oncotype DX®. A further comparison of different gene expression tests (Endopredict® and PAM50) was performed retrospectively in 536 nodal-positive, ER-positive, HER2-negative patients treated in the randomized GEICAM/9906 Phase III study [554]. Between PAM50-ROR and EP a 20-21% recurrence score was found. Both gene expression tests identified a low risk group without significant differences between the tests (10-year MFS: ROR-S 87%, ROR-P 89%, EP 93%). The addition of pathological parameters achieved a superior prognostic significance (10-year MFS ROR-T 88%, ROR-PT 92%, EPclin 100%). A further direct comparison of two gene expression signatures was performed in the TransATAC study in 928 ER-positive/HER2-negative patients treated with either tamoxifen or anastrozole [514]. EP and EPclin showed a greater prognostic significance than RS (EP: LR-χ2=49.3; EPclin: LR-χ2=139.3; RS: LR-χ2=29.1). This effect was particularly strong in nodal-positive tumours and late metastases. However, the comparison of the RS with the EPclin score in this study cannot be readily interpreted clinically, as the established limits of the RS were not considered.
Systematic review of biomarkers by the American Society of Clinical Oncology (ASCO)
In the meantime, extensive studies have been carried out for numerous biomarkers in breast cancer. The American Society of Clinical Oncology Clinical (ASCO) published in 2016 a guideline for the use of biomarkers for adjuvant systemic therapy decisions in patients with early breast cancer and known ER/PgR and HER2 status [485]. Systematic reviews, meta-analyses and randomized studies were used in the literature search. For the preparation of this guideline 50 studies from the years 2006-2014 were used. One randomized prospective and 18 prospective-retrospective studies had evaluated the clinical benefit of additional biomarkers for the decision on adjuvant systemic therapy. Following the publication of the MINDACT study, a focused update of the ASCO biomarker guideline for the use of the MammaPrint® was also published in July 2017 [555]. In summary, no study could be identified for the selection of a specific therapy. In addition to ER, PgR, and HER2, sufficient evidence for a clinical benefit of the above mentioned multi-target tests Oncotype DX®, EndoPredict®, and Prosigna® and MammaPrint were confirmed in nodal-negative patients with ER/PR positive, HER2 negative carcinomas. The quality of evidence for Oncotype DX®, Prosigna® and MammaPrint® was rated "high" and for EndoPredict® "medium". The focused update also identified a potential benefit of MammaPrint® in nodal-positive patients with ER/PR-positive, HER2-negative breast carcinomas and 1 to 3 affected lymph nodes as well as high clinical risk (according to MINDACT categorization) (quality of evidence: high).
Final report "Biomarker-based tests for the decision for or against adjuvant systemic chemotherapy in primary breast cancer" (D14-01) by the Institute for Quality and Efficiency in Health Care (IQWiG)
The final report of IQWiG [556] is contradictory. For this report, 3 randomized [515], [541], [543] and 5 prognosis studies [514], [540], [546], [549], [557] were initially identified. However, none of the five forecast studies and only two of the three randomized studies [515], [541] were considered for IQWiG's evidence assessment. In the final report, the work result was classified as follows: "In the present report, only results of 2 of the 8 included studies could be used for the present report. The results of the remaining 6 studies were not used for the evaluation due to the high proportion of data not included. The data available on the basis of the 8 included studies were not sufficient to answer the question".
Justification of the level of recommendation of the S3 Guidelines presented here
The statement in the present guideline is based on the current ASCO Biomarker Guideline and a systematic literature review, which was conducted in the context of the S3 guideline update and covers the period 2015 to 10/2016. The statement was carefully formulated after extensive discussion at the meeting of the S3 Guidelines Commission in December 2016 and achieved consensus in the current wording. IQWIG's report on gene expression tests for breast cancer, which was published at the same time, was also discussed and taken into account in the S3 Guidelines Commission's decision.
It is noticeable that the ASCO biomarker guideline takes into account the evidence from a total of 19 publications, whereas only 2 studies were used for IQWiG's decision. In IQWiG's final report, a major counter-argument against the prognosis studies referred to above and largely used in the current systematic review for ASCO biomarkers was that less than randomly adjusted 70% of the tumour samples recruited in the studies could be examined with the above-mentioned multi-test. It should be critically noted here that the 70% required by IQWiG cannot be derived from the literature. Since there is no plausible evidence for an exact percentage of the archive material to be examined, in prognosis studies it is important that the patients examined are representative of the study population and have sufficient statistical power to be able to demonstrate differences in survival. Both are given in the above-mentioned studies, which were not considered by IQWiG. A further point of criticism by IQWiG of the prospective-retrospective prognosis studies was that the 95 % confidence interval includes the limit of 5% of the occurrence of metastases after 10 years, as defined by IQWiG. The problem here is that 10% is not accepted as the limit between low and high risk, as is common international practice.
According to IQWIG's defined methodology, test combinations that combine both molecular and clinical factors to a common score were explicitly not considered (final report p. 23) [556]. These include EPclin, but also the ROR-T and ROR-PT scores. This appears problematic, since recent studies with a direct comparison of the different test systems show that the test combinations are superior to the purely molecular tests, especially in nodal-positive patients and late metastases [514], [558]. However, this can also be interpreted to the effect that the test combinations have sufficient prognostic significance only by the addition of clinical parameters, whereby the clinical factors in EPclin are of great importance [540]. In the clinical context the consideration of both molecular and clinical factors is of central importance for a valid risk assessment.
Another critical point raised by IQWiG is the rate of recurrences or deaths that seem "acceptable" for patients to avoid chemotherapy. If metastases / recurrences / deaths due to breast cancer are to be avoided with the highest probability, each patient would have to be treated with adjuvant chemotherapy in addition to endocrine therapy, as this would be the only way to do the maximum possible. However, since chemotherapy, as mentioned above, can have a considerable rate of undesirable side effects, every patient has the right to the best possible medical advice in order to make the best possible decision for herself (for or against chemotherapy). Even if the arguments against multi-dimensional tests, which IQWiG has carefully compiled on 212 pages in the present final report [556], are to be respected, from a medical perspective it must be asked whether we currently have better instruments for our counselling than multi-dimensional tests. As sufficiently published in the prognosis studies mentioned above, the different gene expression signatures consistently have an independent and superior prognostic significance in comparison to the classical prognostic factors such as tumor size, nodal status, histological differentiation grade, lymphangioinvasion or Ki-67. These classical prognostic factors are what we have available to advise patients when multi-tests are not used. After a detailed and critical discussion of the limitations of multi-tests and the above mentioned pros and cons, the guideline group therefore assigned recommendation level 0 after weighing the benefits and harms. Therefore, if in women with ER-/PgR-positive, HER2-negative, nodal-negative invasive breast cancer the conventional prognostic parameters including Ki-67 do not allow for a clear decision for or against adjuvant chemotherapy, a methodologically standardised and clinically validated multigene test can be used for the decision.
For the use of gene expression tests in the nodal-positive situation, the following statement was discussed at the guideline meeting: "In women with ER/PgR-positive, HER2-negative, nodal-positive (1-3 affected lymph nodes) primary invasive breast cancer, a methodologically standardized and clinically validated multigene test can be used in the decision against (neo)adjuvant chemotherapy if it predicts a low risk of relapse". However, there was no majority in favour of this statement, so that it is only presented here in the background text and therefore no consensual recommendation can be formulated for the nodal-positive situation.
It is important that all experts see an urgent need for further investigation and clinical validation of gene expression tests. Randomised therapy studies in which the gene expression test leads to the chemotherapy being given or omitted appear justifiable from an ethical point of view where there is still uncertainty about the best course of action. Otherwise, the recruitment of ongoing randomised trials (e.g. RxPONDER) would have to be stopped immediately. Unfortunately the results from the randomized part of the TAILORx study are not yet available, although they have been announced for some time. In any case, the current results of the MINDACT study do not indicate that refraining from chemotherapy in patients with a low risk of multi-test is clearly the best recommendation. Registry studies are already available for the Oncotype DX® and prove the prognostic significance of the multi-test, also in the context of adjuvant chemotherapy, in the nodal-negative and in the nodal-positive situation [554], [555], [556].
Prediction of adjuvant systemic therapies
To assess the probable effect of adjuvant systemic therapies (prediction), the estrogen/progesterone receptor status for endocrine systemic therapy will be assessed.
To assess the probable effect of adjuvant systemic therapies (prediction), the HER2 status for a targeted anti-HER2 therapy is to be determined.
Zur Einschätzung der voraussichtlichen Wirkung adjuvanter systemischer Therapien (Prädiktion) soll der Menopausenstatus für den Einsatz einer antiöstrogenen Therapie erhoben werden.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1b
Level of Evidence: 1c (Oxford 2009)
- Consensus
- Strong consensus
- References
- [561]
Background 4.80 to 4.82
The recommendations of the predictive factors for endocrine and anti-HER2 therapy are based on international evidence-based guidelines [421], [426], [465], [466] and the results of systematic literature searches and meta-analyses [467], [560], [Early Breast Cancer Trialists' Collaborative, Group et al. 2000].
Menopause status is predictive for all endocrine therapies (see Chapter 4.7.2)
Predictive factors in the context of a neoadjuvant systemic therapy
Various predictive factors have a significant predictive value for the occurrence of pathological complete remission (pCR).
In the run-up to a neoadjuvant systemic therapy, the following data should be collected
- Age
- cT*
- cN*
- histological type
- histological grading
- ER and PgR status
- HER2 status
*Clinical parameters
Background 4.83
The response of the tumor to neoadjuvant systemic therapy provides information on the prognosis of the disease. The pCR, defined as the absence of invasive tumor residuals in mamma and lymph node [564], correlates with the survival of patients [565]. However, the close correlation between pCR and course obviously does not apply equally to all subtypes [564], [565], [566]. Only in triple-negative and HER2-positive breast carcinomas is pCR currently recognized as a surrogate marker for the benefit of chemotherapy or anti-HER2 therapy [564].
According to the pooled data from 7 German neoadjuvant studies including 3332 patients [563] and the results of a meta-analysis including 11,695 patients from 30 studies [562], pCR rate and subtype are significantly associated. The highest pCR rates are achieved in triple-negative and HER2+/HR- subtypes. In patients with a positive HER2 status, an additional neoadjuvant anti-HER2 treatment further increases the pCR rate.
In addition, there is a significant correlation between age, pre-therapeutic tumor size and nodal status as well as histological tumor type and degree of differentiation with the pCR [563].
Other factors are currently under discussion to predict a higher response to neoadjuvant systemic therapy. These include in particular:
- Ki-67 proliferation index
- Tumor infiltrating lymphocytes (TILs)
Based on the determination of the Ki-67 proliferation index in 1166 punch biopsies of the GeparTrio study it was shown that Ki-67 is a significant predictive marker for the response to neoadjuvant chemotherapy [567]. However, the discussion about the results of the study also made clear that the definition of a uniform threshold value for the prediction of the therapy effect is difficult [568], [569] Ki-67 showed a significant predictive and prognostic value over a wide range of cut-offs, so that an optimization of the threshold value based on study data might be problematic. Rather, it can be assumed that the level of the optimal cut-off value is context-dependent, i.e. influenced by the composition of the study collective, the molecular tumor types and the therapeutic agents. The decision for a neoadjuvant therapy is mainly controlled by the hormone receptor and HER2 status. Triple-negative and HER2-positive carcinomas are usually treated neoadjuvantly. In this situation the Ki-67 level is no longer necessarily relevant. Therefore, the majority of the S3 guideline group decided against a recommendation of Ki-67 as a predictive factor for the response to neoadjuvant systemic therapy.
Tumor infiltrating lymphocytes (TILS) can be understood as an immunological biomarker. In recent years, an increasing number of studies have been published showing that the quantification of TILs has a prognostic and predictive value, especially in HER2-positive and triple-negative breast carcinomas [570], [571], [572]. A meta-analysis including 13,100 patients from 23 studies concluded that an increased number of TILs predicts the achievement of pCR and is associated with an improved survival rate [572]. However, different methods for the detection of TILs are used in the studies (HE staining; immunohistochemistry: CD45, CD3, CD8) [572], [573]. Also the procedure of evaluation and the amount of cut-off are different [572], [573], so that from the point of view of the S3-guideline group no recommendation for this parameter can be derived from the study data available so far.
4.5.5 Percutaneous biopsies in the context of interventional diagnostics
Currently available methods for interventional diagnostics:
- High-speed punch biopsy (e.g. 14 gauge)
- vacuum biopsy (e.g. 11 gauge or 8 gauge)
4.5.5.1 Percutaneous biopsy (high-speed punch biopsy, vacuum biopsy)
Indications: Diagnostic confirmation for therapy planning, clarification of unclear and suspected malignant findings.
4.5.5.1.1 Macroscopic processing
Description:
- High-speed punch biopsy: number and (total) length of punch cylinders/parts;
- vacuum biopsy: number of punching cylinders/parts; if necessary, further description (colour, consistency)
Tissue embedding:
- complete embedding of the tissue samples sent
4.5.5.1.2 Microscopic processing and assessment
Machining:
- Sectional stages (see Statement 4.34.; H&E; additional examinations if required)
- special additional examinations in case of detection of invasive carcinoma (hormone receptors; HER2, Ki-67)
Cutting steps for percutaneous biopsies
At least 3 HE incisions should be made and examined from tissue cylinders removed for the clarification of calcifications.
For tissue cylinders that were removed for the clarification of focal findings, one HE incision may be sufficient.
Further incision steps may be necessary if there is no correlation to the clinical-radiological findings or to clarify the diagnosis.
- Consensus
- Strong consensus
Background 4.84
The diagnostic reliability at the punch and vacuum biospies is improved, especially in the presence of microcalcifications, by the preparation of cutting steps [574]. This is also related to the diameter of the cylinders, which is usually larger in biopsies from microcalcifications associated lesions, since vacuum biopsies are increasingly used here. The addition of 2 incision steps on a collective of 40 punch and 63 vacuum biopsies changed the diagnostic category in 13% of biopsies from lesions with microcalcifications. On the other hand, the addition of 266 punch biopsies and 6 vacuum biopsies resulted in a change in the diagnostic category in only 1.5% of the biopsies from other lesions.
Survey:
- The information is documented as in section 4.5.2.3, possibly using a form (see Annex 11.3: Figure 9 - Form 2A).
In punch biopsies, the displacement of benign or malignant epithelial cell clusters into the stroma and/or vessels is possible; in individual cases, the differentiation of true stroma and/or vessel invasion may be difficult.
If necessary, point out the necessity of further bioptic clarification in case of
- lack of a morphological correlate for the imaging findings,
- questionable dignity of the identified lesion (e.g. detection of atypical ductal hyperplasia (ADH) or fibroepithelial neoplasia, where a reliable distinction between fibroadenoma and phylloides tumour is not possible).
In addition, the pathomorphological findings on the punch and vacuum biopsies are classified into the 5 categories of the B-classification (B1-B5) [420], [425] in the mammography screening. Classification of the categories is also recommended on punch and vacuum biopsies of symptomatic findings outside mammography screening [425].
Table 4: B-classification for punch and vacuum biopsies
|
B1 |
Normal tissue or non-recyclable material
|
|
B2
|
Benign lesions
|
|
B3 |
Benign lesions with uncertain biological potential
|
|
B4 |
Suspected malignancy
|
|
B5 |
Malignancy
|
4.5.5.2 Fine needle puncture/aspiration cytology (FNAC)
Is not recommended in Germany to confirm the diagnosis of suspected breast cancer, among other reasons because it is not possible to differentiate reliably between non-invasive and invasive changes. The only areas of application are the clarification of cysts or suspect lymph nodes.
4.5.6 Excision biopsies
In principle, all forms of excision biopsies are handled in the same way as a breast-conserving surgical procedure (possible exception: diagnostic excision).
