7. Spezielle Situationen bei Mammakarzinom – Mammakarzinom

Source M, Lambertini, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, et al. "Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients with Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient-Level Data." [In eng]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 36, no. 19 (2018-7-1 2018): 1981-90. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/29718793/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: Investigation of the role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal patients with early breast cancer.

Design: Systematic review and individual patient-level meta-analysis

Search date:

until August 31, 2017

Searched databases:

PubMed, Embase, and the Cochrane Library

Included study designs: RCTs

Number of included studies: 13 eligible

Of those: individual patient-level data available for 5 trials:

PROMISE-GIM6 [PRevention Of Menopause Induced by chemotherapy:

A Study in Early breast cancer patients—Gruppo Italiano

Mammella 6],

POEMS [Prevention Of Early Menopause Study]/SWOG S0230, Anglo Celtic Group OPTION,

GBG [German

Breast Group]-37 ZORO [ZOladex Rescue of Ovarian function],

Moffitt-led trial

Number of included patients:

5 trials with individual patient-level data:

873 patients

GnRHa group: 436

Control group: 437

(The remaining 8 studies: 708 patients – data not available for this analysis)

Median age at diagnosis:

38 years (IQR, 34-42)

Estrogen receptor positive: 350 patients (40.1%)

Premenopausal patients with early breast cancer

Inclusion criteria:

RCT evaluating the efficacy of adding GnRHa to chemotherapy as a strategy to reduce the occurrence of chemotherapy-induced POI in premenopausal women with early breast

cancer receiving (neo)adjuvant chemotherapy

Exclusion: NR

Intervention

gonadotropin-releasing hormone agonists (GnRHa) during (neo)adjuvant chemotherapy

type of GnRHA used:

Triptorelin (2 trials), Goserelin (3 trials)

Control

(neo)adjuvant chemotherapy alone

Primary Outcome:

Rate of chemotherapy-induced premature ovarian insufficiency (POI)

Post-treatment pregnancy rate

Secondary Outcome:

Safety (toxicity and survival outcomes):

amenorrhea rates 1 and 2 years after chemotherapy

GnRHa-related adverse events (hot flashes, sweating, mood changes, vaginal dryness, headache)

Disease-free survival (DFS)

Overall survival (OS)

Prespecified subgroup analyses investigated the efficacy

and safety of temporary ovarian suppression with GnRHa during

chemotherapy according to age of the patients, estrogen receptor status,

type and duration of chemotherapy administered, and tumor stage

Primary Outcome:

Rate of chemotherapy-induced premature ovarian insufficiency (POI)

data available in 722 (82.7%) patients;

GnRHa group: n=51 (14.1%) of 363 patients

Control group: n=111 (30.9%) of 359;

OR 0.37, 95% CI 0.25 - 0.57, I²=0%

Effect of GnRHa on reducing the risk of POI was homogeneous among subgroups

Age distribution, y

≤ 40:

OR 0.28, 95% CI 0.16 - 0.49
≥41:

OR 0.52, 95% CI 0.29 - 0.92

Estrogen receptor status

Positive:

OR 0.46. 95% CI 0.27 - 0.79

Negative:

OR 0.31, 95% CI 0.17 - 0.56

Type of chemotherapy

Anthracyline only:

OR 0.51, 95% CI 0.30 - 0.87

Anthracycline + taxane:

OR 0.26, 95% CI 0.14 - 0.48

Post-treatment pregnancy rate

Data available in 3 trials

Information on post-treatment pregnancies in 726 (83.2%) of 873 patients

GnRHa group: 37 (10.3%) of 359 women had at least 1 post-treatment pregnancy

Control group: 20 (5.5%) of 367;

IRR, 1.82, 95% CI 1.05 - 3.14, p=0.30, I²=0%; p=0.852

All pregnancies in patients ≤ 40y at time of diagnosis

Secondary Outcome:

5 year DFS

GnRHa group:

79.5% (95% CI, 74.7% to 83.5%)

control group:

80.0% (95% CI, 75.2% - 83.9%)

(adjusted HR, 1.01; 95% CI, 0.72 - 1.42; P = .999;

Subgroup analysis according to estrogen receptor status

no significant interaction: P_interaction = .867;

estrogen receptor–positive:

adj. HR 1.17 (95% CI, 0.62 - 2.20);

estrogen receptor–negative:

adj. HR 0.95 (95% CI, 0.64 - 1.42)

5 year OS

GnRHa group:

90.2% (95% CI, 86.4% - 92.9%);

control group:

86.3% (95% CI, 82.0% - 89.7%) adj. HR, 0.67; 95% CI, 0.42 - 1.06;

P = .083; I² = 51.1%; P = .105

Subgroup analysis according to estrogen receptor status

no significant interaction:

P_interaction = .762;

estrogen receptor–positive:

Adj. HR 0.79 (95% CI, 0.24 - 2.59)

estrogen receptor–negative:

Adj. HR 0.65 (95% CI, 0.39 - 1.07)

Amenorrhea rates

1-year amenorrhea data

available in 760 (87.1%) of 873 patients

GnRHa group:

142 (36.8%) of 386 patients

developed 1-year amenorrhea

control group:

151 (40.4%) of 374  

Adj. OR, 0.92; 95% CI, 0.66 to 1.28; P = .623

2-year amenorrhea data

available in 424 (48.6%) of 873 patients;

this end point was not collected in the PROMISEGIM6

study and in patients who developed DFS and/or OS

events between 1 and 2 years

GnRHa group:

39 (18.2%) of 214 patients developed 2-year amenorrhea,

control group:

63 (30.0%) of 210

Adj. OR, 0.51; 95% CI, 0.31 to 0.85; P = .009 

AMSTAR II critical appraisal tool  

Overall confidence in the results of the review: critically low; 3 critical flaws (items 9, 13, 15)

Additional concerns about quality:

By review authors:

Possible, to obtain only individual patient data from 5 (of 13) RCTs à 55.2% (873 of 1,581) of eligible population;

Similar results to previous Meta-Analysis (Lambertini 2015) except for 1-year amenorrhea;

Lack of data on the extend of ovarian function preservation (e.g. biomarkers like anti-Müllerian hormone)

Missing data: baseline characteristic and end point data

Quality of included studies: n.a.

Level of Evidence:

Oxford 2011

Level 2

Sources of funding: Pfizer, Roche, Celgene, Amgen, Novartis (Inst)

Abbreviations:

GnRHa = Gonadotropin-releasing Hormone Agonists 

POI = Premature Ovarian Insufficiency 

DFS = Disease-free survival

OS = Overall survival

OR = Odds Ratio

HR = Hazard Ratio

IRR = Incidence Rate Ratio

95% CI = 95% Confidence Interval

RCT = Randomised Controlled Trial 

y = years

n.a. = not Available, not Applicable

NR = not Reported

Source: ZY, Li, Dong YL, Cao XZ, Ren SS, and Zhang Z. "Gonadotropin-Releasing Hormone Agonists for Ovarian Protection During Breast Cancer Chemotherapy: A Systematic Review and Meta-Analysis." [In eng]. Menopause (New York, N.Y.) 29, no. 9 (2022-9-1 2022): 1093-100. https://doi.org/doi:10.1097/GME.0000000000002019. https://pubmed.ncbi.nlm.nih.gov/35917530/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: to assess the effects of GnRHa on ovarian function in women with breast cancer

Design: Systematic review and meta-analysis

Search date: 31/01/2022

Searched databases: PubMed, Embase, Cochrane library

Included study designs: RCT

Number of included studies: 10

Number of included patients: 1,219

GnRHa group: 603

Control: 616

Mean/median age: n.a.

Inclusion criteria:

RCTs that compared the effects of GnRHa during

chemotherapy that included cyclophosphamide (GnRHa group)

with chemotherapy including cyclophosphamide alone (control

group)

(1) contained at least two treatment

groups (GnRHa plus chemotherapy and chemotherapy alone),

(2) participants were adult (18 years and older) breast cancer patients,

(3) GnRHa was administered concurrently with chemotherapy,

and

(4) cyclophosphamide was included in both the experimental

and control groups

Exclusion:

(1) studies with incomplete or missing information, (2) reviews and case reports, (3) metastatic breast cancer, and (4) inflammatory

breast cancer

Intervention

GnRHa during

chemotherapy that included cyclophosphamide (GnRHa group)

Control

chemotherapy including cyclophosphamide alone

Ovarian function

Resumed menstruation

Spontaneous pregnancy

Primary Outcome:

Ovarian function

GnRHa group:

474 of 603 patients (78.6%);

Control group:

344 of 616 patients (55.8%)

OR, 3.04, 95% CI 1.87 - 4.94; p<0.001; I²=60%

Resumed menstruation

260 of 337 patients (77.2%):

GnRHa group:

142 of 167 participants (85.0%)

Control group:

118 of 170 participants (69.4%)

OR, 2.51; 95% CI, 1.07 - 5.89; P = 0.03; I²=53%

Spontaneous pregnancy

56 of the 652 participants (9.4%) reported in 6 studies became pregnant naturally;

GnRHa group:

34 of 317 (10.7)

Control group:

22 of 335 (6.6%)

OR, 1.72; 95% CI, 0.99 - 2.99; P = 0.06; I² = 0%, P = 0.65

hormone receptor-negative participants, 39 of 378 (10.3%) became pregnant naturally;

GnRHa group:

25 of 185 (13.5%)

Control group:

14 of 193 (7.3%)

OR, 2.06; 95% CI, 1.03-4.11; P=0.04; I²=0%, P = 0.89

AMSTAR II critical appraisal tool  

Overall confidence in the results of the review: low;

1 critical flaw (item 7)

