8. Qualitätsindikatoren – Mammakarzinom

Source: MG, Davey, O'Flaherty C, Cleere EF, Nohilly A, Phelan J, Ronane E, Lowery AJ, and Kerin MJ. "Sentinel Lymph Node Biopsy in Patients with Ductal Carcinoma in Situ: Systematic Review and Meta-Analysis." [In eng]. BJS open 6, no. 2 (2022-3-8 2022). https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/35380620/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim:

Establish the likelihood of having lymph

node metastases on sentinel lymph node biopsy (SLNB) positive SLNB (SLNB+) in patients being treated

surgically for Ductal carcinoma

in situ (DCIS), and to establish clinicopathological

parameters that may be useful in predicting those likely to be

SLNB+ at the time of breast surgery for DCIS

Design:

Systematic review and meta-analysis

Search date: until 25 May 2021

Searched databases: PubMed, Embase, Scopus

Included study designs:

Prospective studies

Number of included studies: 16

Number of included patients: 4.388

Mean age at diagnosis: 54.8 (range: 24-92)

Inclusion criteria: studies assessing patients with histologically confirmed DCIS breast cancer in the breast preoperatively with or without

positive disease in the axilla (assessed using SLNB);

and studies had to include data that were collected prospectively and included

prospectively collected registry data

Exclusion:

Studies with patients with histologically confirmed invasive breast cancer (e.g. IDC

histological subtype); studies including data that were not

collected prospectively; review articles; studies including fewer than five patients in their series or case reports; or editorial articles

Intervention

Any patient who underwent

staging with SLNB and were subsequently found to have

positive disease in the axilla at the time of their breast cancer

surgery for DCIS

Control

Any patient in who underwent staging with SLNB and were subsequently found not to have positive disease in the axilla at the time of their breast cancer

surgery for DCIS

Primary Outcome:

Included SLNB+ (including

micro- and/or macrometastatic disease in the axillary lymph

nodes) following an initial diagnosis of DCIS

Secondary Outcome:

Included any clinicopathological features predictive

of those likely to have SLNB+ following an initial diagnosis of

DCIS

Primary Outcome:

Axillary lymph node positivity

metastatic disease in axillary lymph nodes in patients with ductal carcinoma in situ

OR=0.00, 95% CI 0.00-0.01, p<0.001; I²=93%

(16 studies)

Secondary Outcome:

Clinicopathological predictors of axillary lymph node positivity

Palpable disease

OR=2.01, 95% CI 0.64-6.24, p=0.23; I²=0%

(2 studies)

Tumour necrosis

OR=3.84, 95% CI 0.85-17.44), p=0.08; I²=83%

(5 studies)

grade 3 ductal carcinoma in situ in predicting metastatic disease in axillary lymph nodes

OR=1.34, 95% CI 0.80-2.23, p=0.27; I²=0%

(7 studies)

AMSTAR II critical appraisal tool 

Overall confidence in the results of the review: critically low; 6 critical flaws (items 2,4,7,11,13,15)

Additional concerns about quality:

Cautious interpretation of the results because of the absence of well-designed RCTs

Observational studies of a non-randomized design, where retrospective analysis of prospectively

collected data is performed, are subject to the inherent risk of

selection and confounding biases.

Detecting

clinicopathological characteristics predictive of SLNB+

however, the paucity of such data may bring the validity of these results into question

Quality of included studies:

ROBINS-I

2: 9 studies

3: 7 studies

Level of evidence:

Oxford 2011:

Sources of funding:

M.G.D., C.O’F., A.N., J.P., and E.R. received funding from the National Breast Cancer Research Institute, Ireland.

Abbreviations:

DCIS = carcinoma in situ

SLNB = sentinel lymph node biopsy

SLNB+ = positive SLNB

OR = Odds Ratio

95% CI = 95% Confidence intervall

Source: F, Schettini, Giudici F, Giuliano M, Cristofanilli M, Arpino G, Del Mastro L, Puglisi F, et al. "Overall Survival of Cdk4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis." [In eng]. Journal of the National Cancer Institute 112, no. 11 (2020-11-1 2020): 1089-97. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/32407488/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Identifying patients that

might benefit most from CDK4/6-inhibitors,

in different clinically relevant subgroups of HR+/HER2-negative MBC.