Forms of excisional biopsy:
- Open biopsies/diagnostic excisions
- Tumour resections/lumpectomies/segmental resections
(in case of non-palpable findings after preoperative localization using a marking wire)
4.5.6.1 Macroscopic processing
Description:
- Total tissue sample received:
- Size (3 dimensions) and weight
- Cut/not cut
- Size and texture of pendulous skin parts
- Marking for topographic orientation of the tissue sample (if performed by the surgeon)
- if necessary, localization of a marking wire
- Palpable tumor:
- Size (3 dimensions)
- Cut surface: boundary (sharp/blurred), consistency, colour
- Correlation to marker wire/preparation radiography, if applicable
- Minimum distance from the resection margin (in mm) taking into account the topography
- Other noticeable findings
Preparation:
- Marking of the surface of the preparation with ink, latex or other suitable material to assess the cut edges
- Lamination of the specimen by parallel cuts perpendicular to the longitudinal axis of the specimen (lamella thickness approx. 5 mm) from one end of the specimen to the other; if necessary, oriented towards the nipple if the topographical markings are appropriate
Tissue samples are used for statements on:
- non-palpable findings or palpable tumour (see below)
- Resection margins
- other changes/surrounding tissue
- special questions (additional examinations)
Note:
The number of tissue blocks depends on the size and type of the material sent in, the number and size of the mammographically and/or palpatorily conspicuous lesions and the underlying process (e.g. macroscopically clearly recognizable carcinoma versus non-demarcable DCIS).
Non palpable findings:
It is necessary to embed the entire mammographically conspicuous focus for the exact identification of the localized and marked change as well as the resection margins and of compacted tissue outside the radiologically conspicuous area (especially low-grade DCIS can be much more extensive than the radiologically conspicuous microcalcifications suggest). Tissue sampling is systematic and oriented to reconstruct, if necessary, the size and topography of the lesion with relation to resection margins; possibilities for this:
- Systematic placing of preparation discs after lamination on a foil and preparation of a preparation radiography or photocopy. In the case of radiologically conspicuous microcalcifications, the preparation radiography of the tissue lamellae enables targeted removal and microscopic examination for exact histological-radiological correlation. Entry of the tissue samples with the corresponding block designations on the radiography or photocopy.
- Use of prefabricated sketches for noting the withdrawals with block designation (see Figure 3).
Palpable tumour:
- Size of the tumor is essential for the extent of the embedding:
- Small tumours up to about 1 cm in diameter: Embedding in toto
- Larger tumours: At least 3 tumour blocks or a complete tumour cross-section desirable
- For representative detection of very large tumours, the removal of at least one tissue block per cm maximum diameter is recommended. If possible, acquisition of the tumour margin with the nearest excision margin in at least one block.
- Always also examination of surrounding fibrous tissue that appears tumour-free
Processing in the presence of a DCIS:
- Targets: Determination of the size, assessment of the resection margins, exclusion of invasive growth
- Tissue sampling: Procedure depending on lesion (non-palpable or palpable; see above)
Mammographic sizing alone is unreliable. In about 30 % of the cases that are operated on with breast-conserving surgery, the size is underestimated in mammography, so that follow-up resections are necessary [575]. Therefore, a complete, sequential histopathological embedding of the surgical specimen is recommended for breast-conserving therapy under consideration of the topographic orientation. Even large DCIS should be completely embedded, since they may contain foci of microinvasion [576].
Surgical preparations after neoadjuvant therapy:
- The processing of the surgical specimens is essentially analogous to the procedure for primary surgical therapy.
- However, the therapy-induced thinning of the tumor can make the macroscopic identification of residual tumor foci difficult and often requires the embedding of more tissue samples.
4.5.6.2 Microscopic processing and assessment
Bearbeitung:
- Bei Nachweis eines invasiven Karzinoms: spezielle Zusatzuntersuchungen (Hormonrezeptoren, HER2, Ki-67), falls nicht bereits an prätherapeutischer Stanzbiopsie erfolgt
Begutachtung:
- Dokumentiert werden die Angaben wie unter Abschnitt 4.5.2.3, evtl. unter Verwendung eines Formblattes (s. Anhang 11.3: Abbildung 10 - Formblatt 2B).
4.5.7 Mastectomy specimens
A mastectomy is usually performed after securing a carcinoma by interventional diagnostics or excisional biopsy. It leads to the final tumor classification and determination of the degree of differentiation with determination of the tumor extent; if necessary, identification of further changes.
In order to achieve a rapid fixation of the tissue, it is recommended to send the preparation to the pathologist immediately after the surgery in order to accelerate the tissue preservation by laminating the preparations.
Forms of mastectomy are the simple mastectomy, "skin-sparing" mastectomy, modified radical mastectomy according to Patey, radical mastectomy according to Rotter-Halstedt or extended mastectomy.
4.5.7.1 Macroscopic examination
Description:
- Mastectomy prep:
- Size (3 dimensions) and weight
- attached tissue (e.g. intact pectoralis fascia, pectoralis muscles, axillary fat tissue)
- Size and condition of the attached skin spindle, location of the nipple (e.g. central, eccentric)
- Orientation of the tissue sample (if performed by the surgeon)
- Location of a pre-biopsy/excision or tumor (quadrant, relation to the resection margins)
- Tumor:
- Size (3 dimensions)
- cut surface: boundary (sharp/unsharp), consistency, colour
- Reference to the resection margin
- other conspicuous findings (e.g. prosthesis capsule, fibrocystic changes)
Taxidermy:
- if necessary, staining of the preparation margin with ink or pigments to identify the resection margin
- Lamination of the preparation from lateral to medial in parallel slices of 5-10 mm thickness, with lamellae remaining in contact with the skin
Tissue samples are used for statements on:
- Nipple/submammary tissue
- Tumor (number of paraffin blocks depending on size)
- Pre-biopsy/excision cave margin (3-4 tissue samples in total)
- Resection margins
- other changes
- additional breast gland tissue from the 4 quadrants (at least 1 block each)
- special questions/additional examinations
If the mastectomy was performed because of a DCIS or if there were radiologically extensive microcalcifications, a preparation radiography of the tissue lamellae can be helpful in order to localize the changes precisely and to be able to carry out a targeted removal to determine the extent and reference to the resection edges.
4.5.7.2 Microscopic examination and assessment
The information is documented as in section 4.5.2.3, possibly using a form (see Annex 11.3: Figure 10 - Form 2B).
4.5.8 Lymph nodes
Lymph node status
The lymph node status is determined by histological examination of all removed lymph nodes.
It should be obligatory: Number of removed and affected lymph nodes, extent of the largest tumour settlement, capsule rupture, pN category (according to TNM classification, 8th edition UICC 2017).
The aim of the work-up is to detect all macrometastases (> 2.0 mm).
- Consensus
- Strong consensus
Background 4.85
Sentinel lymph node biopsy (SLNB):
- Removal of the so-called sentinel lymph node (dye and/or radionuclide labeling).
- Nowadays common primary procedure for the determination of the nodal status. Prerequisite is compliance with the recommended quality criteria [577].
- The minimal aim of the histological examination is the detection of all macrometastases (> 2 mm) [427], [532]. Desirable, but not obligatory, is also the identification of micrometastases (> 0.2 mm and/or more than 200 tumor cells, but not larger than 2 mm). In the presence of micrometastases, it is to be expected that other lymph nodes will be affected in approx. 20 % of cases [578], and with a size of > 1 mm even in approx. 30 % of cases [579]. The histological examination of the SLN does not aim to detect isolated tumor cells (ITC). If ITCs are detected, their correct classification (see below) must be ensured.
Axillary lymphadenectomy:
- Nowadays only in exceptional cases primary surgical procedure to determine the lymph node status. Mostly for completion in case of affected SLN.
- The aim of the histological examination is to detect all macrometastases (> 2 mm).
4.5.8.1 Macroscopic examination
Description:
- Size (3 dimensions) and weight of the entire tissue sample (for axillary lymph node dissection)
- Orientation (if marked)
- Number of lymph nodes
- Dimension of the largest lymph node
Taxidermy:
- Careful examination of the fatty tissue for lymph nodes
- Histological examination of all contained lymph nodes
- In macroscopically affected and interconnected lymph nodes: Examination of a representative cross-section
- In case of macroscopically not clearly affected lymph nodes: complete embedding for histological examination
- If the size of the lymph nodes permits, they should be halved along the longitudinal axis or laminated in slices 2-3 mm thick
4.5.8.2 Microscopic examination and assessment
Processing:
- Sentinel lymph node [427], [577]:
- For macroscopically affected lymph nodes: one H&E incision per block
- In macroscopically not clearly affected lymph nodes: Cutting steps (distance /= 500 µm) H&E stained; number for reliable detection of all macrometastases depending on tissue thickness
- Immunohistochemical reactions with antibodies against cytokeratins are not recommended as standard procedures, but may be diagnostically helpful in individual cases (e.g. invasive lobular carcinoma)
- Axillary lymph node dissections:
- For macroscopically affected lymph nodes: one H&E cut per block
- In macroscopically not clearly affected lymph nodes: According to international guidelines one H&E incision is sufficient [427], [428]. However, depending on the thickness of the total blocked lymph node tissue, it is recommended to make at least 2-3 incisions (distance 100-500 µm) to ensure the detection of all macrometastases (> 2 mm).
Survey:
- The following information is documented, possibly using a form (see Appendix 11.3: Figure 10 - Form 2B):
- Type of tissue sample
- Page reference
- Number of lymph nodes examined (with localization, if marked)
- Number of lymph nodes affected
- Extent of the greatest metastatic infiltration
- Extranodal infiltration, if any
- pTNM stage (including additional tissue samples if necessary) (see sections 4.5.6. and 4.5.7.)
Remarks:
- If the pathological classification is based on a sentinel lymph node examination, this is indicated by the suffix (sn), for example pN0(sn) [429].
The detection of isolated tumor cells (ITC) in regional lymph nodes is classified as pN0(i+). ITC are defined as single tumor cells or small clusters of cells not larger than 0.2 mm in the largest dimension. As an additional criterion it has been proposed to include a cluster of less than 200 cells (in a histological section) in this category [429].
4.6 Adjuvant radiothepary of breastc ancer
After breast-conserving surgery due to invasive carcinoma, radiation of the affected breast should be performed.
For patients with clearly limited life expectancy (<10 years) and a small (pT1), node-negative (pN0), hormone receptor-positive HER2-negative tumor receiving endocrine adjuvant therapy, conditional upon free excision margins and taking an increased risk of local recurrence into account.
Note for all recommendations: All individual items are "or" combinations. "And" links are represented by an "and".
Background 4.86
Postoperative irradiation is the most important and effective measure to reduce the risk of intramammary recurrence; the effectiveness is proven with the highest evidence by numerous randomized studies and meta-analyses [580], [581] To date, no subgroup has been identified in randomized studies where there is no significant effect in terms of improving local tumor control. According to the current state of knowledge, the effectiveness of radiotherapy is also independent of tumor-specific or patient-related prognostic factors. In recent studies, in which the effectiveness of radiotherapy was examined in tumor subgroups defined by molecular biology or gene expression analyses, significant effects of radiotherapy were found in all subgroups [557]. Therefore, although it is possible to identify patient groups with a low risk of relapse, these patients also benefit from radiotherapy with regard to an optimization of local tumor control. Therefore, in contrast to the individualized indication of systemic therapies, predictive markers cannot be used to make a decision on radiotherapy after breast-conserving surgery.
In meta-analyses [580], [581] the irradiation reduced the locoregional relapse rate as well as the rate of all relapses (locoregional and distal relapses). Although primary or adjuvant drug systemic therapies also increase locoregional tumor control, their effect is not sufficient to dispense with radiotherapy after breast-conserving surgery. If the relative risk reduction (i.e. the hazard ratio, similar to the evaluation of drug therapy procedures) is used as a measure of the effectiveness of radiotherapy, the effectiveness of radiotherapy on local tumour control has actually improved considerably in recent years. The hazard ratio in the meta-analyses, which mainly contain studies from the 1970s and 1980s, is about 0.35; of 10 possible recurrences without radiation, 6 to 7 were prevented by radiotherapy [581]. In more recent studies, hazard ratios of about 0.2 or even less are consistently reported, i.e. of 10 possible recurrences without radiation, 8 are prevented by radiotherapy [583], [584], [586]. This improvement in relative effectiveness can be explained radiobiologically well and is based essentially on standardized surgical techniques and improved pathohistological diagnostics (fewer undetected R1 resections, thus less "tumor burden" with a higher success rate with standardized radiation dose).
The improved local tumor control leads to a reduction of breast cancer-specific mortality; this effect was confirmed in consecutive meta-analyses. In the last meta-analysis of the EBCTCG data [581] percutaneous radiotherapy leads to a reduction of disease-specific mortality in pN0 patients by 3.3% in absolute terms and by 8.5% in absolute terms in pN+ patients after 15 years. These effects have been proven for all age groups, but the benefit decreases in older patients [588].
The effect of radiotherapy of the breast on survival - since it is generated secondarily by optimizing local tumor control - is detectable only after a longer follow-up period and increases over time [581]. The greatest benefit of radiotherapy is achieved by patients in whom the risk of relapse is reduced by > 10% by adjuvant radiotherapy. Thus, statistically speaking, 4 local recurrences prevented within the first 10 years can prevent cancer-related deaths within 15 years [580], [581]. The positive effect on survival is lower in more recent studies with overall more favorable tumor stages or is not given in very favorable collectives in the first 10 years after therapy. Nevertheless, radiotherapy remains the most important measure to optimize local control. In more recent studies the risk for intramammary recurrence is lower than the risk for contralateral new carcinomas, so that a protective effect on new carcinomas is discussed [589].
Patients with low-risk tumors also benefit from adjuvant radiotherapy of the breast. The positive effect with regard to local tumor control is clearly documented in all randomized studies [583], [584], [586], [590], [591]. The most important risk factor for a local recurrence in the breast is also in these patients with very favorable tumors the renunciation of radiotherapy [584]. The risk for side effects was not different with and without radiotherapy; most of the side effects result from the adjuvant endocrine therapy [586]. Data from population-based analyses also show that the renunciation of radiotherapy in patients at an advanced age is associated with an increased mortality rate from breast cancer [592]. Radiotherapy of the breast should therefore also be the rule for these patients.
If adjuvant radiotherapy is used, the free resection margin plays a minor role; a R0 resection ("no ink on tumor") is sufficient from [362], [593]. Radiotherapy can therefore help to avoid unnecessary follow-up resections and limit the resection volume (a factor relevant for the final cosmetic outcome).
The risks of radiation therapy are low nowadays; radiation of the breast has the lowest risks of all therapy methods used in the adjuvant therapy of breast cancer. The risk of symptomatic pneumonitis is less than 1%. In older studies, increased cardiac mortality was found in patients with left-sided breast cancer and adjuvant radiotherapy; cardiac excess mortality correlated with the cardiac radiation dose [594]. In studies conducted after about 1990 (i.e. after the introduction of 3D conformational radiation), significant cardiac excess mortality was no longer detectable. In more recent studies, neither co-irradiation of the regional lymph nodes nor combination with trastuzumab was observed to increase the risk of cardiac events [595], [596], [597], [598]. In addition, with Intensity Modulated Radio Therapy (IMRT) and Volu-Metric-Arc-Therapy (VMAT) modern therapy methods with sufficient Level Ib/IIa evidence are available today, which report lower acute skin reactions, late fibrosis and telangiectasia of the breast and thus better cosmetic results than after 3D-irradiation. At the same time, effective protection of the lungs and heart is guaranteed. However, IMRT/VMAT should not be used generally, but should be limited to patients with larger breasts and/or abnormal chest curvature (e.g. funnel chest) [599], [600], [601], [602]. A further method by which the radiation dose to the heart can be minimized to non-critical values even with left-sided irradiation is irradiation in controlled deep inspiration [603]. The risk for radiation-induced secondary malignancies is basically given with radiation application and amounted in the early studies (therapy before 1990) to about 1% after 20 years. However, more recent data from cancer registries (e.g. from the SEER database) show that only a small proportion (<10%) der nach Strahlentherapie auftretenden Zweitmalignome durch die Strahlentherapie bedingt ist [604], [605].
Fractionation
Also recommendation level 0
Radiotherapy of the breast should be performed in hypofractionation (total dose approx. 40 Gy in approx. 15-16 fractions in approx. 3 to 5 weeks) or can be performed in conventional fractionation (total dose approx. 50 Gy in approx. 25-28 fractions in approx. 5-6 weeks).