Additional concerns about quality / limitations

Only 6 studies reported pregnancy data;

10 of 11 trials were open label;

Limited follow-up time of RCTs (no information on long-term impact of GnRHa on recovery of menses and fertility)

Menses are not a reliable measure for ovarian function and fertility

Quality of included studies:

Cochrane Risk of Bias Tool:

moderate risk of study design bias

none of the 11

studies specified that all trial personnel and participants were blinded

throughout each study's course

Level of Evidence

Oxford 2011

Level 2

(downgraded due to indirectness, heterogeneity)

Sources of funding: none reported

Abbreviations:

GnRHa = Gonadotropin-releasing Hormone Agonists

RCT = Randomised Controlled Trial 

OR = Odds Ratio

95% CI = 95% Confidence Interval

n.a. = not Available, not Applicable

Source: M, Lambertini, Blondeaux E, Bruzzone M, Perachino M, Anderson RA, de Azambuja E, Poorvu PD, et al. "Pregnancy after Breast Cancer: A Systematic Review and Meta-Analysis." [In eng]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 39, no. 29 (2021-10-10 2021): 3293-305. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/34197218/.

Aim

Design and participants

Exposure and Control

Outcomes

Results

Quality and comment

Aim:

To assess the likelihood of pregnancy in women with prior history of BC, their reproductive

outcomes, and maternal safety

Design: Systematic Review and Meta-Analysis

Search date: until Oct 31, 2020

Searched databases: Medline, Web of Science, Cochrane Database

Included study designs:

retrospective or prospective case-control or cohort studies and clinical trials reporting on pregnancy after BC

Number of included studies: 39

Number of included patients:

Among the 8,263,980 women included in these studies, 8,093,401 were from the general population, 57,739 had malignancies other than BC, and 112,840 had breast tumors

Among the 112,840 patients with BC, 7,505 had a pregnancy after diagnosis

Mean/median age: NR

Inclusion criteria:

studies with available information on one or more of the

three outcomes of interest (likelihood of pregnancy after

BC, reproductive outcomes, and/or maternal safety); and

availability or possibility to estimate data on relative risk (RR), odds ratio (OR), and hazard ratio (HR), according to

the analyzed outcome, with their 95% CIs

Exclusion:

(1) case reports and case series

including less than 10 patients;

(2) studies reporting on

pregnancy-associated BC (ie, BC diagnosed during pregnancy

or within 5 years after pregnancy) with no data on

pregnancy following BC diagnosis; and

(3) ongoing studies

with the results not presented nor published at the time of the literature search

Exposure

women with breast cancer who became pregnant any time after diagnosis

Control

healthy women from the general population

breast cancer patients diagnosed at reproductive age but without subsequent pregnancy after diagnosis (comparator group for survival analysis)

1) Likelihood of pregnancy (comparison between the proportion of patients who had a pregnancy after prior history of BC versus the proportion of healthy women from the general population who had a

pregnancy and the proportion of survivors who had a pregnancy after prior history of other malignancies)

2) Reproductive outcomes in patients with prior history of BC versus those in healthy women from the general population, in terms of pregnancy completion, induced

abortion, spontaneous abortion, low birth

weight, preterm birth, intrauterine fetal death, small for gestational age, pre-eclampsia, congenital abnormalities, elective delivery, emergency caesarean section, and postpartum bleeding

3) Maternal safety by comparing survival outcomes between

BC patients with or without a subsequent pregnancy, in terms of disease-free survival (DFS) and

overall survival (OS)

1) Likelihood of pregnancy

7 records included:

Of 3,393,632 women

included in these studies, 3,289,113 were from the general population, 57,739 had malignancies other than BC, and 46,780 had breast tumors

BC survivors had a

60% reduced likelihood of having a subsequent pregnancy

(RR, 0.40; 95% CI, 0.32 to 0.49)

2) Reproductive Outcomes

9 records included:

4,817,692 women

with a pregnancy were included, of whom 4,814,452 from the general population and 3,240 had previous BC

No difference was observed between patients with BC and the general population in terms of completed pregnancies:

(OR, 1.21; 95% CI, 0.48 to 3.03),

spontaneous abortions:

(OR, 1.04; 95% CI, 0.86 to 1.26)

induced abortions:

(OR, 1.40; 95% CI, 0.71 to 2.76)

developing pre-eclampsia:

(OR, 1.03; 95% CI, 0.27 to 3.98)

and postpartum bleeding:

(OR, 0.88; 95% CI, 0.57 to 1.37)

increased risk of caesarean section was observed in patients with BC

(OR, 1.14; 95% CI, 1.04 to 1.25)

Offspring of patients with BC was at increased

risk of low birth weight

(OR, 1.50; 95% CI, 1.31 to

1.73), preterm birth (OR, 1.45; 95% CI, 1.11 to 1.88)  and small for gestational age (OR, 1.16; 95% CI, 1.01 to 1.33)

compared with the general population

No significantly

increased risk of congenital abnormalities was observed for the offspring of BC survivors (OR, 1.63; 95% CI, 0.89 to 2.98)