Design: Systematic review and meta-analysis

Search date: end of October 2019

Searched databases: PubMed (+ European Society for medical Oncology (ESMO) and American Society and Clinical Oncology meetings and San Antonio Breast Cancer Symposium online databases)

Included study designs:

Phase II or III RCT

Number of included studies:

6 papers reporting OS results:

PALOMA 1 / 3

MONALEESA 2 / 7 / 3

MONARCH 2

Number of included patients: 3,421 for OS

Mean/median age: n.a.

Inclusion criteria:

HR+/HER2-neg metastatic breast cancer; first- or second line

Intervention

Palbociclib + letrozole (PALOMA 1)

Palbociclib + fulvestrant (PALOMA 3, MONALEESA 3)

Ribociclib + letrozole (MONALEESA 2)

Ribociclib + tamoxifen or AI + GnRHa (MONALEESA 7)

Abemaciclib + fulvestrant (MONARCH 2)

Control

letrozole (PALOMA 1; MONALEESA 2)

fulvestrant (PALOMA 3; MONALEESA 3)

fulvestrant [+ GnRHa in pre/peri pts] (MONARCH 2)

tamoxifen or AI + GnRHa (MONALEESA 7)

Primary Outcome:

Overall survival

Secondary Outcome: n.a.

Primary Outcome:

Overall survival

Benefit for CDK4/6-inhibitors combinations compared with standard ET:

HR 0.76, 95% CI 0.68-0.85, I²=0.0%

Secondary Outcome: n.a.

Subgroup analysis

visceral disease (yes vs no)

HR 0.73, 95% CI 0.65-0.83, P<0.001, I²=0.0%

bone-only disease (yes vs no)

HR 0.74, 95% CI 0.62-0.89, P<0.001, I²=0.0%

number of metastatic sites (<3 sites vs ≥3)

HR 0.77, 95% CI 0.65-0.91, P<0.002, I²=0.0%

endocrine sensitivity and resistance (yes vs no),

HR 0.77, 95% CI 0.68-0.86, P<0.001, I²=0.0%

previous CT for the metastatic setting (yes vs no),

HR 0.77, 95% CI 0.62-0.94, P<0.01, I²=0.0%

age (<65 vs ≥65 years)

HR 0.77, 95%CI 0.66-0.88, P<0.001, I²=12.0%

menopausal status

(pre-perimenopausal vs postmenopausal)

HR 0.75, 95% CI 0.67-0.84, P<0.001, I²=0.0% 

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: 4 critical flaws (items 2, 4, 7, 15)

(no information about review protocol

no comprehensive search strategy

no list of excluded studies

no adequate investigation of publication bias)

Overall quality of evidence: critically low

Quality of included studies:

Assessed with the Cochrane Collaboration’s Risk of Bias tool

Sources of funding: no funding

Abbreviations:

MBC = Metastatic Breast Cancer

RCT = Randomised Controlled Trial

OS = Overall Survival 

CT = Chemotherapy

n.a. = not Available, not Applicable

HR = Hazard Ratio

95% CI = 95% Confidence Interval

Source: J, Li, Huo X, Zhao F, Ren D, Ahmad R, Yuan X, Du F, and Zhao J. "Association of Cyclin-Dependent Kinases 4 and 6 Inhibitors with Survival in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: A Systematic Review and Meta-Analysis." [In eng]. JAMA network open 3, no. 10 (2020-10-1 2020): e2020312. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/33048129/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

The primary objective was to evaluate the association of CDK4/6 inhibitors plus ET, compared with ET alone, with OS in patients with HR-positive, ERBB2-negative metastatic breast cancers. The secondary objective was to assess the association of PFS, objective response rate (ORR), adverse events (AEs), and grade 3 or grade 4 (grade 3/4) AEs with treatment of CDK4/6 inhibitors plus ET vs ET alone among patients with HR-positive, ERBB2-negative metastatic breast cancer

Design: Systematic Review and Meta-analysis

Search date: up to 30/03/2020

Searched databases:

PubMed and Embase

Included study designs:

RCTs

Number of included studies: 9

MONALEESA-2 / -3 / -7

PALOMA-1 / -2 / -3

MONARCH-2 / -3 / -plus

Number of included patients: 5043 (HR+ metastatic BC)

Inclusion criteria:

(1) phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer

(2) with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone,

(3) having OS or PFS outcomes

Exclusion:

(1) phase 1 trials,

(2) retrospective studies, or

(3) studies without survival outcomes

Intervention

CDK4/6 inhibitors plus ET

Control

ET

Primary Outcome:

Overall Survival (OS)

Secondary Outcome:

Progression-Free Survival (PFS)

Objective Response Rate (ORR)