Background 4.87
Until a few years ago, treatment with small single doses (daily 1.80 Gy to 2.00 Gy, so-called conventional fractionation) was considered the only sensible fractionation for curative therapy intentions. This applied to all tumours and was well justified from a radiobiological point of view. In the meantime, data are available from four large randomized studies with a total of more than 7000 patients, which have shown equally good results both in terms of tumor control and late toxicity with moderate hypofractionation (about half as many fractions as with conventional fractionation) in breast cancer [607], [608], [Trialists' Group, The START et al. 2008], [612]. This surprising result is explained by an unexpectedly low α/β value of breast carcinomas, which according to more recent calculations is in the order of 3 to 3.5 Gy.
Hypofractionation means that the number of fractions is reduced; the individual dose increases, and the total dose is reduced according to radiobiological calculations. However, a distinction must be made between pure hypofractionation (the total treatment time remains the same, e.g. only every second day of irradiation, e.g. START-A study) and accelerated hypofraction (the treatment time is shortened by daily irradiation). From the data available so far, it can be concluded that moderate hypofractionation (15 to 16 fractions for breast irradiation instead of 25 to 28 fractions for conventional fractionation) is well possible and can be combined with moderate acceleration (reduction of the total treatment time from 5-6 weeks to three weeks). These variants are well justified not only by studies but also by radiobiological model calculations.
It is unclear whether a further reduction in the number of fractions (extreme hypofractionation) or the treatment time (extreme acceleration) is possible. Two British studies (FAST and FAST-FORWARD) test these concepts [613]. So far, only data on acute toxicity are available, which (as expected) is not amplified [614]. The crucial questions of tumor control and late toxicity are expected to be answered from about 2020.
In summary, based on the data available, a moderate hypofractionation with moderate acceleration (i.e. about 15 to 16 fractions with irradiation on workdays, total treatment time about 3 weeks) can be recommended for the follow-up irradiation of the whole breast in breast cancer; a possibly indicated boost should be administered sequentially (after the hypofractionated irradiation of the breast). The advantage of hypofractionation in comparison to conventional fractionation with the same local tumor control is a clear reduction in acute skin reactions and also a tendency to slightly lower late sequelae [607], [615]. A further advantage for the patients is the shortened treatment period of only 3 to 5 weeks in connection with hypofractionation. So far, there is no evidence that clinical or molecular biological factors can be used to identify subgroups which benefit from the use of a specific fractionation regime [616]. The recommendation for hypofractionation is therefore currently valid across the board for all adjuvant radiotherapy of the mammary gland without lymph drainage channels.
Exceptions concern patients with radiation of the lymphatic outflow pathways. These were underrepresented in the hypofractionation studies. Although the data available to date (in accordance with radiobiological models) do not show any increased late toxicity for this collective with significantly larger irradiation volumes, the data situation is considered weak. Furthermore, an increased risk of late sequelae at the nerve plexus and with regard to the occurrence of lymphedema is possible [617] The late toxicity of hypofractionated regimens when irradiating also the regional lymph nodes is currently being investigated in large studies. In practice (outside of studies), conventional fractionation is therefore recommended as the fractionation of first choice when the lymph nodes are also irradiated.
Also recommendation grade B
Boost irradiation
Local dose saturation (boost radiation) of the tumor bed lowers the local recurrence rate in the breast without providing a significant survival benefit.
The boost irradiation
- should therefore be used for all /= 50 year old patients and
- should only be performed in > 51-year-old patients with an increased local risk of relapse (G3, HER2-positive, triple-negative, > T1).
Background 4.88
A local dose saturation of the tumor bed (so-called boost) can further reduce the relapse rate after breast-conserving surgery. Data are available from two large randomized studies. Both studies compared irradiation of the whole breast (dose 50 Gy) versus irradiation of the breast with subsequent boost. In the French study the boost dose was 10 Gy [621]; in the larger EORTC study the boost dose was 16 Gy [619]. In both studies the risk of relapse was significantly reduced. Follow-up data from the larger EORTC study are available for 20 years, which were updated and published every 5 years; furthermore, several analyses of prognostic factors have been published from this study [366], [618], [619], [620], [622], [623], [624]. The benefit of the boost on local tumor control has remained stable over 20 years or even increased. Local control was also significantly improved for prognostically favorable subgroups; there is no subgroup that does not benefit from a boost with respect to local tumor control. The relative risk reduction is similar in all subgroups; the absolute advantage is greater in younger patients with higher risk than in older patients with low-risk tumours. The rate of late complications (fibrosis grade 3 in boost volume) was low in the EORTC study and higher in older patients than in younger ones; therefore, the individual benefit-risk ratio (local control versus fibrosis) is very favourable in younger patients and decreases with age.
As a consequence of these data, a boost is strongly recommended and clearly indicated in all premenopausal patients as well as in postmenopausal patients with an increased risk of relapse or histological risk factors (G3, HER2-positive, tripelnegative, > T1) - Elderly patients with evidence of concomitant DCIS, affected lymph nodes, missing hormone receptors, lymph vessel invasion and after close R0 or R1 resection may also benefit from a boost. A boost is generally unnecessary in older patients without risk factors.
In the past, the boost was predominantly (e.g. in the EORTC study) applied with electrons with five to eight fractions following the irradiation of the breast (so-called sequential boost). After the introduction of 3D irradiation planning, techniques with photons have become standard. Alternative procedures are interstitial brachytherapy or a single intraoperative irradiation (with KV-radiation or electron radiation). All procedures have advantages for certain clinical situations and limitations. However, there is no evidence to date that any of these procedures is clearly superior to others. For boost irradiation, therefore, the procedures that are available locally and with which experience exists should be selected.
A new procedure is the simultaneous integrated boost (SIB) during external irradiation. Here, the sequential boost dose of 10-16 Gy/5-8 fractions, which was previously administered after breast irradiation, is divided into the number of fractions (25-28) required for breast irradiation and integrated at the tumor bed as a simultaneous boost. The SIB has physical-technical and biological advantages (overdoses outside the boost volume are reduced) and leads to a reduction of the total treatment time by about 1 to 1.5 weeks depending on the amount of the boost dose [625], [626], [627]. A major disadvantage of the boost (namely the extension of the treatment time of the external irradiation) is eliminated by the SIB. When using a SIB, the indication for boost irradiation can therefore be set rather generously. The combination of conventional fractionation when irradiating the breast with SIB has been evaluated in large prospective non-randomized studies and is considered safe and effective [589], [628]. The combination of hypofractionation when irradiating the breast and SIB is still considered experimental. Several randomized studies worldwide are currently investigating this question (in Germany: HYPOSIB study).
Partial breast irradiation and IORT
Partial breast irradiation alone (as an alternative to post-irradiation of the entire breast) can be performed in patients with a low risk of recurrence.
Background 4.89
An individual risk-based indication for adjuvant partial breast irradiation (PBI (partial breast irradiation) or APBI (accelerated partial breast irradiation)) after complete tumor excision with breast preservation and limitation of the irradiation volume to the tumor region can be performed in patients with a low (local) risk of recurrence.
The different concepts with different radiation qualities and technical procedures for partial breast irradiation mostly correspond to those used in PBI as boost RT before or after irradiation of the entire breast (WBI) [635], [636], [637], [638], [639], [640], [641], [642], [643], [644], [645], [646].
In multi-catheter brachytherapy, the applicator tubes can be placed during or even after the surgery. The same applies to balloon brachytherapy, in which the balloon is inserted into the wound cavity with a central brachytherapy catheter already during the surgery ("open cavity"), but also afterwards ("closed cavity"). Irradiation is typically performed over a few days, sometimes several times a day (e.g. twice a day for 5 days).
Two prospective randomized studies with long follow-up times are available for multicatheter brachytherapy. The Budapest study [630] showed similar results with APBI and WBI up to 10 years after therapy, but this monoinstitutional study was closed early due to poor recruitment, so that it did not have enough power for the hypothesis of non-inferiority of APBI. Results from the randomized phase III study of the GEC-ESTRO group were recently published [633]. 1184 patients (> 40 years, tumor up to 3cm) were randomized between 2004 and 2009. The primary endpoint was ipsilateral local recurrence with a non-inferiority margin of 3% after 5 years. The 5-year recurrence rate was 0.9% for EBRT and 1.4% for APBI as the sole RT modality (p = 0.42). Overall survival was 95.6% for EBRT and 97.3% for APBI (p = 0.11).
The IORT as sole radiotherapy modality represents the extreme variant of the combination of hypofractionation and APBI and is performed immediately after surgical tumor extirpation as a single radiation treatment limited to the tumor resection cavity with application of a total dose considered curative to the expanded tumor bed. For an IORT, electrons of a linear accelerator (= IOERT), an orthovolt therapy with 50 kV X-rays of a miniature X-ray device or a balloon brachytherapy technique are used [636], [637], [640], [642], [647], [648]. Altogether, almost 5000 patients were randomized in two prospective randomized studies (TARGIT, ELIOT). Although the results of the studies available to date showed a slightly increased recurrence rate in the breast for the overall group of patients, local tumor control rates for certain subgroups of older patients with unifocal small breast cancer were comparable to those achievable with radiotherapy of the entire breast [631], [632], [649].
A monocentric study [650] randomized 520 patients over 40 years of age with tumors up to 2.5 cm for percutaneous APBI with 5 x 6 Gy as IMRT compared to conventional whole breast irradiation. After a median follow-up of 5 years the local recurrence rate was 1.5% in both arms with a more favorable toxicity profile and better quality of life according to APBI [651].
A recently published meta-analysis [652] summarized all published prospective studies on APBI that had published survival data and could clearly show that there is by no means an inferiority of APBI in terms of overall survival after 5 years to whole breast irradiation, whereby the studies essentially included older patients with small, clinically nodal-negative breast cancer. In terms of disease-free survival, APBI also does not appear inferior to whole breast irradiation, although possibly increased local recurrence rates and reduced non-breast-cancer mortality seem to compensate.
Irradiation treatment of parts of the breast (PBI) limited to the primary tumor area as the sole ("definitive") intra- or postoperative radiation treatment may also be an option for selected patients with a higher risk of local recurrence in whom homogeneous irradiation of the entire breast is not feasible (e.g., patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence, patients with a high risk of localized tumor recurrence). e.g. pre-irradiation, age, comorbidity) [28], [466], [629], [643], [653], [654].
Postmastectomy radiotherapy (PMRT)
Postoperative radiotherapy of the chest wall after mastectomy reduces the risk of locoregional recurrence and improves overall survival in locally advanced and nodal-positive breast cancer.
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [655]
Radiation therapy of the chest wall after mastectomy should be indicated in the following situations
- PT4,
- pT3 pN0 R0 in the presence of risk factors (lymph vessel invasion (L1), grading G3, premenopausal, age < 50 years),
- R1-/R2-resection and lack of the possibility of a rehabilitative resection.
a) In more than 3 affected axillary lymph nodes, postmastectomy radiation should be performed regularly.
b) In 1-3 axillary lymph nodes affected by tumours, post-mastectomy radiation should be performed if there is an increased risk of recurrence (e.g. if HER2-positive, triple-negative, G3, L1, Ki-67 > 30%, > 25% of the removed lymph nodes are tumour-infected; age ≤ 45 years with additional risk factors such as medial tumor localization or tumor size > 2cm, or ER negative).
c) PMRT should be avoided in 1-3 tumour-infected axillary lymph nodes and tumours with a low risk of local recurrence (pT1, G1, ER-positive, HER2-negative, at least 3 characteristics must apply).
d) For all other patients with 1-3 tumour-infected axillary lymph nodes, the individual indication should be determined on an interdisciplinary basis.
Background 4.90 and 4.91
This update of the S3 guideline presents the current evidence on the indication for postmastectomy radiotherapy. Compared to the S3-Guideline version of 2012, the indication is more clearly differentiated according to risk constellations and, under certain circumstances, completely withdrawn. The authors emphasize that the indication for postoperative radiotherapy always includes information about possible treatment alternatives with all their consequences and is based on a clear "informed consent" of the patients. With a normal risk constellation, postoperative radiation of the chest wall and lymph drainage channels can be avoided after a mastectomy. There are, however, situations with a high risk of locoregional recurrence, in which adjuvant radiotherapy of the chest wall with possibly lymph drainage pathways is indispensable in view of the otherwise threatening high locoregional recurrence rates. Analogous to the situation after breast-conserving surgical therapy, postoperative radiotherapy also has a positive influence on local and regional tumour control after mastectomy and ultimately on tumour-specific and overall survival. The locoregional risk of relapse and the indication for postoperative radiotherapy correlate positively. The higher the risk of locoregional relapse, the higher the absolute improvement of locoregional tumor control and survival by postoperative radiotherapy. The high risk of relapse is defined as > 20% and the intermediate risk as 10-20% probability of a locoregional relapse.
A high risk of relapse exists for patients with T4 tumours, pT3 pN0 R0 with risk factors (lymph vessel invasion (L1), grading G3, premenopausal status, age
There is an intermediate risk of relapse for patients with T1 or T2 tumors with only 1-3 tumor-affected axillary lymph nodes with the simultaneous presence of other risk factors, such as grading G3, lymph vessel invasion (L1), intravascular tumor cell detection (V1), Ki-67 > 30%, > 25% of removed lymph nodes tumor-affected, age ≤ 45 years and medial tumor site.
There is a low risk of relapse for patients with 1-3 tumor-affected axillary lymph nodes if 3 of the 4 following factors are present simultaneously: pT1, G1, ER-positive, HER2-negative. For other patients with 1-3 tumour-infected lymph nodes, the individual indication must be determined on an interdisciplinary basis.
In general, the benefit of chest wall radiotherapy in patients with a high risk of locoregional relapse is assured and is recommended internationally in this situation. For patients with pN1 (1-3 LC) and intermediate risk, radiotherapy may have a survival benefit. For patients with pN0 and intermediate risk, the indication for radiotherapy after mastectomy is not secured due to pending data.
After primary (neoadjuvant) systemic therapy, the indication for radiotherapy of the chest wall, possibly including locoregional lymph drainage areas, continues to be based on the pre-therapeutic T-N category due to the lack of available RCTs, regardless of the extent of response to primary systemic therapy. In analogy to adjuvant radiotherapy after mastectomy, the indication for radiotherapy after neoadjuvant chemotherapy is also given in the case of histopathologically confirmed full remission (ypT0), although prospectively randomized phase III studies that could support this recommendation are currently lacking.
Postmastectomy radiotherapy after primary systemic therapy
After primary (neoadjuvant) systemic therapy, the indication for postmastectomy radiotherapy should be based on the pretherapeutic clinical stage; for pCR (ypT0 and ypN0), the indication should be determined in the interdisciplinary tumour board depending on the risk profile.
Background 4.92
The neoadjuvant systemic therapy aims to bring the tumour into remission. The degree of remission is on the one hand associated with the prognosis of the disease, on the other hand it could also have an influence on the local therapy [565]. The significance of adjuvant radiotherapy of the chest wall and the lymphatic outflow pathways within the neoadjuvant therapy concept is not clarified by evidence from randomized studies [673]. Data from retrospective observational studies mainly refer to the indication for postmastectomy radiation.
Under the hypothesis that the combination of all therapy modalities contributes to the survival benefit, the order in which the therapies are administered should be irrelevant. This would speak for the indication for radiotherapy after the initial stage [674], [675], [676]. In view of the lack of randomized studies on this question, this will continue to be the standard, especially for high-risk patients. This is especially true for patients who have not achieved pathologically complete remission in the breast or axilla [677].
On the other hand the histopathologically proven complete remission after neoadjuvant therapy is a strong prognostic factor independent of the primary tumor biology. In cases of a pathologically complete remission in the tumor area as in the axilla, it seems obvious to reduce the extent of local adjuvant radiotherapy [678], [679]. However, data of randomized clinical studies are missing.