Subgroup analysis

As compared with offspring of women from the general population, the increased risk of low birth weight and small for gestational age appeared to be restricted to BC patients with previous exposure to chemotherapy

Maternal Safety

DFS (patients with or without pregnancy after BC)

11 studies:

Among them: 4 studies: relapse-free survival, 1 study distant recurrence-free survival, 1 study distant DFS

better DFS in those with post-treatment pregnancy:

(HR, 0.66; 95% CI, 0.49 to 0.89)

no effect of pregnancy after BC was observed in patients with hormone receptor–positive

(HR, 1.10; 95% CI, 0.73 to 1.66) or hormone receptor–negative

(HR, 0.72; 95% CI, 0.55 to 0.95) disease

The lack of detrimental effect of pregnancy after BC was

also observed irrespective of pregnancy outcome and timing of pregnancy after BC)

OS

Reported in 21 studies

compared to patients with BC without subsequent

pregnancy, those with a post-treatment pregnancy showed

better OS (HR, 0.56; 95% CI, 0.45 to 0.68)

subgroup analysis:

lack of detrimental effect of

pregnancy after BC was observed irrespective of nodal status, previous treatment, pregnancy outcome and timing of pregnancy after BC;

no effect of pregnancy after BC was observed in BRCA-mutated patients

(HR, 0.85; 95% CI, 0.51 to 1.43)

AMSTAR II critical appraisal tool 

Overall confidence in the results of the review: critically low; 4 critical flaws (items 2, 7, 9, 13)

Additional concerns about quality / limitations

Limited data for several reproductive outcomes; lack of data (patient characteristics, tumor size, anticancer therapies);

High heterogeneity in some analyses (inclusion of studies with diefferent design, sample size, inclusion criteria, period of conduction, and controlling factors)

Quality of included studies: most studies were retrospective observational

Sources of funding:  

Supported in part by the Italian Ministry of Health—5x1000 funds 2017 (no grant number) and the Italian Association for Cancer Research (AIRC; MFAG 2020 ID 24698)

Level of Evidence

Oxford 2011

Level 3

Abbreviations:

BC = Breast Cancer

DFS = Disease-Free Survival

OS = Overall survival 

HR = Hazard Ratio

OR = Odds Ratio

RR = Relative Risk

95% CI = 95% Confidence Interval

NR = not Reported

Source: V, D'Ambrosio, Vena F, Di Mascio D, Faralli I, Musacchio L, Boccherini C, Brunelli R, et al. "Obstetrical Outcomes in Women with History of Breast Cancer: A Systematic Review and Meta-Analysis." [In eng]. Breast cancer research and treatment 178, no. 3 (2019-12 2019): 485-92. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/31451975/.

Aim

Design and participants

Exposure

Outcomes

Results

Quality and comment

Aim: to evaluate the strength of association between history of BC and obstetrical outcomes

Design: Systematic Review and Meta-Analysis

Search date: up to 04/2019

Searched databases:

PubMed, Embase, Medline, Cinahl, clinicaltrials.gov

Included study designs:

retrospective cohort studies

Number of included studies: 4

published between 2006 and 2017;

study sizes: 165 to 4,031,349

Number of included patients: 1,466 cases of BC survivors;

6,912,485 controls

Mean/median age:

Maternal age:

Study group: 34.3 (range 34-34.6);

Control: 28.4 (range 27-30)

Median interval between BC diagnosis and first pregnancy: 2.21 years

Min: 1.5 y

Max: 3.08 y

Inclusion criteria:

Prospective / retrospective cohorts

reporting and describing the prevalence of

obstetrical outcomes in pregnant women with BC history

Exclusion:

personal communications,

case reports,

reviews,

conference abstracts, and case series with < 3 cases

Pregnant women with a history of BC

Comparison:

Pregnant women without a history of BC

Obstetrical complications

Preterm birth (PTB)

< 37 weeks at delivery

low birth weight (LBW):

birth weight < 2500 g;

Cesarean section

Intrauterine fetal death (IUFD): fetal demise after 20 weeks of pregnancy

Fetal anomalies: minor and major malformations, including

chromosomal anomalies

Preterm birth

Higher risk in BC patients:

OR, 1.68, 95% CI 1.43 – 1.99, I²=12%

Low-birth weight

Higher risk in BC patients:

OR, 1.88, 95% CI 1.55 – 2.27, I²=0%

Cesarean section

Higher risk in BC patients:

OR, 1.78, 95% CI 1.39 – 2.27, I²=89%

Intrauterine fetal death

OR, 1.25, 95% CI 0.36 – 4.35, I²=0%

Fetal anomalies

Higher risk in BC patients:

OR, 1.45, 95% CI 1.01 – 2.09, I²=56%

AMSTAR II critical appraisal tool 

Overall confidence in the results of the review: critically low; 3 critical flaws (items 11, 13, 15)

Additional concerns about quality / limitations

small number of included studies, their retrospective,

non-randomized design, differences between the included

populations, and dissimilar approach for the BC management

overall sample sizes might be unbalanced,

with 0.02% in the study group and 99.98% in the control group

Quality of included studies:

Assessed with Newcastle-Ottawa Scale

Level of Evidence:

Oxford 2011: Level 3

Sources of funding: no specific funding

Abbreviations: 

BC = Breast Cancer

PTB = Preterm birth

LBW = Low birth weight 

IUFD = Intrauterine Fetal Death

OR = Odds Ratio

95% CI = 95% Confidence Interval

y = years

Source: RJ, Rodgers, Reid GD, Koch J, Deans R, Ledger WL, Friedlander M, Gilchrist RB, Walters KA, and Abbott JA. "The Safety and Efficacy of Controlled Ovarian Hyperstimulation for Fertility Preservation in Women with Early Breast Cancer: A Systematic Review." [In eng]. Human reproduction (Oxford, England) 32, no. 5 (2017-5-1 2017): 1033-45. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/28333356/.

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: safety and efficacy of controlled ovarian hyperstimulation (COH) for fertility preservation in women with early breast cancer

Design: Systematic review

Search date: up to 04/2016

Searched databases: Medline, Embase, Cochrane library

Included study designs:

Prospective (n=8) and retrospective studies (n=7)

Number of included studies: 15

Number of included patients: 1,516

COH: 991

Control: 525

Mean/median age: n.a.

Study population:

premenopausal women diagnosed with Stage I– IIIB breast cancer who underwent COH in the immediate post-operative period, prior to the administration of chemotherapy

Inclusion criteria:

All COH protocols included; studies reported data on primary and secondary outcome

Exclusion: NR

Intervention

Controlled ovarian hyperstimulation

Letrozole: 882

Tamoxifen: 102

Anastrozole co-administration: 7

Control

No COH

Primary Outcome:

Breast cancer mortality /

Recurrence

Secondary Outcome:

Peak oestradiol concentration (pg/ml)

Oocyte yield

Treatment complications

Primary Outcome:

Breast cancer mortality /

Recurrence

Data from 4 studies, encompassing 464 women

1) prospective non-randomized study

COH with letrozole co-administration:

N= 120 women with Stage I–III

FU: 5.0y (SD 2.1)

Control: N=217 women with similar disease who declined fertility preservation

Treatment

FU: 6.9y (SD 3.6)

breast cancer relapse-free survival:

 HR 0.77, 95% CI 0.28–2.13; P = 0.61

recurrence:

COH group: 6/120 (5%) recurrence

Control group: 12/217 (5.5%)

P=0.86

COH prior to surgery

COH group: 1/14 (7.0%)

Control group: 5/106 (4.0%)

P=0.47

2) prospective observational study

N=29 women with Stage 0–IIIB breast cancer

COH using tamoxifen only (12 women, 13 cycles; median follow-up of 418 days (SD 109))

tamoxifen plus FSH (7 women, 9 cycles; median follow-up of 609 days (SD 89));

letrozole plus FSH (11 women, 11 cycles; median follow-up of 272 days (SD 31);

control:

31 women not undergoing fertility preservation treatment (median follow-up of 660 days (SD 71))

recurrence rate after COH

COH group:

3/29 (10.3%) women

Control group: 3/31 (9.7%) women

HR, 1.5; 95% CI, 0.29–7.4,

The duration of follow-up was significantly shorter in the letrozole-IVF

group (P < 0.001) as the letrozole protocol was added to the study after its commencement

3) Prospective observational study (national cancer registry)

COH plus tamoxifen

43 women with ER+ breast cancer

COH without tamoxifen

27 women with an oestrogen receptor negative (ER−) breast cancer

Follow-up: 3–10 years

cancer recurrence

FSH plus tamoxifen versus tamoxifen alone groups:

2/33 (6.1%) versus 2/13 (15.4%) 

Mortality:

2/33 (6.1%) versus 1/13 (7.7%)

4) Retrospective study

Recurrence

2 of 24 (8.3%) women with breast cancer who underwent COH for fertility preservation during the follow-up period of 20–52 months

(no control group, BC stage at diagnosis not reported)

Secondary Outcome:

1) Co-administration of an AI:

Peak oestradiol concentration (pg/ml)

Reduction, when letrozole is administred (5 studies)

2 studies: compared the GnRH agonist and hCG triggers in women undergoing COH with letrozole co-administration:

No difference found in peak oestradiol concentrations

Impact on oocyte yield

2 studies encompassing 122 women: no change in the oocyte yield;

2 studies: small but significant decrease in oocyte yield

2) Tamoxifen during COH

4 studies

Peak oestradiol concentrations were significantly higher in women who were administered tamoxifen versus women undergoing natural cycle IVF 