Grade 3/4 Adverse Events (AEs)

Primary Outcome:

Overall Survival(OS)

HR, 1.33; 95% CI, 1.19-1.48; P < .001

Secondary Outcome:

Progression-Free Survival

HR, 1.84; 95% CI, 1.70-1.98; P < .001

Objective Response Rate

OR, 2.02; 95% CI, 1.61-2.53; P < .001

Grade 3/4 AEs

The combination of CDK4/6 inhibitors plus ET was associated with increased cases of :

Neutropenia (HR, 57.05; 95% CI, 38.26-85.05; P < .001),

Leukopenia (HR, 36.36; 95% CI, 19.35-68.34; P < .001

Diarrhea (HR, 4.97; 95% CI, 2.84-8.69; P < .001),

Subgroup analysis

First- and Second-Line Therapy Subgroups

The combination of CDK4/6 inhibitors plus ET vs ET alone was associated with improved OS for the first-line therapy subgroup (HR, 1.35; 95% CI, 1.18-1.54; P < .001), as well as for the second-line therapy subgroup (HR, 1.30; 95% CI, 1.09-1.54; P = .004)

Premenopausal and Postmenopausal Subgroups

Treatment with CDK4/6 inhibitors plus ET was associated with improved OS for both the premenopausal subgroup (HR, 1.32; 95% CI, 1.04-1.66; P = .02), and for the postmenopausal subgroup (HR, 1.34; 95% CI, 1.18-1.52; P < .001).

Visceral Metastasis and Bone-Only Metastasis Subgroups

Treatment with CDK4/6 inhibitors plus ET was associated with improved OS for the visceral metastasis subgroup (HR, 1.31; 95% CI, 1.12-1.53; P < .001).

Treatment with CDK4/6 inhibitors plus ET was not associated with improved OS for the bone-only metastasis subgroup (HR, 1.22; 95% CI, 0.88-1.68; P = .23).

Age Subgroups

Treatment with CDK4/6 inhibitors plus ET was associated with improved OS both for the younger patient subgroup (HR, 1.25; 95% CI, 1.06-1.49; P = .010), and for the older patient subgroup (HR, 1.38; 95% CI, 1.11-1.72; P = .003)

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: 6 critical flaws (items 2, 4, 7, 9, 13, 15)

Overall quality of evidence:

Limitations: studies included in search were only in English;

all data were extracted from published literature, and no individual patient data were used in this study;

some studies in this meta-analysis included randomized clinical trials, but the subgroup analysis did not include all of those studies àfor example, in the age subgroup analysis, some studies used 40 years as the cut point, whereas other studies used 65 years as the cut point

Quality of included studies: n.a.

Sources of funding:

 supported by a grant from the Innovation Team for the Study of Pathogenesis and Anti-tumor Mechanism of Chinese-Tibetan Medicine in the Qinghai area (Talent Highland Program) and grant 2018-ZJ-T02 from the Qinghai province Medical Gene Detection Technology Platform

Abbreviations:

ET = Endocrine Therapy

OS = Overall Survival 

PFS = Progression-Free Survival 

ORR = Objective Response Rate

AE = Adverse Event

BC = Breast Cancer 

RCT = Randomised Controlled Trial 

HR = Hazard Ratio

OR = Odds Ratio

95% CI = 95% Confidence Interval

n.a. = not Available, not Applicable

Source: Q, Tian, Gao H, Zhou Y, and Yang J. "Overall Survival and Progression-Free Survival with Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy in Breast Cancer: An Updated Meta-Analysis of Randomized Controlled Trials." [In eng]. European review for medical and pharmacological sciences 25, no. 23 (2021-12 2021): 7252-67. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/34919224/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: to better define the efficacy and safety of CDK4/6i in HR+, Her2- ABC (advanced breast cancer) patients and aimed to identify a suitable patient population for CDK4/6i therapy through subgroup analysis

Design: updated meta-analysis

Search date: 01/2014 to 01/2020

Searched databases: MEDLINE, EMBASE and the Cochrane Library databases

Included study designs:

RCT phase 2 or 3

Number of included studies: 8 RCT (6 RCT for OS and 8 RCT for PFS)

PALOMA 1 / 2 / 3

MONALESA 2 / 3 / 7

MONARCH 2 / 3

Number of included patients: 4,580

Inclusion criteria:

1) phase 2 or 3 RCTs designed to evaluate the efficacy and safety of CDK4/6i plus ET vs. ET alone in HR+, Her2- ABC patients and

2) the hazard ratios (HRs) for the PFS and OS outcomes were reported.