The indication for radiotherapy after neoadjuvant therapy is complicated by the fact that following national and international therapy recommendations the excision of the sentinel lymph node is preferred after neoadjuvant therapy [680], [681]. The pre-therapeutic information on axillary lymph node infiltratrion is lost in some cases. However, this concerns only a very small group of patients, because in the case of suspicious pretherapeutic findings the diagnosis should be histologically confirmed [680], [681]. A potential undertherapy would only exist in patients with mastectomy who had three or more clinically occult lymph node metastases, but which were no longer detectable in the posttherapeutic sentinel excision.
Breast-conserving therapy: Regardless of the response to neoadjuvant chemotherapy, radiotherapy of the breast within the framework of breast-conserving therapy is generally indicated [682].
Complete remission: In pathologically proven complete remission (ypT0/is ypN0), most patients undergo breast-conserving surgery. The indication for radiotherapy of the lymph drainage system is under discussion. Arguments for irradiation of the lymphatic drainage system are preoperative nodal status (≥ 3 lymph nodes), estrogen receptor status (ER-negative), grading (G3), tumor size (T3), age (
A rule of thumb could be [663], [682], [683]:
1. in pathologically complete remission of primarily clinically positive lymph nodes (generally histologically confirmed by needle biopsy), radiotherapy of the lymphatic outflow pathways can be limited to the high-risk cases according to current guidelines (see footnote 4).
2. in patients with pathologically complete remission (ypT0/is ypN0) with primarily clinically negative lymph nodes, radiotherapy should be performed within the framework of BET as in the situation without neoadjuvant therapy (radiotherapy of the breast with standard tangent). This would correspond to the procedure of the ACOSOG Z0011 study [412].
3. no recommendation can be made for the rare situations in which a mastectomy has been performed and primarily no high-risk situation was present, but only the suspicion (cN1) or possibility (cN0) of axillary lymph node metastases.
No remission (non-pCR): It is generally agreed that there is an increased risk of relapse in the absence of remission of the primary tumor or axillary lymph nodes. The indication for postoperative radiotherapy (radiotherapy of the lymphatic outflow pathways and - in case of mastectomy - also of the chest wall) should be determined after the stage before the start of therapy and adapted to the current tumor development if necessary [663].
In inflammatory breast carcinoma (IBC) and primarily inoperable breast carcinoma the therapy concept basically consists of primary systemic therapy, mastectomy and radiation; a reduction of this concept is associated with a shorter mean survival time [684], [685]. Postoperative radiotherapy (PMRT) must therefore be considered obligatory. Radiotherapy of the lymphatic outflow pathways in inflammatory breast carcinoma should be based on the original tumor stage.
In any case the indication and the radiation field should be discussed interdisciplinary and should be determined bindingly for all treatment partners.
Table 5: Indication algorithm for radiation therapy after neoadjuvant therapy
| Pretherapeutic | Posttherapeutic | RT-BET¹ | PMRT² | RT-LAW³ |
| Locally advanced | pCR / no pCR | yes | yes | yes |
| cT1/2 cN1+ | ypT1+ or ypN1+ (no pCR) | yes | yes | yes |
| cT1/2 cN1+ | ypT0/is ypN0 | yes | At-risk cases⁴ | |
| cT1/2 cN0 (Sonogr. obligato) | ypT0/is ypN0 | yes | no | no |
|
1 with classic tangent, 2 if a mastectomy was performed, 3 together with PMRT or RT because of BET 4 criteria for high risk of relapse: - pN0 premenopausal, high risk: central or medial seat, and (G2-3 and ER/PgR negative) - pN1a high risk: central or medial seat and (G2-3 or ER/PgR negative) or premenopausal, lateral seat and (G2-3 or ER/PgR negative) |
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Radiotherapy of the regional lymph nodes
Irradiation of the supra-/infraclavicular lymph nodes
Irradiation of the supra-/infraclavicular lymph nodes can be performed in patients with pN0 or pN1mi in the following situation, provided that the following conditions are all met Premenopausal and central or medial seat and G2-3 and ER/PgR negative.
Irradiation of supra-/infraclavicular lymph nodes should be performed in patients with 1-3 affected lymph nodes in the following situations:
- central or medial seat and (G2-3 or ER/PgR negative)
- premenopausal, lateral seat and (G2-3 or ER/PgR negative)
Irradiation of supra-/infraclavicular lymph nodes should generally be performed in patients with > 3 affected axillary lymph nodes.
Irradiation of the A. mammaria interna lymph nodes
Irradiation of the A. mammaria internal lymph nodes can be performed in axillary pN0 or axillary pN1mi patients in the following situation:
- Premenopausal and central or medial seat and G2-3 and ER/PgR negative
Irradiation of the A. mammaria interna lymph nodes should be performed in patients with 1-3 affected lymph nodes in the following situations:
- central or medial seat and (G2-3 or ER/PgR negative)
- premenopausal, lateral seat and (G2-3 or ER/PgR negative)
Irradiation of the A. mammaria interna lymph nodes should be performed in patients with > 3 affected axillary lymph nodes in the following situation:
- G2-3 or ER/PgR negative
If there is evidence of infestation of the A. mammaria interna lymph nodes, these should be irradiated.
Irradiation of the A. mammaria interna lymph nodes should be decided individually and interdisciplinarily in case of increased cardiac risk or therapy with trastuzumab.
Background 4.93 to 4.101
Adjuvant radiotherapy of supra- and infraclavicular and parasternal lymph nodes was investigated in 3 large randomized studies [595], [597], [686] and a population-based cohort study [596], [687] in more than 10,000 patients. In a meta-analysis of the 3 randomized studies, a consistent, statistically significant survival advantage for irradiation [687] was demonstrated, which is also supported by the Danish cohort study [596]. The improvement in survival results from a reduced remote metastasis rate (HR = 0.84). The absolute survival advantage is 2-3% on average of all included patients after 10 years. In patients who received both chemotherapy and hormone therapy, the survival advantage was significantly higher in the EORTC study [595]. In the Canadian study [597], patients with hormone receptor negative tumors benefited the most from lymph drainage irradiation. In both studies the supra- and infraclavicular as well as parasternal lymph nodes were irradiated either together or both regions were not irradiated. In contrast, irradiation of the breast/breast wall was performed in all patients. In the French study [686] an advantage could only be shown for the subgroup of patients who also received adjuvant chemotherapy. In the Danish cohort study, the greatest benefit was found in the group of premenopausal patients and those with > 3 affected axillary lymph nodes. In the latter two studies, supra- and infraclavicular lymph drainage was irradiated in all patients and only the additional effect of irradiating parasternal lymph drainage was investigated. Although the patients included and the subgroups analysed were different in the studies, the results of all studies indicate that patients with an increased risk of distant metastasis have the greatest benefit from lymph drainage irradiation. As HER2 status is not available in any of the trials, no conclusions can be drawn in this respect.
Fears that lymph drainage irradiations more frequently lead to more late effects for the patients due to the significantly more extensive irradiation volumes have not been confirmed. Although a significantly increased rate of low-grade radiogenic pneumonitis (grade I-II) was reported [595], [597], but not for higher-grade pneumonitis. In the Canadian study [597], lymphatic drainage irradiation led to a 4% higher probability of grade II and III lymphedema of the arm (p 10 years). Studies [595], [686] have not observed an increased rate of cardiac late sequelae due to lymphatic drainage irradiation. Whether the irradiation of the parasternal lymph nodes after more than 10 years still induces a higher cardiac toxicity or whether more secondary tumors are induced by the higher load on the lungs cannot be conclusively assessed at present.
In the EORTC [595] and the French study [686], patients without axillary lymph node involvement could be treated with central or medial tumor site, and in the Canadian study [597] with an increased risk of relapse regardless of the location (>/= 5 cm tumor, >/= 2 cm tumor and
In the case of nodal-positive breast carcinomas, the advantage of additional lymph drainage radiation is not generally greater than in nodal-negative patients, but due to the higher number of cases, it is statistically more reliable. Especially in the Danish study [596], patients with > 3 affected axillary lymph nodes benefited significantly from lymph drainage radiation, whereas in 1-3 affected lymph nodes a clinically relevant advantage of lymph drainage radiation results only in premenopausal patients and higher grading (G2-3) [687]. The indications for irradiation of the mammary internal lymph nodes differ from those of supra/infraclavicular lymph drainage only in so far that in case of proven lymph node infestation the mammary internal lymph nodes should be irradiated independently of other risk factors, predominantly based on the results of the Danish study [596]. The importance of irradiation of only the mammaria internal lymph nodes without additional irradiation of the supra/infraclavicular lymph nodes was not investigated in any study and therefore no recommendation could be made in this respect.
In summary, the benefit of lymph drainage radiation in patients with an increased risk of relapse clearly outweighs the risks. Since the currently available study results do not allow a good differentiation between the benefits of irradiation of the supra- and infraclavicular lymph nodes and the benefits of irradiation of the parasternal lymph nodes, the indication for lymph drainage irradiation was largely seen as a package in the statements of the guideline. Isolated irradiation of the supra- and infraclavicular lymph nodes is only recommended for a smaller proportion of patients, especially those with previous cardiac diseases and with additional adjuvant therapy with trastuzumab. If the radiation of the parasternal lymph nodes exceeds the typical dose loads on the heart and lungs [692], [693], which can be a problem especially with left-sided tumors, the benefits and risks of radiation therapy must be weighed individually and a waiver of parasternal radiation is a sensible option in these cases. In these cases a radiation with held breath in deep inspiration can often reduce the dose to heart and lungs in such a way that a low-risk radiation of the parasternal lymph nodes is possible after all [694].
Whether irradiation of the supra- and infraclavicular lymph nodes alone without irradiation of the parasternal lymph nodes in addition to irradiation of the breast/breast wall leads to a survival advantage cannot be answered from randomized studies. However, in more than 3 affected axillary lymph nodes, the relapse rate in the supraclavicular lymph nodes is so high (approx. 17% [688]) that irradiation of the supra- and infraclavicular lymph nodes is indicated for this reason alone. In patients with 1-3 affected axillary lymph nodes with additional risk factors, the supraclavicular relapse rate without radiotherapy is 9.6% (G2 with 2 positive lymph nodes or G3 with 1 positive lymph node) and 21% (G3 with 2-3 positive lymph nodes or G2 with 3 positive lymph nodes), respectively, and is also so high that irradiation of the supra- and infraclavicular lymph nodes alone is also indicated [689].
Irradiation of the axillary lymph nodes
Also recommendation level 0
An extended axillary irradiation can be performed in patients with 1-2 affected axillary sentinel lymph nodes, provided that no axillary dissection has been performed or no further local axillary therapy has been agreed upon (analogous to ACOSOG Z0011). The decision on the appropriate procedure should be made on an interdisciplinary basis.
Background 4,102
All irradiation techniques used for homogeneous irradiation of the entire breast lead to co-irradiation of parts of the ipsilateral axillary lymph drainage area. The amount of this portion and the doses achieved there differ depending on the volume of the breast to be irradiated in Levels I and II and also depend on the individual positioning of the patient during the radiation treatment. The total doses resulting in these axilla portions are between 20 - 40 Gy for a standard 50 Gy CT of the entire breast and thus influence the rate of axillary recurrence [698].
If irradiation of supra- and infraclavicular lymph nodes is performed, according to the current recommendations of ESTRO and RTOG the axillary lymph node level III is included in the clinical target volume [699], [700] and the irradiation technique is chosen in such a way that there is no gap between the target volume for lymph drainage and the target volume for the breast/breast wall. Because of the positioning uncertainties in the shoulder region, a safety margin is added around the clinical target volumes to generate the planning target volumes. This ensures that the medial portion of Level II in particular is irradiated with the full dose. Consequently, in radiation therapy of the supra- and infraclavicular lymph nodes and the entire breast/breast wall, only the cranial portions of Level I and the lateral portions of Level II are not irradiated with the full dose. Radiation of the axilla is usually understood by the radiooncologist as an expansion of the target volume to include the lateral portions of level II and the cranial portion of level I according to the expansion in the ESTRO consensus [700].
Irradiation of the entire axilla, also called "extended axillary irradiation" in the statements, is only sensible if there is a high risk of infestation of these regions and no surgical removal has been performed. In the AMAROS study [695], patients were randomized to receive either axillary radiotherapy (50 Gy in 25 fractions in 5 weeks) or dissection of the axillary lymph nodes prior to axillary sentinel lymph node biopsy in the case of axillary lymph node involvement (n =1425). The majority of the included patients had 1-2 positive sentinel lymph nodes. The axillary relapse rate, DFS and overall survival after 5 and 10 years did not differ statistically and clinically significantly in both arms. The rate of arm edema of all degrees was significantly higher after axillary dissection (23% after 5 years) than after axillary radiotherapy (11% after 5 years).
In the Z0011 study [406], after breast-conserving surgery with 1-2 positive sentinel lymph nodes, either an axillary dissection was randomized to receive an axillary dissection or no targeted axillary therapy was performed. According to the protocol, irradiation of the breast was planned for all patients. Overall survival and DFS in the 856 evaluable patients were not significantly different after 5 years (p=0.24/p=0.14). According to this, a further axillary therapy can be dispensed with in 1-2 affected sentinel lymph nodes. However, the study shows a number of weaknesses: The study was closed prematurely before the planned number of patients was reached; 38% of the patients had only micrometastases; and the irradiation techniques were only examined in a subgroup of 228 patients. Of these 228 patients, about 50% had a so-called high tangent to the radiation of the breast and another about 17% had radiation of the entire axilla, i.e. a considerable proportion of the patients had received partial or complete radiation of the axilla [697]. Consequently, there remains an uncertainty as to which patients with positive sentinel lymph nodes can be spared further axillary therapy by dissection or radiation therapy without risk. If more than 2 sentinel lymph nodes are affected and the axilla is not dissected, extended axillary irradiation is clearly recommended. In 1-2 affected lymph nodes, the indication must be discussed in the interdisciplinary tumor board. If only micrometastases are present, further axillary therapy is not necessary. Since caked lymph nodes or lymph nodes with massive extracapsular tumor growth (ECE) were an exclusion criterion for treatment in the Z0011 study, the further procedure should also be coordinated interdisciplinarily in these cases. Although ECE is an independent negative prognostic factor for DFS and overall survival [701], the axillary relapse rate after axillary dissection without radiotherapy is low [696] and does not represent an indication for extended axillary radiotherapy. In the AMAROS study, ECE was not an exclusion criterion, although the results for patients with ECE were not reported separately. If there is no axillary dissection [702], extended axillary radiotherapy may be considered in these cases. Radiation therapy is to be considered if a residual tumor is detected in the axilla.
Dose and fractionation for irradiation of the regional lymph drainage
Radiotherapy of lymphatic drainage should be performed in conventional fractionation (1.8 Gy to 2.0 Gy 5 times a week, total dose approx. 50 Gy in approx. 5-6 weeks) or can be performed in hypofractionation (total dose approx. 40 Gy in approx. 15-16 fractions in approx. 3 to 5 weeks).
- Consensus
- Strong consensus
Background 4,103
All studies on irradiation of the lymphatic drainage system were carried out in conventional fractionation with 5x2 Gy per week up to a total dose of 50 Gy. In the studies on hypofractionated radiotherapy of the breast or breast wall, less than
Radiotherapy for locally advanced tumours and primary inoperability
Patients with primarily inoperable or inflammatory carcinomas should receive primary systemic therapy followed by surgery and postoperative radiotherapy, or if inoperability of sole or preoperative radiotherapy persists.
Background 4,104
Locally advanced breast cancer (LABC) describes a group of tumors that combine two criteria: 1. primary resection is not possible or is not considered appropriate. 2. neoadjuvant therapy is primarily considered.
Hagensen and Stout first coined the term "locally advanced breast cancer" in 1943 and established diagnostic criteria which today roughly correspond to stages IIIA and B: Lymphedema of the skin, satellite lesions, inflammatory carcinoma, non-mobilizable lymph node metastases. In practice, the following criteria, of which at least one must be fulfilled, have become established for the definition of "locally advanced": tumours > 5 cm (T3), skin or chest wall infiltrations (T4a, T4b), inflammatory carcinomas (T4c), fixed axillary lymph node conglomerates (cN2) or infraclavicular lymph node metastases (cN3). The term "inflammatory carcinoma" also has a vague definition. It is a clinical-pathological entity in which there is a tumor-associated inflammation of at least part of the skin with the classic sign of inflammation.