AMSTAR II critical appraisal tool  

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

Additional concerns about quality / limitations

Only observational data; small patient numbers; relatively short follow-up

Safety of COH is based on a limited number of observational studies

Quality of included studies:

Level of Evidence:

Oxford 2011

Level 3

(downgraded:

Low quality review; observational data)

Sources of funding: none

Abbreviations:

COH = Controlled Ovarian Hyperstimulation 

FU = Follow-Up

HR = Hazard Ratio

SD = Standard Deviation

n.a. = not Available, not Applicable

NR = not Reported

Source: LY, Xia, Hu QL, and Zhou Q. "Use of Trastuzumab in Treating Breast Cancer During Pregnancy: A Systematic Review and Meta-Analysis." [In eng]. BMC women's health 21, no. 1 (2021-4-21 2021): 169. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/33882925/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: to evaluate fetal safety in pregnant, breast cancer patients on trastuzumab therapy

Design: Systematic review and Meta-Analysis

Search date: up to 18/02/2020

Searched databases: Medline (PubMed) and Embase

Included study designs:

Case reports, small sample reviews

Number of included studies: 22 (included in Meta-Analysis)

Number of included patients: 22 pregnant women and 23 fetuses

Mean age of pregnant patients: 31.8

Range: 27 – 38 years

Hormone-receptor status: reported by 20 patients

15/20 (75%): hormone-receptor negative

5/20 (25%) hormone-receptor positive

Inclusion criteria:

(1) breast cancer patients were exposed to trastuzumab during pregnancy,

(2) studies including at least one of the main outcomes

Exclusion:

(1) spontaneous abortion,

(2) voluntary termination of pregnancy

Intervention

trastuzumab

2 pregnant women and 3 fetuses: combination of trastuzumab + endocrine therapy (1 case: tamoxifen; 1 case tamoxifen + goserelin)

6 pregnant women and 6 fetuses: combination of trastuzumab and chemotherapy

14 of 20 patients (70%)  that reported gestational week patients chose to continue using trastuzumab after

pregnancy confirmation

average duration use of trastuzumab: 17 weeks;

average total dose: 2791 mg

gestational age of exposure to trastuzumab: 0-34 weeks

Control: n.a.

Pregnancy,

fetal and newborn complications,

follow-up results of neonatal health

1) Pregnancy:

Gestational weeks of delivery ranged from 27 to 39 weeks, with an average of 34.3 weeks

Cesarean section

13 patients (61.9%)

Spontaneous labor

8 patients (38.1%)

(no information in 1 patient)

Complications during pregnancy:

Occurred in 77.2% of patients

Amniotic fluid reduction: 15/22 (68.2%)

Decreased ejection fraction: 2/22 (9.1%)

2) Fetal and newborn complications

Newborn

Average apgar score: 7.9

Average birth weight: 2310

Healthy newborns: 9/23 (39.1%)

Compliactions: 14/23 (60.9%)

Most common neonatal complications:

Respiratory related problems (transient tachypnoea and respiratory distress syndrome)

Trastuzumab only exposed in early pregnancy:

Fewer pregnancy and fetus related complications (compared to other periods) p=0.043

No significant difference in the incidence of neonatal complications (p=0.178)

Complications and patient age

Patients with gestational age greater than 30 years were more likely to have neonatal complications after trastuzumab during pregnancy (OR = 7.778, 95%CI 1.2–50.424, P = 0.04)

Complications and influencing factors

Pregnancy and fetal complications, neonatal complications and child deaths were not statistically different in terms of tumor stage, trastuzumab schedule, exposed time, total dose of trastuzumab, combined endocrine therapy and combined chemotherapy

3) Follow-up

4/23 (17.4%) of the children died after an average FU of 25.3 months (all of them suffer serious complications after birth) 

AMSTAR II critical appraisal tool  

Overall confidence in the results of the review: critically low; 6 critical flaws (items 2, 7, 9, 11, 13, 15)

Additional concerns about quality:

Case studies (no prospective studies have been conducted)

Only few reports on use of trastuzumab during pregnancy available

Only 2 patients used trastuzumab in early pregnancy

Quality of included studies:

Level of Evidence:

Oxford 2011

Level 4

Sources of funding: n.a.