Exclusion: Non/randomized prospective studies, retrospective studies, single-arm studies, reviews, meta-analyses and case

Intervention

CDK4/6i plus ET

Control

ET alone

Primary Outcome:

Overall survival (OS)

Progression-free survival (PFS)

Objective response rate (ORR)

Adverse events (AEs)

Overall survival

HR: 0.76 (95% CI: 0.67– 0.84)

Progression-free survival

HR 0.55 (95% CI: 0.50–0.59)

Objective response rate

CDK4/6i meaningfully improved the ORR in both the intention-to-treat population (RR=1.47; 95% CI: 1.29–1.67) and patients with measurable disease (RR=1.47; 95% CI: 1.30– 1.67)

Adverse events (AEs)

RR=2.69; (95% CI: 2.43–2.97)

Subgroup analysis

1) Subgroup analysis of Overall survival as outcome

Types of drug

The addition of ribociclib (HR=0.72; 95% CI: 0.60-0.84) and abemaciclib (HR=0.76; 95% CI: 0.59- 0.93) to ET resulted in a numerically larger improvement in OS benefits than the addition of palbociclib (HR=0.83; 95% CI: 0.66-1.00).

Combinations

The combination treatment improved OS outcomes in patients with treatment-naïve advanced disease (HR=0.74; 95% CI: 0.61–0.87) and in patients who had received up to one line of prior endocrine therapy for advanced disease (HR=0.77; 95% CI: 0.66–0.88).

Menopausal status

Consistent treatment effects on OS outcomes were observed in both postmenopausal patients (HR=0.75; 95% CI: 0.66–0.85) and pre-, perimenopausal patients (HR=0.74; 95% CI: 0.56–0.91).

Metastasis site

A numerically larger effect was observed in patients with visceral disease (HR=0.74; 95% CI: 0.58–0.91) compared to the effect on those with non-visceral disease (HR=0.79; 95% CI: 0.56–1.01) or bone-only disease (HR=0.76; 95% CI: 0.50–1.03).

Endocrine resistance

The subgroup analysis of patients with primary vs. secondary endocrine resistance showed a statistically significant OS benefit in patients with secondary endocrine resistance (HR=0.75; 95% CI: 0.61–0.89) compared to that in patients with primary resistance (HR=0.85; 95% CI: 0.42–1.27).

2) Subgroup analysis of Progression-free survival as outcome

Improvements in PFS outcomes were consistent among all subgroups.

Types of drug

Three CDK4/6 inhibitors, palbociclib (HR=0.53; 95% CI: 0.45–0.60), ribociclib (HR=0.59; 95% CI: 0.50–0.64), and abemaciclib (HR=0.54; 95% CI: 0.46–0.62), showed similar PFS benefits when combined with ET

Treatment line

The PFS advantage was obtained regardless of whether the treatments were applied as first-line (HR=0.55; 95% CI: 0.49–0.61) or subsequent-line (HR=0.53; 95% CI: 0.46–0.60) therapies

Race

The addition of CD-K4/6i to ET showed a numerically larger effect in the Asian population (HR=0.42; 95% CI: 0.33-0.52) than in the non-Asian population (HR=0.56; 95% CI: 0.47-0.64)

PR status

PR-negative patients (HR=0.43; 95% CI: 0.33-0.53) obtained a greater PFS benefit from the combination treatment than PR-positive patients (HR=0.57; 95% CI: 0.50-0.64).

Menopausal status

the PFS advantage was significant in postmenopausal patients (HR=0.55; 95% CI: 0.50– 0.60) and pre-, perimenopausal patients (HR=0.52; 95% CI: 0.41–0.62)

Metastasis site

Analysis by metastasis site indicated consistent PFS benefits for visceral (HR=0.52; 95% CI: 0.45–0.58), nonvisceral (HR=0.48; 95% CI: 0.40–0.56) and bone-only (HR=0.48; 95% CI: 0.38– 0.57) metastases:

Endocrine resistance status

Subgroup analysis by endocrine resistance status indicated consistent PFS improvements among patients with both primary (HR=0.48; 95% CI: 0.34–0.63) and secondary (HR=0.49; 95% CI: 0.35–0.63) ET resistance

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: 3 critical flaws (items 2, 7, 11)

Quality of included studies: Most studies had low risk of bias in most domains. Two studies had high risk of bias in domain blinding and one studie had high risk of attrition bias.