The initiation of primary systemic therapy is considered the standard of care for patients with locally advanced breast cancer and inflammatory carcinoma as well as for patients with distant metastases. The response to neoadjuvant chemotherapy (NAC), in particular the achievement of pathological complete remission (pCR), has been shown to be a favourable prognostic marker associated with improved survival. Randomized clinical studies focused on the further development of effective systemic therapies, with radiotherapy usually being an integral part of these studies, as its importance for locoregional tumor control was undisputed. Here, the scientific field has changed to the extent that the significance of radiotherapy in the case of complete remission after mastectomy is being questioned.
The neoadjuvant therapy concept with systemic therapy for LABC used today was first described in the late 1970s by De Lena [705]. By neoadjuvant chemotherapy often a reduction of tumor size and inflammatory components could be achieved. Furthermore, a down-staging of the axillary lymph node involvement and thus a secondary surgical therapy could be enabled. Neoadjuvant therapy concepts with a multimodal approach have therefore long been accepted as standard treatment for primarily inoperable LABC. If no invasive and non-invasive tumour cells are detectable in breast tissue and axillary lymph nodes after neoadjuvant therapy, this is referred to as pathologically complete remission (pCR). In the NSABP-18 study as well as in other studies, a close correlation was found between the response of the primary tumour and the long-term prognosis. Patients who had a histopathological complete remission (pCR) had a significantly better disease-free survival than patients with only partial remission. This led to the fact that pCR serves as an early surrogate marker for survival and therefore different neoadjuvant therapy regimes can be compared against each other.
Careful examination of the local tumor extent with lymph node determination as well as good staging examinations are essential for the determination of the therapeutic concept, since the pre-therapeutic disease extent influences the type of surgery and the radiotherapy.
In 1971, EORTC's phase III study for the treatment of locally advanced and inflammatory breast cancer was published. A total of 410 patients were randomized to receive either radiotherapy alone, radiotherapy plus chemotherapy (CMF), radiotherapy combined with tamoxifen, or radiotherapy combined with tamoxifen and CMF. The surgery was not a planned part of the treatment sequence, but was reserved as a "salvage measure" in case of local recurrence. With radiotherapy alone, a 10-year overall survival of 13% and a distant metastasis-free survival of 15% was achieved, which was considered an indication of curative potential. As expected, the addition of chemo- or hormone therapy led to a significant increase in the time to local recurrence, to distant metastasis or to an improvement in overall survival. With the combination treatment the greatest therapeutic effect could be achieved. The 10-year overall survival could be improved by 8-15% by the addition of the systemic therapy.
In the following years, the systemic therapy could be improved by the addition of anthracyclines and taxanes within the framework of corresponding studies, with a gradual improvement in 5-year overall survival for LABC of approx. 70% and 40% for inflammatory breast carcinomas, respectively. Irradiation after mastectomy (in case of resectability) after neoadjuvant chemotherapy was performed in the majority of patients. Here, too, it was shown that patients with pCR during mastectomy had substantially better overall survival than patients with partial response or residual tumour. This supported the use of the pCR rate as a surrogate marker of overall survival for future treatment concepts. However, the subgroup analyses also showed that the pCR rate was determined to a greater extent by the biology of the tumours than by the chosen chemotherapy regimen.
Regardless of the response to the neoadjuvant therapy, the question arose to what extent additional local treatments would improve the results. Randomized studies on the necessity of surgery and radiotherapy in this situation are not available. Radiation therapy is usually recommended for persistent resectability after NAC. Resectability should then be re-examined approximately 6-12 weeks after completion of irradiation.
In stage III patients with resectable tumors after neoadjuvant chemotherapy (NAC), the effect of surgery and radiotherapy was investigated in three small randomized trials. Patients undergoing neoadjuvant chemotherapy (in two studies with anthracyclines, in one study with CMF) were randomized to undergo either mastectomy or radiotherapy. Overall survival, disease-free survival and locoregional tumour control were comparable between both local therapies. However, the local relapse rate after 2-5 years was in the order of 40-60%, regardless of whether surgery or radiation was performed. Finally, an indirect indication that patients should be operated and irradiated in order to reduce the local recurrence rates. In none of these studies was the response rate after neoadjuvant therapy documented. In this respect, the question remains open as to the extent to which surgery and radiation therapy are required after complete remission after neoadjuvant chemotherapy.
The challenge for radiotherapy lies in the decision which patients after NAC followed by mastectomy will benefit from post-mastectomy radiotherapy (PMRT). Ultimately, this decision is subject to numerous (additional) influences. At present, the current data situation tends to favour an extension of the indication for PMRT to nodal positive carcinomas with low lymph node involvement (1-3 positive lymph nodes). The addition of different systemic therapies has increased the rate of patients with complete remission after NAC. It could be shown that a ypN0 status after neoadjuvant chemotherapy was associated with a low risk of locoregional recurrence, even without the use of PMRT.
The role of PMRT was finally substantiated in the two large studies of the Danish Breast Cooperative Group (DBCG) and the so-called British Columbia Trial. In the DBCG study 82 b and c [667], [668] as well as in the so-called British Columbia Clinical Trail [706], more than 3500 women were randomized in the period 1979-1990, either in favor of PMRT or only follow-up after surgery and systemic therapy. Systemic therapy in these studies included either CMF or Tamoxifen. More than 90% of these patients in these studies had positive lymph node metastases (pN+). These studies showed a substantial decrease in the long-term locoregional recurrence rate, which was also reflected in improved breast cancer-specific and overall survival. Based on these results, PMRT is ultimately recommended without restriction for patients with ≥ 4 pathologically affected lymph nodes or patients in stage III.
Two smaller studies investigated the significance of surgery after radiotherapy (after neoadjuvant chemotherapy):
Merajver et al. [707] initially treated 90 patients in stage III with 9 cycles of an anthracycline-containing neoadjuvant chemotherapy. After the last cycle the initial tumor region was biopsied again. In case of complete remission patients received radiotherapy of the thoracic wall and regional lymph node stations without surgery. Patients with residual tumor as part of the biopsy received a mastectomy followed by radiotherapy at the same dosage. Renouncing surgery in patients with pCR was not associated with a higher local recurrence rate, which was about 20% after five years of follow-up.
Ring et al [708] (n=136) and Daveau et al [709] (n=165) extracted from their prospective data collections the treatment results of stage III patients with complete remission after neoadjuvant chemotherapy who had received radiotherapy but no surgery. These were compared to patients with pCR after chemotherapy, who had received a mastectomy including postoperative radiation. The treatment results regarding overall survival, disease-free survival and distant metastasis-free survival were almost identical. A trend towards improved locoregional tumor control was observed in patients who received both surgery and radiation. Even in the absence of evidence, surgery is ultimately recommended after neoadjuvant systemic therapy regardless of response, if complete resection seems possible.
The determination of the type of surgical procedure following neoadjuvant chemotherapy (NAC) is complex and not standardised. There are no defined criteria according to which breast-conserving therapy (BET) may/can be sought for patients after NAC and for which a mastectomy offers more safety. Due to the high local recurrence rate, mastectomy with axilla clearance is generally recommended for primarily inoperable LABC and inflammatory tumours, even if good remission is achieved after preoperative therapy. In the case of "large operable" tumours, the primary goal is to operate in a breast-conserving manner. The pattern of tumour reduction also influences the further surgical procedure. If there is concentric shrinkage to a single tumour node, it may also be possible to remove it completely by BET.
There are two retrospective studies on the extent to which radiotherapy is required after mastectomy, especially in cases of complete pathological remission:
Huang et al. [710] examined the clinical outcome of 670 breast cancer patients who had received six different neoadjuvant chemotherapy regimens in clinical trials after mastectomy and axilla dissection. Of these patients, 134 did not receive PMRT, while 542 patients received radiotherapy after mastectomy. The patients had been treated between 1974 and 2000, with a median follow-up of 69 months. As expected, a selection bias was found in the non-randomised comparison, with significantly higher T and N stages among the patients who were irradiated: In the PMRT cohort 83% of the women represented stage III (-IV) compared to only 50% in the cohort that did not receive irradiation. The pCR rate after neoadjuvant chemotherapy was 14% in the PMRT arm versus 6% without irradiation. Overall, the 10-year local recurrence rate was 11% for women receiving PMRT versus 22% without radiation (p=0.0001) and overall survival was also better with radiation therapy. In a subgroup of 46 patients in clinical stage III (-IV) (35 received PMRT, 11 were not irradiated), who each achieved complete remission after neoadjuvant chemotherapy, the 10-year local recurrence rate was 3% with radiotherapy (PMRT) compared to 33% without PMRT (p=0.0006).
In the multivariate analysis regarding the factors associated with local recurrence, the most significant factor was found to be the decision not to undergo postmastectomy radiotherapy (PMRT) (HR 4.7; 95% CI: 2.7-8.1). Other factors were ≥ 20% pathological lymph nodes involved according to NICE, clinical stage ≥ I IIB, no tamoxifen, and hormone receptor negative status. Overall cancer-specific survival after 10 years was comparable in both treatment groups: 58% versus 55%. However, the univariate analysis showed an improvement in disease-specific survival for the subgroup of patients with PMRT, including those with clinical stage ≥ IIIB, cN2-N3 status and stage ≥ IV pathological lymph nodes.
In another publication McGuire et al. [674] identified 106 patients in stage II-III who had been treated with neoadjuvant chemotherapy (92% anthracycline-based chemotherapy, 38% with taxanes) and mastectomy between 1982 and 2002 and who had pCR at the time of surgery. Of these, 34 patients received PMRT, compared to 72 patients who did not receive radiation. Overall, the 10-year local recurrence rate did not differ between the PMRT and non-PMRT group (5% versus 10%, p=0.4), probably most influenced by the 0% 10-year recurrence rate of the 32 patients in clinical stage I-II. In contrast, PMRT led to a significant decrease in the 10-year local recurrence rate for the 74 patients in stage III (7% versus 33%, p=0.04). Overall survival was also significantly improved for stage III patients who received PMRT (77.3% vs. 33.3%, p=0.002). Consequently, the authors concluded that PMRT should be performed in stage III patients who had achieved complete pathologic remission after neoadjuvant chemotherapy.
From this database, further specific subgroups were retrospectively analysed. Garg et al. [711] analysed the effect of radiotherapy on 107 younger patients (younger than 35 years) in stage IIA-IIIC treated with neoadjuvant chemotherapy and mastectomy with PMRT (n = 80) or without PMRT (n = 20) in the period 1975 to 2005. 84% of stage III patients received PMRT compared to 42% who did not receive any. The pCR rate was 19% in the PMRT group versus 1% in the non-irradiated group. As documented in the preliminary analysis (Huang et al.), PMRT significantly improved locoregional control (88% versus 63%) and overall survival (67% versus 48%) in this subgroup of young patients.
Nagar et al. [675] reported on 162 women in clinical stage T3 N0 treated from 1985-2004 after neoadjuvant chemotherapy followed by mastectomy and PMRT (n =119) or no PMRT (n = 43). The 5-year local recurrence rate was 9%, but was significantly higher in patients who had not received PMRT (24% versus 4%, p
In summary, these study results show that women in clinically advanced stage III (especially those with cN2-N3 involvement and with ypN+ lymph nodes that were still affected at the time of surgery) are at the highest local recurrence risk after neoadjuvant chemotherapy and mastectomy. The risk of local recurrence seems to be significantly lower for patients in clinical T3N0 stage, especially with a ypN0 status at the time of surgery.
Locoregional irradiation in patients with synchronous metastasis
Locoregional irradiation is currently being investigated in the oligometastasis concept together with other tumor entities in various ongoing studies, without any reliable results so far. Radiation therapy can certainly contribute to symptom relief, but the influence on survival is inconsistent in the retrospective data. Some retrospective analyses document improved survival for both surgery and radiotherapy, but in some cases there is no influence from local therapy.
By Badwe et al. [712] the data of the randomized study from India were finally published in 2015. Untreated patients with "de novo" metastasis were randomized to surgical local therapy followed by radiation (n =173) vs. no local therapy (n =177) or chemo-/hormone therapy alone [712]. Median overall survival was 19.2 months with local therapy vs. 20.5 months without local therapy (p = 0.79). Therefore, local therapy is not recommended as standard for initial metastasis. However, this negative result does not exclude a possible benefit for subgroups. A second randomized study on the same issue was initiated in Turkey. Results have so far only been published in abstract form at congresses. For the endpoint overall survival no benefit for local therapy was seen in this data collective: after 54 months 35% with local therapy vs. 31% without local therapy. However, subgroup analyses (HR+, patients
Therapy sequence of adjuvant systemic therapy and radiotherapy
Postoperative chemotherapy and radiotherapy should be sequential.
Note: the superiority of a specific sequence (first chemotherapy or first radiotherapy) is not proven. In clinical practice, the sequence of chemotherapy followed by radiotherapy has become established.
Adjuvant endocrine therapy can be initiated independently of radiotherapy. (1a)
A therapy with trastuzumab can be continued during radiotherapy. In the case of simultaneous A. mammaria lymph node irradiation, the procedure should be determined on an interdisciplinary basis. (4)
Background 4.105 to 4.107
So far, there is no evidence that a specific sequence of radiotherapy and drug therapy is clearly superior in the adjuvant situation. In principle, both drug therapy and radiotherapy should be started as early as possible and not unnecessarily delayed [677], [720], [721].
Antihormonal therapy can be carried out independently of radiotherapy (even simultaneously); this has now been proven by randomized studies [719], [722], [723], [724], [725], [726]. If only endocrine therapy (without chemotherapy) and radiotherapy are indicated, radiotherapy should therefore normally be started within 4 to 6 weeks after surgery; anti-hormonal therapy can be started before, during or even shortly after radiotherapy. A delayed start of radiotherapy (time interval between surgery and the start of radiotherapy 8 - 12 weeks) may not be disadvantageous; in the case of justified delays (e.g. intercurrent diseases) a longer time interval can be accepted. However, unnecessary delays should be avoided.
A sequential approach is recommended for the combination of chemotherapy and radiotherapy (first chemotherapy, then radiotherapy or vice versa); randomized studies and meta-analyses showed no advantage for a specific temporal sequence [713], [714], [715], [716]. The sequence of the therapeutic procedures should take into account the dominant individual risk of recurrence (systemic or locoregional) and be determined on an interdisciplinary basis. In most cases chemotherapy is performed first and then (usually within 2 to 4 weeks after the last course of chemotherapy) radiation therapy is followed by [727]. This is particularly useful for patients with a high systemic risk of relapse. In the case of very long adjuvant therapy regimens, this can result in a time interval of about 6 months up to a maximum between surgery and the start of radiotherapy. Fears that this long delay in radiotherapy (which is considered to be clearly disadvantageous in the case of radiotherapy alone without chemotherapy) could be associated with a reduced effect of radiotherapy and an increased locoregional relapse rate have not been confirmed. However, if the planned chemotherapy cannot be started postoperatively within the usual time frame for individual reasons, radiotherapy should be brought forward if necessary. This should be discussed in particular when using hypofractioned radiotherapy regimens.
A therapy with targeted drugs for HER2-positive tumours can be continued during radiotherapy. All studies show no increased toxicity or increased rate of cardiac events, not even with left-sided radiotherapy [728]. However, there is very little data concerning the combination of trastuzumab and simultaneous radiotherapy of the left parasternal lymph nodes; in these cases indication and therapy sequence should be determined interdisciplinary.
4.7 Systemic adjuvant therapy (endocrine, chemo-, antibody therapy)
4.7.1 Selection of adjuvant therapy and risk assessment
The recommendations for adjuvant therapy of breast cancer consider tumor size, lymph node status, grading, hormone receptor status, HER2 status, menopause status and age as the most important factors in deciding on the necessity and type of adjuvant therapy [367], [529].