Abbreviations:

95% CI = 95% Confidence Interval

n.a. = not Available, not Applicable

Source: A, Andrikopoulou, Apostolidou K, Chatzinikolaou S, Bletsa G, Zografos E, Dimopoulos MA, and Zagouri F. "Trastuzumab Administration During Pregnancy: An Update." [In eng]. BMC cancer 21, no. 1 (2021-4-26 2021): 463. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/33902516/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: effect of trastuzumab on fetal and maternal outcome

Design: Systematic Review

Search date: up to 01/09/2020

Searched databases: MEDLINE, ClinicalTrials.gov

Included study designs:

Case studies

Number of included studies: 28

Number of included patients: 30 patients and 32 fetuses (exposed to trastuzumab during pregnancy)

Mean/median age:

Mean age of patients at pregnancy

31.1 years (SD: 3.96; median:

31.5; range 23–38)

mean age at breast cancer diagnosis was 29.9 years (SD: 4.21; median: 30.0; range: 22–38)

Inclusion criteria:

All studies that examined the efficacy and safety of trastuzumab during pregnancy

administration of trastuzumab at some

point during pregnancy even if treatment commenced

prior to pregnancy initiation

prospective, retrospective studies, case reports

Exclusion:

all cases where therapeutic or spontaneous

abortion occurred

articles

assessing trastuzumab administration before or after the

gestation period

Intervention

Trastuzumab during pregnancy

As monotherapy regimen (14 cases);

Combination with: pertuzumab (1 study);

vinorelbine (2 studies);

paclitaxel (2 studies);

docetaxel and carboplatin (2 studies);

tamoxifen (3 studies);

tamoxifen and lapatinib (1 study);

docetaxel and cyclophosphamide (1 study);

doxorubicin and cyclophosphamide and paclitaxel (1 study);

concurrently with brain RT (1 study)

in more than half of the cases administered in metastatic setting

The mean duration of trastuzumab administration

during gestation was 15.7 weeks (SD: 10.8; median: 17.5;

range: 1–32)

23.3% of patients

were exposed to trastuzumab during all trimesters of pregnancy

20.0% of patients with breast cancer were exposed to trastuzumab

exclusively during the first trimester

Control

-

Fetal outcomes:

Oligohydramnios or anhydramnios;

Cesarean section;

Gestational age at delivery;

Birth weight at delivery;

Completely healthy neonate;

Maternal outcomes: cardiotoxicity; decreased ejection fraction

Adverse events

1) Fetal outcomes

Complications with Oligohydramnios or anhydramnios in 58.1%

17 of 24 pregnancies (70.8%) trastuzumab was administered during the second or/and third

trimester

1 of the 6 cases (16.7%) of trastuzumab exposure exclusively during first trimester

à trend pointing to a

positive association between the duration of trastuzumab

treatment and the development of oligohydramnios or

anhydramnios:

OR 1.05, 95% CI: 0.96–1.14, increment: 1 week, P = 0.316

Cesarean section:

in 67.9% of cases;

9 pregnancies: vaginal delivery

Gestational age at delivery:

Mean: 34.6 weeks (SD: 3.26)

Median: 35.4 (range: 27-39)

Birth weight at delivery

Mean: 2371g (SD: 771.2)

Median: 2490 (range: 1015-3820)

Completely healthy neonate:

In 13 cases (43.3%)

The remaining cases:

renal agenesis/hypoplasia (2 cases),

mild transient tachypnoea (three cases),

respiratory distress syndrome (six cases),

respiratory failure (two cases), renal failure (three cases), transient respiratory failure

and elevated creatinine (one case),

severe pulmonary hypoplasia (one case),

capillary leak syndrome

and necrotizing enterocolitis (one case),

pulmonary hypertension and persistence of arterial canal (one case),

prematurity-related disorders (two cases),

conductive hearing loss and mild hypertonia/hyperreflexia

(one case),

bacterial sepsis (one case),

cardiorespiratory arrest (one case)

41.7% (10 out of 24) of fetuses exposed to trastuzumab during the second and/or third trimester

were born completely healthy

and 75.0% of fetuses (3 cases) exposed exclusively in the first trimester

à trend pointing to a negative association between the duration of trastuzumab administration and the delivery of a completely

healthy neonate did not reach statistical significance

OR = 0.921, 95% CI: 0.85–1.00, P = 0.061

2) Maternal outcomes

all patients with breast cancer were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months), while

only two patients relapsed during follow-up according to

existing data;

three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy 

AMSTAR II critical appraisal tool

Overall confidence in the results of the review; critically low; 4 critical flaws (items 2, 7, 9, 13)

Additional concerns about quality:

Case studies

Quality of included studies: n.a.

Level of Evidence:

Oxford 2011: Level 4 (downgraded due to low quality review and low quality studies)

Sources of funding: no specific funding

Abbreviations:

RT = Radiation Therapy

SD = Standard Deviation

OR = Odds Ratio

95% CI = 95% Confidence Interval 

n.a. = not Available, not Applicable

Source: TN, Schuurman, Witteveen PO, van der Wall E, Passier JLM, Huitema ADR, Amant F, and Lok CAR. "Tamoxifen and Pregnancy: An Absolute Contraindication?" [In eng]. Breast cancer research and treatment 175, no. 1 (2019-5 2019): 17-25. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/30707336/.