Sources of funding:

no funding received

Abbreviations:

ET = Endocrine Therapy

PFS = Progression-Free Survival

OS = Overall Survival 

ORR = Objective Response Rate

AE = Adverse Events

HR = Hazard Ratio 

RR = Risk Ratio

95% CI = 95% Confidence Interval

RCT = Randomised Controlled Trial 

Source: Trastuzumab for Early-Stage, Her2-Positive Breast Cancer: A Meta-Analysis of 13 864 Women in Seven Randomised Trials. [In eng]. The Lancet. Oncology 22, no. 8 (2021-8 2021): 1139-50. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/34339645/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: Long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality.

Design: Meta-Analysis of individual patient data from RCTs

Search date: until March 31, 2020

Searched databases: MEDLINE, Embase, Cochrane Library

Included study designs: RCTs

Number of included studies: 7

FinHER trial

NSABP trial B-31

NCCTG trial N9831

HERA trial

PACS 04

BCIRG 006

NOAH trial

Number of included patients: 13,864 women

Inclusion criteria: Trials were eligible if they began before Jan 1, 2010, and randomly assigned women with node-negative or node-positive, operable breast cancer to either chemotherapy (adjuvant or neoadjuvant) plus trastuzumab or to the same chemotherapy alone

Exclusion:

Trials of trastuzumab added to other biological therapies (eg, trials comparing lapatinib, pertuzumab, or neratinib with or without trastuzumab) were not eligible

Intervention

Chemotherapy (adjuvant or neoadjuvant) plus trastuzumab

Control

Same chemotherapy [as in intervention] alone

Primary Outcomes:

Any recurrence of invasive breast cancer (distant, loco-regional, or new primary in the contralateral breast), breast cancer mortality, and all-cause mortality

Prespecified primary subgroup investigations:

Site of recurrence, concurrent or sequential trastuzumab and chemotherapy, level of HER2 amplification, age, ER status, PR status, nodal status, tumour diameter (grade, histology [ie, ductal or lobular], BMI, proliferation index (Ki-67 <10%, 10-19%, or ≥20%), follow-up period (years 0-1, 2-4, 5-9, ≥10)

Primary Outcome:

Effect of trastuzumab versus control on recurrence and mortality

Breast cancer mortality

13,864 women

RR 0.66 (95% CI 0.62-0.71)

10-year gain 9.0% (95% CI 7.4 to 10.7)

Death without any recurrence

13,864

RR 0.67 (95% CI 0.61 to 0.73)

10-year gain 6.4% (95% CI 4.9 to 7.8)

Death from any cause

13,854 women

RR 0.90 (95% CI 0.72 to 1.12)

10-year gain 0.4% (95% CI –0.3 to 1.1)

Breast cancer mortality rates

13,864 women

RR 0.69 (95% CI 0.64 to 0.75)

10 year gain 6.5% (95% CI 5.0 to 8.0)

Subgroup analysis

Effect of trastuzumab versus control on recurrence by ER status

Recurrence analyses include any loco-regional or distant recurrence, but exclude contralateral disease

ER-negative:

6,837 women

0.62 (95% CI 0.56–0.69)

10-year gain 10.1% (95% CI 7.7–12.5)

ER-positive:

7,018 women

RR 0.67 (95% CI 0.60–0.74)

10-year gain 7.8% (95% CI 5.5–10.0)

Effect of trastuzumab versus control on recurrence by nodal status

Recurrence analyses include any loco-regional or distant recurrence, but exclude contralateral disease

N0

2,803 women

RR 0.67 (99% CI 0.54–0.83)

5-year gain 5.7% (99% CI 3.1–8.3)

N1-3

5,335 women

RR 0.61 (99% CI 0.53–0.69)

5-year gain 6.8% (99% CI 4.7–9.0)

N4+

4,690 women

RR 0.67 (99% CI 0.60–0.74)

5-year gain 10.7% (9% CI 7.7–13.6)

Effect of trastuzumab versus control on recurrence by tumour diameter

1-10 mm (T1a+b)

RR 0.61 (99% CI 0.38-0.99)

11-20 mm (T1c)

RR 0.65 (99% CI 0.54-0.79)

21-50 mm (T2)

RR 0.63 (99% CI 0.55-0.72)

>50 mm (T3 or T4)

RR 0.69 (99% CI 0.50-0.94)

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: moderate

Sources of funding:

Cancer Research UK, UK Medical Research Council

Abbreviations:

RCT = Randomised Controlled Trial 

RR = Rate Ratio

95% CI = 95% Confidence Interval 

Keine Bewertung auf Endpunktebene verfügbar

Keine Bewertung auf Endpunktebene verfügbar

Keine Bewertung auf Endpunktebene verfügbar

Keine Bewertung auf Endpunktebene verfügbar

1. Primary: Percentage of Participants Achieving Pathological Complete Response (pCR)
2. Secondary: Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography
3. Secondary: Progression Free and Disease Free Survival

S, Chen, Liang Y, Feng Z, and Wang M. "Efficacy and Safety of Her2 Inhibitors in Combination with or without Pertuzumab for Her2-Positive Breast Cancer: A Systematic Review and Meta-Analysis." [In eng]. BMC cancer 19, no. 1 (2019-10-21 2019): 973. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/31638935/.

Source and Purpose

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: to assess the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) +

P (pertuzumab) versus H in the (neo)adjuvant treatment of operable

HER2+ breast cancer (in neoadjuvant and metastatic setting)

Design: Systematic Review and meta-Analysis

Search date: published between 2005 (based on the first reported trial of pertuzumab efficacy in humans) and Dec 30, 2018

Searched databases:

PubMed, Cochrane, Science Direct, Embase, the clinical trial registry

Included study designs:

Prospective, retrospective, controlled trials

Number of included studies and patients: 38 trials in qualitative synthesis; 26 trials for meta-analysis

Of those:

14 single-arm trials with 1,098 patients (included 13 studies: pertuzumab combined with trastuzumab;

1 study: pertuzumab combined with T-DM1);

12 controlled trials with 8,774 participants (included 7 studies: pertuzumab combined with trastuzumab vs trastuzumab alone; 4 studies: pertuzumab + T-DM1 vs T-DM1 alone)

Mean/median age: n.a.

Inclusion criteria:

assessed the effectiveness and safety of H + P versus

H in patients with HER2+ breast cancer, irrespective of

the trial phase, the cohorts (whether prospectively or

retrospectively defined), the choice of chemotherapy,

and the stage of the HER2+ breast cancer patients

Exclusion:

Studies lacked original data

Intervention

trastuzumab or trastuzumab emtansine ± chemotherapy +

pertuzumab

Control

trastuzumab or trastuzumab emtansine ± chemotherapy

Primary Outcome:

Pathologic complete response (pCR);

Progression-free survival (PFS);

Overall survival (OS) only in metastatic setting

Secondary Outcome:

Safety (rash, diarrhea, myalgia, epistaxis, mucosal inflammation, cardiac toxicity [LVEF decline])

Neoadjuvant setting

Primary Outcome:

pCR

4 single-arm studies; included 205 patients;

treated with H+P

pCR range: 0.27 to 0.62:

absolute pCR rate: 0.56;  95% CI, 0.45–0.68; Significant heterogeneity was observed

(I² = 82.4%; P < 0.001)

Sensitivity analysis

0.59; 95% CI, 0.36–0.63; (after removing the studies conducted by Luca Gianni and Jasmeet C. Singh)

4 controlled trials;

included 1.448 patients

pCR in H+P group significantly higher than in the H group:

1.33; 95% CI 1.08 - 1.63; P = 0.006

I² = 0.0%; P = 0.78

Secondary Outcome:

AEs grade ≥3 (common)

Neutropenia, diarrhea, anemia

In controlled trials, the rates of diarrhea and anemia in the experimental

group were significantly higher than those in the controlledgroup [(OR = 2.42; 95% CI, 1.94–3.02; P = 0.0001)

and (OR = 1.43, 95% CI, 1.14–1.79, P = 0.002), respectively].

significant difference was not observed in neutropenia:

(OR = 0.99, 95% CI, 0.86–1.13, P = 0.814)

Cardiac toxicity:

controlled trials:

H + P did not increase the

incidence of LVEF compared with the effect of H (OR = 1.26; 95% CI, 0.81–1.95; P = 0.309)

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: critically low; 4 critical flaws (7, 9, 11, 13)

Additional concerns about quality:

several of the controlled trials lacked complete data

and included nonrandomized controlled trials, and fewer samples were included in the single-arm trials

Sources of funding: none

Abbreviations:

pCR = pathologic Complete Response

PFS = Progression-free survival  

OS = Overall survival 

H = Trastuzumab or Trastuzumab Emtansine ± Chemotherapy

P = Pertuzumab

LVEF = Left Ventricular Ejection Fraction 

OR = Odds Ratio

95% CI = 95% Confidence Interval

n.a. = not Available, not Applicable