The St. Gallen recommendations of 2009 point to endocrine sensitivity and the recommendations of 2011 to molecular subtypes as decisive criteria for the indication of adjuvant chemotherapy [529]. The immunohistochemically determined markers ER, PgR, HER2 and Ki-67 [529] are considered as surrogate parameters for the molecular subtypes. ER- and/or PgR-positive, HER2-negative tumours with a low proliferation rate are considered to be Luminal A, while Luminal B is these tumours with a high proliferation rate. It must be taken into account that there is no validated threshold value for Ki-67 (e.g. for the classification of Luminal A vs. B or for the decision for/against adjuvant chemotherapy).
Indications for adjuvant chemotherapy are
- In HER2-positive tumors, simultaneous anti-HER2 therapy with trastuzumab for 1 year in combination with (neo)adjuvant chemotherapy is standard
- for endocrine non-sensitive tumours (ER- and PgR-negative)
- for endocrine sensitive tumours
- in the case of nodal-positive tumours (studies are currently evaluating whether adjuvant chemotherapy can be dispensed with in patients with low nodal infestation (1-3 affected LK) and favourable tumour biology (Luminal A))
- G 3
- young age of disease (
Chemotherapy is always indicated when the individual expected benefit is higher than possible side effects and late damage. This requires a differentiated education of the patients, especially if the expected benefit is only small.
4.7.2 Endocrine therapy
Indications for endocrine therapy
Patients with estrogen- and/or progesterone receptor-positive (°) invasive tumors should receive endocrine therapy.
° (>/=10% progesterone receptor-positive tumor cell nuclei)
This should not be started until after completion of chemotherapy, but can be done in parallel with radiotherapy.
Background 4,108 and 4,109
Adjuvant endocrine therapies such as tamoxifen and aromatase inhibitors significantly reduce the probability of a relapse by about 40% and the probability of death by about 30% [234], [367], [730], [733].
This relative risk reduction is independent of the age of the patient, the tumor stage and the pre-therapy like adjuvant chemotherapy, but always refers to women with hormone receptor-positive breast cancer.
These favorable effects of endocrine therapy are only realized with sufficient adherence to therapy. But only about half of the women with breast cancer carry out this treatment over the recommended 5 years. This lack of compliance is associated with a significantly increased risk of death. It is important to convince patients of the necessity of therapy, to raise awareness of side effects and of symptoms that occur independent of therapy by means of careful anamnesis and to treat them adequately. In the case of serious side effects that jeopardise the adherence to therapy, a switch from aromatase inhibitors to tamoxifen and vice versa or between aromatase inhibitors (steroidal vs. non-steroidal) can be considered in postmenopausal patients. If these measures succeed in increasing adherence to therapy, this may save more lives than additional chemotherapy.
In some analyses ([734] N=251) the group of patients with a weakly ER-positive breast carcinoma (1-9% stained tumor cell nuclei) behaves prognostically more like receptor-negative patients and shows (examined on smaller numbers of patients, N=26) similar molecular characteristics to triple-negative breast carcinomas on [473], [474]. In a study of 314 patients with a low ER staining (1-9%), they showed a similar frequency of BRCA-1 mutations as ER-negative patients [476].
Since this group of patients (1-9% positive ER) obviously behaves prognostically differently than those with an ER-positivity of > 10% [735], an additional adjuvant or neoadjuvant chemotherapy should be considered.
Carcinomas with a weak PR staining (<10%) und negativen ER-Färbung könnten molekular dem triple-negativen Mammakarzinom entsprechen [736], [737]. Diese Daten werden unterstützt durch die EBCTCG-Analyse von 2008 “Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer”, in der nachgewiesen wurde, dass Tamoxifen nur einen geringen Effekt auf die Rezidivrate und das Überleben bei Patientinnen mit einer schwachen Östrogenrezeptor-Expression hatte und einen nur geringen zusätzlichen Effekt zur adjuvanten Chemotherapie.
Data from some studies (such as Tam-02, [738], [739]) indicate that a later start (up to 5 years after completion of local therapy and/or chemotherapy) with adjuvant endocrine therapy is better than dispensing with this endocrine therapy altogether. This later start of endocrine therapy also prolonged DFS and OS or DDFS. The MA.17 study [740], which also allowed a longer therapy-free interval between tamoxifen and letrozole, showed similar results. These are indications that in case of side effects a therapy break is preferable to a general discontinuation.
Endocrine therapy
Also recommendation grade B
After 5 years of tamoxifen, the indication for extended endocrine therapy should be evaluated for each patient with ER+ breast cancer.
Indications should be based on the weighing of the risk of relapse and the therapy-associated side effects (toxicity, reduced adherence).
The current menopausal status of the patient should be taken into account when choosing endocrine therapy.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [741]
Background 4,110
Endocrine adjuvant treatment of early breast cancer is one of the most effective therapeutic options. Recent publications prove this for a time interval of up to 15 years. A distinction was made between initial adjuvant therapy (IAT, years 0-5) and extended adjuvant therapy (EAT: years 6-10).
The therapy-associated side effect rate of these continuous therapies reduces therapy adherence and leads to a loss of effectiveness. Therefore, studies should be conducted to determine whether intermittent adjuvant endocrine therapy could be as effective as EAT.
Currently, there is a lack of reliable diagnostic tools to reliably predict the risk of late metastasis (after year 5) for such an intervention. To this end, multi-gene assays, for example, could be prospectively evaluated in studies.
After 5 years of tamoxifen, a further 5 years of adjuvant tamoxifen reduces the recurrence rate (-2.8% in absolute terms in the ATLAS study) and prolongs overall survival (-2.48% in absolute terms in the ATLAS study, [742], [743], [744]) in patients with hormone receptor-positive breast carcinomas, regardless of menopausal status (however, only 9% of patients in the ATLAS study were premenopausal). The incidence of pulmonary embolism and endometrial carcinoma was significantly increased after 10 years of tamoxifen compared to 5 years of tamoxifen without effect on mortality. Ischemic heart disease and myocardial infarction were significantly less common after 10 years than after 5 years of tamoxifen.
If the patients became postmenopausal after 5 years of adjuvant tamoxifen, the subsequent administration of letrozole for 5 years adjuvant improved DFS and OS, especially in women who were premenopausal before letrozole or had lymph node metastases [740]. Approved for this EAT in Germany after 5 years of tamoxifen are tamoxifen and letrozole.
Therapy for premenopausal patients
Premenopausal patients should be treated with tamoxifen for at least 5 years.
Antiestrogenic therapy with tamoxifen 20 mg per day should be carried out over a period of 5 - 10 years or until relapse, depending on the risk of relapse.
The indication for extended therapy depends on the risk of recurrence and the patient's wishes.
Background 4,111
Extending the administration of tamoxifen from 5 to 10 years will reduce ipsi and contralateral recurrence rates and prolong overall survival in the ATLAS study. However, the rates of pulmonary embolism and endometrial carcinoma are increased without any influence on mortality [742], [743], [744]. The risk-adapted duration of tamoxifen administration (longer administration with increased risk of recurrence) is recommended by ASCO [741].
Endocrine therapy
For patients with an ER+ breast cancer and increased risk, who are still premenopausal after completion of chemotherapy, an aromatase inhibitor can be used to eliminate ovarian function.
- Consensus
- Consent
Ovarian suppression alone can be considered either by administration of GnRHa or by bilateral ovariectomy for premenopausal women with ER+ breast cancer who cannot or do not wish to receive tamoxifen.
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [733]
Ovarian suppression (GnRHa or bilateral ovariectomy) in addition to tamoxifen or an aromatase inhibitor should only be considered in cases of high risk of recurrence and premenopausal situation after adjuvant chemotherapy. If an aromatase inhibitor is used, ovarian suppression should be mandatory.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [733]
Background 4.112 to 4.114
In various studies (e.g. SOFT, TEXT, [746]), the effect of suppressing ovarian function for up to 5 years together with the administration of Exemestan or together with tamoxifen vs. the administration of tamoxifen alone in the adjuvant therapy of women with hormone receptor-positive breast cancer who were premenopausal or became premenopausal again within 8 months after completion of adjuvant chemotherapy. After the individual analysis of each of these studies and after the combined analysis of two of these studies (SOFT, TEXT), an increased effectiveness of the additional elimination of ovarian function was found only in the group of patients under 35 years of age who had a high risk of recurrence (and therefore received chemotherapy). In a meta-analysis of all these studies [747] showed a higher efficacy in terms of DFS, but an increased rate of side effects up to more deaths for the combination of ovarian function suppression with an aromatase inhibitor than for the combination of ovarian function suppression together with tamoxifen. The higher rate of side effects implies a risk of reduced adherence to therapy.
According to the results of various studies (e.g. ZIPP study, [748]) and meta-analyses, the administration of a GnRH analogue is equivalent to the administration of tamoxifen alone, but is associated with an increased rate of side effects and thus a higher discontinuation rate compared to tamoxifen. Although reliable data are lacking, an increased late toxicity (e.g. coronary diseases, osteoporosis, dementia) can also be expected.
Therapy in postmenopausal patients
Adjuvant endocrine therapy for postmenopausal patients with ER+ breast cancer should include an aromatase inhibitor.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [733]
Background 4,115
In the meta-analyses [367], [729], [730], [749], a superiority of the adjuvant administration of aromatase (AI) alone or in sequence with tamoxifen compared to tamoxifen alone in postmenopausal patients with a hormone receptor-positive mammary carcinoma was shown with regard to OS and DFS. In the EBCTCG meta-analysis 2 cohorts were formed:
Cohort 1 as a comparison between 5 years of AI vs. 5 years of tamoxifen and cohort 2 with the administration of AI after 2-3 years of tamoxifen for a total of 5 years. The administration of 5 years of AI after 5 years of tamoxifen was not included in this meta-analysis. Since the analysis only included data up to 2006, the ABCSG 12 studies and the switch arms of the BIG 1-98 study were not included in this meta-analysis. In cohort 1, the significant superiority of AI administration over tamoxifen was demonstrated in terms of DFS but not in terms of mortality. In cohort 2, the significant benefit of additional AI administration was shown in terms of DFS and survival compared to tamoxifen alone.
The administration of the aromatase inhibitor alone over 5 years reduces the recurrence rate particularly effectively in high-risk breast carcinomas and/or lobular invasive breast carcinomas.
If after 5 years of tamoxifen the patient has become postmenopausal and has an increased risk of recurrence, the MA.17 study recommends the administration of letrozole for another 5 years [740]. This procedure is also recommended by ASCO [750] after its meta-analysis of all studies completed by 2013.
At the SABCS 2016 further studies on the prolonged (EAT) administration of an aromatase inhibitor after 5 years were presented, e.g. NSABP B-42 (10 vs. 5 years AI, [751]) or IDEAL trial (5 years AI after 5 years of adjuvant endocrine therapy with tamoxifen and/or AI) [752]. In none of these studies a significant prolongation of survival or a significant reduction of mortality could be shown by this prolonged AI administration, at best a reduction of the ipislateral and contralateral recurrence rate (summary by Gnant 2016). The MA.17R study, which has already been published [753], came to the same results. With younger postmenopausal patients who had already received endocrine therapy with AI in the first 5 years and tolerated it well, an extended endocrine therapy with AI can be discussed under certain circumstances (increased risk of recurrence e.g. with positive nodal status, no osteopenia/osteoporosis) [754].
4.7.3 Adjuvant chemotherapy
An indication for adjuvant chemotherapy should be provided at:
- HER2-positive tumours (from pT1b, N0; pT1a, N0 if further risk: G3, ER/PR neg., Ki-67 high)
- Triple-negative tumors (ER- and PgR-negative, HER2-negative)
- Luminal B tumors with high risk of recurrence (Ki-67 high, G 3, high risk multigene assay, young age, lymph node involvement)
Chemotherapy should be administered in the recommended dosages.
If the cycles are underdosed or reduced, there is a risk of loss of effectiveness.
Administration of the cytostatic drugs
Cytostatic drugs can be administered simultaneously or sequentially (according to evidence-based protocols).
In cases of high tumour-related mortality risk and suitable patients, dose-controlled therapies should be used.
Anthracycline/taxane containing adjuvant standard chemotherapy
Background 4.116 to 4.121
The positive effects of adjuvant chemotherapy on the risk of recurrence and death, as proven by data of the Oxford Review (EBCTCG), are most pronounced in women under 50 years of age. There is also a benefit for postmenopausal women [757].
The data on adjuvant chemotherapy with taxanes is supported by current study results. Especially women with lymph node involvement or with nodal-negative carcinomas and additional risk criteria (e.g. G2/3, ER- and PgR-negative, pT > 2 cm, age
Several effective regimes are available. Against an adequate anthrazylin standard have been tested: FEC x 3 → Doc x 3 (PACS-01), 3 x FEC → 8 x Pac weekly as well as DocAC ( TAC, BCIRG 006) [785]3, [785], [786], [787]. 6 x DocAC and 4 x AC → 4 x Doc are equi-effective but differ in their spectrum of side effects.
In the sequence after 4 x AC, 4 x docetaxel every 3 weeks (100 mg/m2 ) and 12 x paclitaxel weekly (80 mg/m2 ) are to be considered equivalent to [756], [788]. 4 cycles of AC - 4 x paclitaxel q21 ( Henderson-like ) are inferior to 6 x CEF (MA-21 [789]).
The dual combination 4 x DocC (TC) is superior to the old standard 4 x AC with regard to DFS and OS and avoids anthracycline-associated toxicities [756]0, [790].
In general, the administration of a longer adjuvant chemotherapy seems to be advantageous, as the comparison of 4 cycles vs. 8 cycles has shown [763], [779]. Several studies show that 6 cycles of TC are as effective as an anthracycline-taxane sequence therapy for certain patient groups. Whether these current efficacy data for 6 cycles of TC also apply to 4 cycles of TC cannot be decided at present on the basis of the available data. A corresponding reduction in the number of cycles should therefore only be made in the case of intolerable toxicities.
The Danish DBCG-07-READ study in TOPO2A-normal early breast cancer showed no difference in DFS and OS for 6x TC vs. 3x EC - 3x DOC [783]. The WSG-PlanB study also showed no difference between 6x TC and 4x EC - 4x docetaxel for HER2-negative early breast cancer [784]. The pooled analysis of 3 US studies (ABC Trials) could not formally confirm the non-inferiority between 6x TC and an anthracycline-taxane-containing sequence therapy (iDFS HR 1.202; 95% KI 0.97-1.49 with a predefined threshold value of 1.18). However, the absolute difference between the two arms was small (difference 4-year iDFS 2.5%) and subgroup analyses showed that the greatest benefit in favour of anthracycline-taxane-containing sequence therapy was found in [782] when the clinical risk was high (e.g. > 3 affected lymph nodes).
The significance of new substances in adjuvant therapy (e.g. gemcitabine, capecitabine) as the fourth substance in addition to anthracyclines, taxanes and cyclophosphamide cannot yet be conclusively assessed. While the addition of Gemcitabine is not associated with an advantage [791], some data for Capecitabine indicate a trend towards a further improvement of DFS or OS [792], [O'Shaughnessy, J et al. 2010]. However, this improvement was associated with increased toxicity [767]0, [O'Shaughnessy, J et al. 2010]. In the FinXX study, the improvement of DFS and OS was no longer significant after 5 years in the overall collective, only in risk patients (triple-negative, > 3 LK), Cave: Standard arm [794].
In recent studies, a higher efficacy of the dose-dense (q2w) [765], [769] or the dose-intensified dose-dense chemotherapy [768], [795] could be shown compared to conventional chemotherapy (q3w). Especially for patients at high risk (≥ 4 affected LK), dose-intensified dose-dense chemotherapy (ETC) is a standard regime. Patients with a low or moderate risk of recurrence, however, do not benefit from dose-intensified therapy compared to standard chemotherapy [796], [797].
Myeloablative high-dose chemotherapies currently have no place in unselected high-risk collectives: Compared to conventional chemotherapy they show a better event-free survival, but overall survival remains unaffected [798], [776]0. Therapy-associated mortality and side effects are significantly increased [799], [800].
4.7.4 Neoadjuvant therapy
Neoadjuvant systemic therapy
A neoadjuvant (primary, preoperative) systemic therapy is regarded as the standard treatment for patients with locally advanced, primarily inoperable or inflammatory breast carcinomas as part of a multimodal therapy concept.
- Consensus
- Strong consensus
If the same postoperative adjuvant chemotherapy is indicated, neoadjuvant systemic therapy should be preferred.
- Consensus
- Strong consensus
Neoadjuvant or adjuvant chemotherapy
If chemotherapy is indicated, it can be carried out before the surgery (neoadjuvant) or afterwards (adjuvant). Both procedures are equivalent in terms of overall survival.
The neoadjuvant therapy can lead to a higher rate of breast-conserving therapies.
A resection in the new tumor borders is possible if an R0 resection can be achieved.
- Consensus
- Strong consensus
Primary hormone therapy in postmenopausal patients
In postmenopausal patients with endocrine sensitive breast cancer, if surgery or chemotherapy is not possible or not desired, primary endocrine therapy can be performed.
- Consensus
- Strong consensus
The neoadjuvant endocrine therapy is not a standard therapy, in special situations (inoperable, multimorbid patient) a neoadjuvant endocrine therapy can be considered.
- Consensus
- Strong consensus
Neoadjuvant chemotherapy combination
If a neoadjuvant chemotherapy combination is used, it should contain an anthracycline and a taxane. The duration of preoperative therapy should be 18-24 weeks.
For HER2-positive tumours and indication for neoadjuvant chemotherapy, therapy with trastuzumab should be used. In case of HER2-positivity and high-risk situation (clinical/sonographic or punch biopsy N+, tumor size > 2cm) therapy should be supplemented with pertuzumab.
- Consensus
- Strong consensus
Platinum salts increase the complete remission rate (pCR rate) in triple-negative breast cancer (TNBC) regardless of the BRCA status. The benefit on progression-free survival (PFS) and overall survival is not conclusively clarified. The toxicity is higher.
- Consensus
- Strong consensus
Postneoadjuvant treatment
With adequate anthracycline-taxan-containing neoadjuvant chemotherapy, no additional adjuvant chemotherapy is recommended for tumor residuals in the breast and/or lymph nodes. Postneoadjuvant chemotherapy treatment should only be carried out within the framework of studies.
- Consensus
- Strong consensus
Background 4,122 to 4,131
Numerous studies have shown that there is no difference in long-term survival between neoadjuvant and adjuvant chemotherapy when the same therapeutic agents are used and the same dose and number of cycles are administered. In some studies, the local risk of recurrence seems to be increased with neoadjuvant therapy, whereby chemotherapy regimens and surgical strategies that are inferior or no longer up to standard were used [804], [805].
Reasons for the use of neoadjuvant chemotherapy (NACT) are, in addition to the improvement of operability or the increase in the rate of breast-conserving surgery, the gain in knowledge about the effectiveness of the therapy and the possibility of developing individual therapy approaches more quickly in post neoadjuvant studies [801]. In patients with HER2-positive/hormone receptor-negative or triple-negative disease a very favorable long-term prognosis can be assumed in the case of pathological complete remission (pCR) [563], [565].
The NACT should contain an anthracycline and a taxane and should be performed for at least 6 cycles, all prior to surgery. In patients with HER2-overexpressing tumor, the preoperative administration of trastuzumab as well as trastuzumab and pertuzumab simultaneously with chemotherapy can significantly increase the pCR rate [806], [807], [808], [809], [810], [811]. Trastuzumab therapy should be completed postoperatively for a period of one year.
Histopathological complete remission (pCR), defined as non-invasive detection of tumor cells in the breast and axilla after NACT, has shown a clear correlation with long-term survival in studies, i.e. patients who do not respond to NACT until surgery or already after the first chemotherapy cycles have a less favorable prognosis than those who respond to therapy [565], [802], [803]. Despite this observed correlation within the studies, there are no reliable data to date that show that differences in the pCR rate in study arms reliably predict differences in event-free survival or overall survival [565], [812], [813]. Thus, the pCR rate currently does not represent a valid surrogate endpoint for assessing the efficacy of neoadjuvant therapy with regard to patient-relevant endpoints.
The most important predictive marker for the response of a taxane-anthracycline containing regime is the hormone receptor status. In patients with negative hormone receptor status a pCR rate of up to 70-80% can be achieved. Predictors of response are: Younger age of onset of disease, patients with cT1 or cT2 carcinoma, nodal negativity, G3, negative hormone receptor status, triple-negative breast cancer
In postmenopausal patients with endocrine sensitive breast cancer, neoadjuvant endocrine therapy can be performed if surgery and chemotherapy are not possible. In this indication aromatase inhibitors of the third generation are recommended [814], [815], [816].
After completion of the NACT, the patient should receive surgical therapy as described above. The extent of excision should make use of the achieved effect of the neoadjuvant therapy and can be performed in the new tumor borders. Since the identification of the original tumor site can be difficult when a pCR is achieved, the localization of the tumor bed with the help of a clip is recommended already at the pre-therapeutic punch biopsy. In the case of radiologically complete remission under primary systemic therapy, an excision of the former tumor localization should be performed to determine whether vital tumor cells are still present in the tumor bed. The indications for postoperative radiotherapy correspond to those described for the adjuvant situation and are based on the pre-therapeutic initial findings [801]. The de-escalation of the locoregional radiotherapy is clarified in prospective studies (NSABP B 51).
For surgery or axillary intervention before and after adjuvant chemotherapy see Operative Chapter 4.4.
4.7.5 Antibody Therapy
Indications for antibody therapy
Patients with HER2-overexpressing tumours with a diameter of ≥ 1 cm (immunohistochemical score 3+ and/or ISH-positive) should receive (neo-)adjuvant treatment with anthracycline followed by a taxane in combination with trastuzumab. Trastuzumab should be administered over a total period of one year.
Adjuvant treatment with trastuzumab should preferably be started simultaneously with the taxane phase of adjuvant chemotherapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus
- References
- [818]
If there is an indication for chemotherapy for HER2+ tumours /= 5 mm, trastuzumab should be given additionally.
TCH (docetaxel, carboplatin, trastuzumab) can also be recommended adjuvant over 6 cycles every 3 weeks. Cardiotoxicity is lower than after anthracyclines.
- Consensus
- Consent
Background 4,132 to 4,134
A prerequisite for trastuzumab therapy is the quality-assured determination of the HER2 status (algorithm see chapter Pathology 4.5). The detection of the amplification of the HER2 gene by means of in situ hybridisation (ISH) can technically be carried out as fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) (approved kits see chapter Pathology 4.5). For silver enhanced in situ hybridization (SISH) less data is available for [481], [819], [820], [821]. A currently published algorithm can help to critically question one's own results and to start a quality initiative [822].
The participating laboratories have to undergo quality assurance by means of ring tests [823], [824].
Five studies independently showed that adjuvant treatment with trastuzumab in sequence or in combination with standard chemotherapy consistently reduced the recurrence rate of HER2-overexpressing tumours by relatively 45% to 50% and mortality by approximately 30% [818], [825], [826], [827], [828], [829], [830], [831], [832], [833], [834], [835], [836], [837], [838] [839].
In a meta-analysis with a follow-up period of 2.9 to 5.5 years (median values of the examined studies) it could be shown that the simultaneous therapy (trastuzumab simultaneously to the taxane phase of the applied adjuvant chemotherapy regimen) is probably superior to the sequential therapy with trastuzumab after completion of the adjuvant chemotherapy: for DFS HRsim = 0.62 vs. HRseq = 0.74, for OS significant benefit only with simultaneous application with an HRsim = 0.68 [817], [818].
Several retrospective case series show that even in patients with small tumours (diameter
Even in patients with small tumours (diameter
Adjuvant treatment with trastuzumab is generally indicated in patients with nodal-positive tumors and nodal-negative tumors ≥ 1 cm diameter with HER2 overexpression. The duration of therapy is one year. The infusions can be administered in weekly or 3-weekly intervals. Additional studies were conducted on the duration of therapy. The two-year arm of the Hera study showed no significant difference compared to the one-year arm [840]. The Phare study compared half a year with one year of trastuzumab and it could not be shown that the shorter duration is not inferior. Thus, one year of trastuzumab therapy remains the standard [841], [842].
A further prerequisite for adjuvant trastuzumab treatment is adequate cardiac function. Monitoring of the left ventricular ejection fraction during therapy is also obligatory, since trastuzumab can cause clinically relevant heart failure (NYHA III/IV) up to 4.1% especially after anthracyclines [831], [843]. In retrospective analysis, this seems to affect mainly older patients (> 50 years) with previous cardiac diseases. The 3-year analysis of the American studies did not show an increased late cardiotoxicity, it was 2.5% after 3 years. The long-term results of the NSABP /NCCTG, the Hera study as well as the BCIRG study showed that after 18 months no additional trastuzumab-related cardiotoxicity occurred [837], [838], [839], [842].
In the Cochrane analysis by Moja et al (2012), the absolute benefits and risks are summarised as follows: Mortality is relatively reduced by 30% with trastuzumab and the cardiac risk is five times higher compared to chemotherapy alone. If 1,000 patients are treated with chemotherapy without trastuzumab, 900 survive and 5 have cardiotoxicity.
If 1,000 patients were treated with chemotherapy and trastuzumab, 933 would survive (i.e. 33 more than without trastuzumab), 740 would survive without disease relapse (95 more than in the arm without trastuzumab) and 26 would have cardiotoxic side effects (i.e. 21 more than without trastuzumab). This Cochrane publication is based on the 2010 analysis, but long-term data are now available from these trials. No additional cardiotoxicities occurred.
4.7.6 Bone-directed therapy
In breast cancer, interactions between the bone and its metabolism on the one hand and the tumor cells on the other hand can be observed. These effects can be achieved directly by the breast carcinoma cells or indirectly via systemic therapeutics.
Bone targeted treatment plays an important role in breast cancer in several respects:
- Therapy and prevention of cancer treatment induced bone density and structure loss (cancer treatment induced bone loss)
- Adjuvant therapy of primary breast carcinoma to improve bone metastasis-free and overall survival
- Preventive therapy of skeletal related events (SRE) in osseous metastasized breast cancer
Bone modifying agents used in breast cancer are bisphosphonates and the antibody Denosumab, which is directed against the ligand of the Receptor Activator of Nuclear Factor-Kappa B (RANK ligand).
4.7.6.1 Therapy and prevention of cancer treatment induced bone loss
In malignant diseases the risk of loss of bone density, destruction of bone structure and thus therapy-associated osteoporosis with a consecutively increased risk of fracture is significantly increased [844]. In addition to the frequently observed immobilization and lifestyle changes (e.g. discontinuation of estrogen therapy), drug therapies are the most important factors for the osseous changes. Supportive therapies (e.g. cortisone preparations) can damage the bone as well as cytotoxic or endocrine medications. In particular, the high cure rates of numerous solid tumours and especially breast carcinoma are causing the problem to become increasingly prominent.
In premenopausal women with a hormone receptor-positive breast cancer a suppression of ovarian function (ovarian function suppression, e.g. by GnRH analogues) alone as well as in combination with tamoxifen or an aromatase inhibitor and therapy with tamoxifen alone lead to a loss of bone density and to an increased incidence of osteoporosis compared to a healthy control collective [845], [846], [847]. The combination of ovarian suppression combined with an aromatase inhibitor leads to the greatest decrease in bone density [845].
In postmenopausal women, therapy with aromatase inhibitors also leads to a loss of bone density and an increased incidence of fractures compared to women treated with tamoxifen [848], [849], [850], [851].
Chemotherapy can also lead to a relevant loss of bone density [852], [853].
An indication for preventive treatment should be based on gender, age and bone density, taking into account family history and lifestyle. Primary prevention of cancer-therapy induced bone loss should be considered in particular if there is a special risk constellation [854], [855]. This includes, among other things: advanced age, low body mass index, nicotine abuse, aromatase inhibitor therapy, family disposition, long-term cortisone therapy, immobility, endocrine diseases, medication intake (Dachverband der deutschsprachigen wissenschaftlichen Osteologischen Gesellschaft e.V., http://www.dv-osteologie.org; [856].
Bone-directed therapy
Patients with an increased risk of bone loss due to medical history or cancer therapy should have a bone density measurement performed at the beginning of therapy.
Depending on the result and other risk factors, the bone density measurement should be repeated at regular intervals.
- Consensus
- Strong consensus
To avoid cancer-therapy induced osteoporosis, preventive treatment should be considered depending on the individual risk constellation for the development of osteoporosis (http://www.dv-osteologie.org; ESMO bone health guidance).
- Consensus
- Consent
Bone protective therapy should be considered in premenopausal patients with GnRH and/or tamoxifen and in postmenopausal patients on aromatase inhibitor therapy.
Background 4,135 to 4,137
Preventive treatment of cancer-associated bone loss differs little from the treatment of non-cancer-associated osteoporosis. The following general recommendations can be given to affected patients:
- Avoidance of underweight
- Avoidance of noxious substances (e.g. nicotine (ab)usus)
- Avoidance of cortisone preparations and drug therapies that negatively influence bone metabolism as far as possible
- Avoidance of vitamin D deficiency and reduced daily calcium intake
- Avoidance of immobilization or increase of physical activity as far as possible
Hormone therapy with estrogens should not be used in breast cancer patients to prevent cancer-associated osteoporosis, as an increased recurrence rate cannot be ruled out, especially in hormone receptor-positive patients.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [857]
In addition to the general recommendations, bisphosphonates or denosumab can be used for the primary prevention of cancer therapy-induced bone loss.
- Consensus
- Strong consensus
Background 4.138 and 4.139
In a primary prevention study in postmenopausal breast cancer patients treated with aromatase inhibitors, the RANK ligand antibody Denosumab led to a prevention of bone density loss and to a significant reduction of the fracture rate by 50% [858][859], independent of age and bone density.
A primary preventive use of bisphosphonates could significantly prevent a loss of bone density under endocrine therapy in both pre and postmenopause (postmenopausal: [860], [861], [859]; premenopausal: [862], [863]). However, in no study could a significant reduction of osteoporotic fractures be demonstrated by the bisphosphonates. The greatest evidence for the prevention of bone density loss exists for the bisphosphonate zoledronate [862], [861], [859], but other bisphosphonates have also been investigated in smaller RCTs for the prevention of therapy-induced bone density loss in breast cancer: clodronate, ibandronate, pamidronate, alendronate, risedronate.
A risk reduction for fractures as part of endocrine therapy has only been clearly demonstrated for Denosumab, but not for bisphosphonates at present.
- Level of evidence
- 1
- Consensus
- Strong consensus
The bone-directed therapy to prevent therapy-associated osteoporosis should be carried out as long as the endocrine therapy is performed.
- Consensus
- Strong consensus
4.7.6.1.1 Therapy of cancer therapy induced osteoporosis
If a fracture occurs without adequate trauma, a bone metastasis should be ruled out.
- Consensus
- Strong consensus
Background 4,142
After exclusion of the bone metastasis an adequate therapy of the osteoporosis should be carried out. This should consider all possible aspects and, if necessary, be interdisciplinary (e.g. pain therapy, surgical stabilization and reconstruction, minimally invasive procedures (e.g. vertebroplasty, kyphoplasty, radiotherapy, drug therapy)).
4.7.6.2 Adjuvant therapy to improve bone metastasis-free and overall survival
According to the "seed and soil" theory, luminal breast cancer cells in particular metastasize preferentially in the bone and can be detected there as disseminated tumor cells [864], [865], [866]. Bisphosphonates and probably also denosumab seem to have a therapeutic effect on the persistence of these cells and thus on the incidence of secondary bone metastases [867].
Two meta-analyses investigated studies on the adjuvant use of different bisphosphonates. Ben-Aharon and colleagues found a positive effect on survival in postmenopausal breast cancer patients (HR 0.81 (0.69-0.95) [868]. An Oxford meta-analysis by Coleman and colleagues showed a significant, positive effect on bone metastasis-free survival of 34% and overall survival of 17% for postmenopausal patients (including premenopausal patients under ovarian suppression with GnRH analogues; ABCSG-12) [869].
For premenopausal patients (without ovary suppression using GnRH analogues), the meta-analyses did not show a significant advantage with regard to disease-free, bone metastasis-free and overall survival. An evaluation of the secondary endpoint in a subpopulation of premenopausal patients (largely without ovary suppression) showed no effect on the prognosis despite a higher therapy density at the beginning of treatment (AZURE study [856]).
To date, however, no bisphosphonate has been approved for the indication of adjuvant therapy in the European Union, so that treatment can only be carried out outside the approval status (off-label use).
Background 4,143
A preventive effect of Denosumab against the occurrence of bone metastases and the prolongation of overall survival could not be clearly demonstrated so far. Prospective studies with this question are currently being conducted.
For premenopausal patients without ovary suppression, no recommendation can currently be made for the adjuvant use of bisphosphonates or Denosumab.
Background 4,144
Bisphosphonates with evidence of an adjuvant therapeutic benefit (according to meta-analysis by Coleman et al., 2015 [870]):
- Alendronate p.o. 70 mg/w
- Clodronate p.o. 1600 mg/d
- Clodronate p.o. 1040 mg/d
- Ibandronate p.o. 50 mg/d
- Pamidronate p.o. (in oral form not available in D)
- Risedronate p.o. 35 mg/w
- Zoledronate i.v. 4 mg/6 m
4.7.6.3 Bone-directed therapy for patients with bone metastases
In the case of breast carcinoma, metastases are most frequently found in the bones carrying bone marrow. Especially the luminal tumors show an affinity to the skeletal system. The most frequent complications in bone metastases are pain, pathological fractures, vertebral compression syndromes and hypercalcemia [870]. If the above-mentioned symptoms (except for pain) occur, morbidity is significantly increased. Various measures can be taken to prevent these serious complications.
In the interdisciplinary AWMF-S3 guideline 032-054OL "Supportive Therapy in Oncological Patients" the diagnosis and therapy of bone metastases are discussed in detail [871]).
4.7.6.4 Tolerance of bisphosphonates
Possible side effects of bisphosphonates are:
When administered intravenously
flu-like symptoms ("flu like symptoms") especially with the first i. v. administrations
Deterioration of renal function, especially in cases of reduced renal function prior to the start of therapy until renal failure develops
For peroral administration
gastrointestinal complaints (e.g. B. Nausea, vomiting, diarrhoea).
The rate of jaw bone necrosis caused by the bisphosphonates and Denosumab was not increased in the studies on adjuvant use [848], [872]. Only in the AZURE study, which showed a higher dose density in the first 30 months of treatment (see above), were increased rates of jawbone necrosis described [856].
Before the start of adjuvant osteoprotective therapy, a visit to a dentist should take place. Otherwise, the recommendations of the S3 guideline on "Antiresorptive-associated jaw necrosis" apply.
- Consensus
- Strong consensus
4.7.7 Lifestyle factors that can be influenced
Exercise therapy and physical activity
Patients should be motivated to be physically active and to normalize their body weight (in case of an increased BMI). Assistance should be provided. It is especially recommended:
a.) to avoid physical inactivity and return to normal everyday activity as soon as possible after diagnosis (LoE 2a)
b.) to achieve the goal of 150 minutes of moderate or 75 minutes of strenuous physical activity per week (LoE 1a)
Background 4,146
Follow-up care should not only focus on the detection of a relapse of the disease, but also on general health maintenance with training and counselling. This includes information about lifestyle, e.g. exercise and nutrition, especially in the case of obesity with a BMI ≥ 30 kg/m². The increasing body weight is related to the mortality due to a breast cancer disease [879]. Retrospective studies have shown that patients with a BMI ≥ 30 kg/m² compared to a BMI
Insufficient physical activity increases the risk of osteoporosis [880]. Initial strategies to reduce morbidity associated with osteoporosis include education about risk factors and a healthy lifestyle. In addition, overweight and obese survivors should be advised to reduce the consumption of high-calorie foods and beverages, promote physical activity and thereby achieve weight loss.
It is recommended that primary health care providers provide the following interventions based on clinical indication against the background of musculoskeletal symptoms, including pain acupuncture, physical activity, recommendation for physical therapy and rehabilitation. Exercise therapy could also reduce the risk of cardiotoxicity and cardiovascular disease [873].
|
Category |
BMI (kg/m²) |
|
|
massive underweight |
< 16,00 |
|
|
moderate underweight |
16,0 - |
Underweight |
|
slight underweight |
17,0 - |
|
|
Normal weight |
18,5 - |
Normal weight |
|
Preadiposity |
25,0 - |
Overweight |
|
Obesity grade I |
30,0 - |
|
|
Obesity grade II |
35,0 - |
Obesity |
|
Obesity grade III |
≥ 40,0 |
|
|
Source: WHO, 2003 |
Meanwhile, numerous systematic reviews and meta-analyses document the many health effects of physical activity in breast cancer patients, including the reduction of treatment-specific symptoms (e.g. fatigue), improvement of quality of life and physical functions. Data from a meta-analysis of 16 studies suggest an average relative risk of 0.72 for physically active breast cancer patients (95% CI, 0.60-0.85) and 0.52 for all-cause mortality (95% CI, 0.42 0.64) [881].
Breast cancer patients should return to normal daily activities as soon as possible after diagnosis and should also be advised to continue regular physical activity. Breast cancer patients should exercise at least 150 minutes of moderate or 75 minutes of intensive physical activity per week. Exercise therapy should include strength training at least 2 days per week [878], [882], [883]0.
On lifestyle factors in breast cancer there are it's a layman's terms "Make smart decisions together" -Recommendation based on this guideline.
Background 4,147
Movement therapy, including stretching and other methods of movement therapy, show effective effects in the treatment of postoperative musculoskeletal symptoms [888], [889]. Recent data from the Hormones and Physical Exercise Trial, a prospective RCT study, show that participation in an intensive exercise program reduced aromatase inhibitor-associated pain by 20% [886]. To date, apart from acupuncture [890], only exercise therapy shows statistically significant improvements in aromatase inhibitor-associated symptoms according to [886]. This RCT study was able to prove that primarily intensive strength training units led to a reduction of pain and aromatase inhibitor-associated symptoms. Breast cancer patients under irradiation also benefit from strength training, which is safe, feasible and an effective method to reduce the fatigue syndrome is [887].
Physical activity reduces pain in breast cancer patients, as shown in a meta-analysis of RCT studies [891].
Patients should be advised and guided to regular sports therapy and physical activity for the treatment of breast cancer-associated fatigue.
Background 4,148
It is recommended that primary health care providers should advise and guide patients to regular physical activities to treat fatigue. A regular, physical exercise program can reduce fatigue, help survivors to feel better physically and emotionally, and to cope with the disease, as several RCTs show [878], [893], [894].
In manifest chemotherapy-induced polyneuropathy, exercise therapy should be used to improve functionality.
This may include:
- Balance exercises,
- sensomotoric training,
- Coordination training,
- Vibration training,
- Fine Motor Training
Background 4,149
The following section on polyneuropathy and exercise therapy is based almost entirely on the S3 guideline supportive therapy (http://leitlinienprogramm-onkologie.de/Supportive-Therapie.95.0.html).
It is recommended that primary care should offer interventions such as physical activity to treat neuropathy and relieve pain. The effectiveness of non-drug interventions is evaluated in a review by Streckmann et al. [896]. In this review 18 studies on "exercise interventions for neuropathic patients" were analysed. The majority of the studies (11 of 18) refer to diabetes mellitus-induced neuropathy and the others to neuropathy of different etiologies (such as polyneuropathy after liver transplantation, Charcot-Marie-Tooth syndrome and others). Only one study refers primarily to neuropathy in the context of an oncological disease [896].
In this study, a total of 61 patients with lymphoma were randomized to different therapy times. The patients received a combined training of aerobic endurance, strength and sensorimotor training. The study was terminated prematurely due to clear effects in favour of the intervention group regarding quality of life, depth sensitivity, activity level (measured in metabolic equivalent (MET)/week), balance control, lactate values and side effects of oncological therapy (recorded by SGA; HADS and questionnaire of experienced deficits in attention). In further RCTs with breast cancer patients, physical activity showed that arthralgias, neuropathies and neuropathy symptoms improved, but in which "reduction of neuropathy" was not the primary endpoint [885], [886].
In the review, a positive effect for exercise therapy for the treatment of PNP of different genesis is documented [897]. Training methods such as endurance training, balance training, vibration training, Tai Chi, walking and standing training, also using weights, are used. Basically, this review results in an advantage for balance training regardless of the underlying genesis. For CIPN, a combination of endurance, strength and sensomotoric training is found to be effective. Whether a prophylactic effect can also be generated is currently still the subject of several ongoing studies.
For CIPN in comparison to PNP of other genesis a deviating/different pathogenetic mechanism is suspected depending on the aetiology.
This limits the comparability of studies on PNP and should give reason for caution when transferring results from studies on PNP of other aetiology to CIPN.
Based on data from a randomized study on healthy volunteers to improve balance (tested on a one-legged stand), it could be shown that exclusive strength training or also strength and endurance training had no effects, but that sensorimotor training was required [898].
With regard to other therapeutic measures such as occupational therapy or physical therapy/electrotherapy, no randomized studies on the treatment of CIPN are available. In a review from 2011, therapies used in oncological rehabilitation are described as beneficial [899]. In the intervention group, occupational therapy sensitivity training (e.g. exercises in a bean bath, electrotherapy) was used and the course during rehabilitation was evaluated. Success criteria were the reduction of CIPN symptoms and assessment of future performance in working life. The intervention group showed a clear benefit in this respect.
A systematic review of rehabilitative interventions also lists publications that show an improvement in functional limitations. However, these reviews include patients with Guillain-Barré syndrome [900].
In line with this, positive effects of Tai Chi in the training of balance could be achieved with older people [901].
In summary, there are clear indications for the improvement of functional limitations by non-drug methods such as sports therapy, occupational therapy, physiotherapy and physical therapy including electrotherapy. In addition, there is no evidence of a damaging effect of the intervention. Furthermore, there is evidence for the effectiveness of exercise therapy to reduce further side effects in female tumor patients, such as Fatigue [894]. Exercise training, primarily as sensomotoric and balance training, as well as occupational therapy, physiotherapy and physical therapy including electrotherapy under consideration of the contraindications are therefore recommended.
Exercise therapy and physical activity
Patients after surgical treatment of breast cancer and the occurrence of lymphedema should be introduced to supervised, slowly progressive strength training for lymphedema treatment.
Background 4,150
Patients after surgical treatment of breast cancer and the occurrence of lymphedema should be introduced to supervised, slowly progressive strength training for lymphedema treatment. This is safe and effective in reducing arm swelling in high risk breast cancer survivors (five or more lymph nodes). In the past, patients with axillary lymphonodectomy/radiation have been advised to avoid physical activity and heavy lifting with the arm of the affected side. However, one study found that supervised, slowly progressive strength training after breast cancer is safe and effective. In addition, this type of physical activity can reduce the likelihood of arm swelling in high-risk breast cancer survivors (five or more lymph nodes) and improve symptoms of existing lymphedema [876].
Body Weight
Patients should be advised (a) to achieve and maintain a healthy body weight and (b) in the case of overweight or obesity, to limit the intake of high-calorie foods and beverages and to increase physical activity in order to promote moderate weight loss and maintain it in the long term.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [873]
Background 4,151
Increased body weight is accompanied by a reduction in life expectancy. As causes of death, cardiovascular diseases are in the foreground, but cancers as a whole also increase the mortality [908]. A more recent analysis by IARC recently confirmed that an increase in fat mass increases the risk of postmenopausal breast cancer and other cancers [909]. In another analysis using the GLOBOCAN database, 10.2% of all postmenopausal breast cancers were due to obesity (population attribute fraction) [910].
If there is a breast carcinoma, the presence of obesity (BMI 30 ≥ kg/m²) increases the overall mortality risk by 75% for women with premenopausal breast carcinoma and by 34% for women with postmenopausal breast carcinoma. Per BMI increase of 5 kg/m² a risk increase for total mortality of 8-17% and for breast cancer-related mortality of 17-29% was observed [911].
In recent years, several weight loss studies have been conducted in obese women with breast cancer. These studies showed that a moderate weight reduction with improvement of various accompanying phenomena (biomarkers, psychosocial parameters, quality of life) is possible with moderately energy-reduced diets and increased exercise, and no particular side effects are to be expected [912]. In a more recent evaluation of the ENERGY trial it was reported that a program with dietary changes and increased exercise improves the quality of life in obese women with breast cancer, but this effect weakened over time starting with [913].
In older persons with obesity (BMI 30 kg/m²) there is only weak evidence that these persons benefit from weight reduction with reduction diet and increased exercise [914].
Nutrition
Patients should be advised to achieve and maintain a diet rich in vegetables, fruits, whole grains and legumes, low in saturated fats and limited in alcohol intake.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [873]
Background 4,152
So far there are only few nutritional intervention studies in women with breast cancer. These studies were mostly of short duration and almost exclusively recorded surrogate parameters. Two larger intervention studies started more than 20 years ago led to contradictory results, which may be explained by different compliance [915], [916]. In both studies the intervention aimed at a significant reduction of fat intake. The WHEL study also recommended a high consumption of vegetables, fruit and wholemeal products [916].
From prospective cohort studies, similar findings are found for breast cancer as for chronic diseases in general. According to these findings, a western diet rich in fat and sugar also increases the risk of breast cancer, while a health-promoting diet reduces the risk. The WCRF therefore also recommends a balanced mixed diet for cancer patients. Recently, a secondary analysis of the PREDIMED study reported that a Mediterranean diet, supplemented with olive oil or nuts, was associated with a 62% and 34% lower incidence of breast cancer [917].
Concerning the specific role of individual food groups, a number of analyses and meta-analyses have now been published from cohort studies, which essentially show an inverse relationship between dietary fiber consumption and breast cancer risk [918], while a high consumption of meat and processed meat products was associated with an increased risk of breast cancer [919]. In another meta-analysis, the consumption of milk and dairy products was associated with a reduced risk [920]. In sum, it follows that a diet according to the Nutrition Circle of the German Society for Nutrition (DGE) [921] is also recommended for women with breast cancer. Alternatively, a Mediterranean diet or a diet according to the principles of the Mediterranean diet can be recommended.
The recommendations made so far are almost exclusively from prospective cohort studies; controlled intervention studies are largely lacking and are urgently needed in order to be able to make nutritional recommendations with greater evidence.
The data on alcohol consumption in women with breast cancer is contradictory [922]. According to expert panels, alcohol consumption should be limited to a maximum of 10 grams per day [923].
Avoidable noxae
Patients should be advised not to smoke, and smoking cessation programmes should be recommended to women smokers.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus
- References
- [873]
Background 4,153
The meta-analysis of various observational studies by Berube et al. [924] shows a 33% increased risk of breast cancer-specific mortality in patients who smoked at the time of initial diagnosis compared to previous smokers. Already during the primary therapy and later also during the aftercare the patients should be influenced by suitable means to keep abstinence from tobacco. In this context, reference is made to the S3 guideline "Screening, diagnosis and treatment of harmful and dependent tobacco consumption" AWMF-Register No. 076-006.
To avoid later relapses (> 5 years after initial diagnosis), patients with receptor-positive disease should avoid a daily alcohol consumption of > 12 g pure alcohol.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus
- References
- [925]
Background 4,154
While the data on the increase in breast cancer risk for healthy women through regular alcohol consumption can be regarded as robust, there has been inconsistent and contradictory evidence in recent years on the significance of alcohol consumption for the probability of recurrence. In the USA, about 7% of patients with primary breast cancer say that they consume more alcohol [873]. The OAS and DFS of breast cancer patients seems to be unaffected by a daily intake of less than 12g of pure alcohol per day ("one drink" in the US guidelines). However, the pooled analysis of prospective cohort studies in receptor-positive disease with a daily intake of > 12g showed a significant deterioration of DFS after the first 5 years ("late recurrences") [925]. In this context, the authors explain that regular consumption from the time of diagnosis was decisive for the classification into the respective group. Thus, the consumption behaviour 5 years after diagnosis was not decisive.
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