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: effect of tamoxifen exposure during pregnancy

Design:  Systematic Review

Search date: up to 04/10/2018

Searched databases:

PubMed, database of the Netherlands

Pharmacovigilance Centre Lareb, database of the International Network on Cancer, Infertility and Pregnancy

Included study designs:

case reports and reviews of case reports

Number of included studies: 14

Number of included patients: 238 pregnancies

Mean/median age: n.a.

Inclusion criteria:

English / Dutch language

study reporting on the

research question of this review

Exclusion:

studies not meeting

the research question

animal studies

Intervention

Tamoxifen

Control

-

Safety of tamoxifen

congenital abnormalities

fetal defects

total number of 238 pregnancies during tamoxifen therapy

Of the 142 live

births documented, 13 infants had a congenital malformation (1:11)

including the pregnancies without live birth but with documented fetal outcome, a total of 21 out of 167 pregnancies were complicated by fetal defects (1:8)

71 of the reported 238 pregnancies were not included in this evaluation, since 56 pregnancies had an unknown outcome, 12 spontaneous abortions occurred without known cause, and 2 induced abortions and 1 ectopic pregnancy were reported

total incidence of congenital anomalies cannot be assessed adequately based on these findings

number of reports on tamoxifen therapy after the first trimester was very limited, but one article was found showing three known congenital abnormalities out of 15 pregnancies

overall miscarriage rate: 6.7%

AMSTAR II critical appraisal tool  

Overall confidence in the results of the review: critically low; 3 critical flaws (items 2, 7, 9)

Additional concerns about quality:

General low quality of evidence (based on case reports and other retrospective data); reporting bias due to the fact that adverse outcomes are much more likely to be documented

no causal relationships;

additional risk factors; lack of long-term follow-up of the exposed infants;

Quality of included studies:

Low quality studies

Level of Evidence:

Oxford 2011

Level 4 (downgraded due to low quality review and low study quality)

Sources of funding: n.a.

Abbreviations:

n.a. = not Available, not Applicable

Source: AC, Fledderus, Gout HA, Ogilvie AC, and van Loenen DKG. Breast Malignancy in Female-to-Male Transsexuals: Systematic Review, Case Report, and Recommendations for Screening. (2020-10 2020). https://pubmed.ncbi.nlm.nih.gov/32679529/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: Authors aimed to provide an insight into the reported

number of Female-to Male (FtM) transsexuals developing breast cancer after

testosterone therapy by systematically reviewing the literature and

evaluating the evidence regarding associations between testosterone

therapy and breast cancer

Design: Systematic Review

Search date: Search was performed 06/2020

Searched databases:

PubMed/Medline, Ovid/Embase

Included study designs:

Case reports, Cohort studies

Number of included studies: 22

Number of included patients: n.a.

Mean: 42 years

Median age: 41 year

Inclusion criteria:

All articles evaluating breast cancer in FtM transsexuals after testosterone therapy were deemed

eligible.

Exclusion: /

Incidence

Incidence:

The incidence of breast cancer cases described in the FtM transsexuals

cohort studies is shown to be significantly lower than the breast

cancer incidence in natal women.

The lower incidence of breast cancer found in the studies can

be attributed to the performed mastectomies.

Breast cancer screening of FtM transsexuals prior to mastectomy and histological examination of the mammalian tissue after mastectomy could be considered. When breast tumors are discovered before

mastectomy, tumors can be removed more precisely.

In consultation with every individual FtM transsexual, physicians can decide if screening before and after mastectomy is necessary.

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: 3 critical flaws (items 2, 7, 13)

Overall quality of evidence: critically low

Additional concerns about quality:

Due to the low level of

evidence (case reports) and high risk of bias of the included cohort

studies, it is not possible to conclude a correlation between hormone therapy and the development of breast cancer. All cohort studies and case reports did not report screening for cancer in advance of testosterone therapy, which complicates the

evaluation of its potential causal relationship with cancer.

Confounders were

poorly described and none was appropriately corrected for in the

analysis.

Quality of included studies: JBI tools used.

Case Reports do not match the AMSTAR 2 criteria.

Due to the small study population we propose to downgrade the level of evidence from 3a to 3b

Sources of funding:

There was no funding for this study.

Abbreviations:

FtM = Female-to Male 

n.a. = not Available, not Applicable

Source: R, Joint, Chen ZE, and Cameron S. "Breast and Reproductive Cancers in the Transgender Population: A Systematic Review." [In eng]. BJOG : an international journal of obstetrics and gynaecology 125, no. 12 (2018-11 2018): 1505-12. https://doi.org/doi:. https://pubmed.ncbi.nlm.nih.gov/29706033/.

Aim

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: To assess breast and reproductive cancer prevalence in

the transgender population. To elucidate any associations between

gender-affirming hormones and risk of these cancers.

Design: Systematic Review

Search date: Search was performed 02/2017

Searched databases:

MEDLINE, Embase, PsycINFO, The Cochrane Library, Web of Science

Included study designs:

Case-control, Cohort, Case report,

Number of included studies: 43

Number of included patients: n.a.

Mean/median age: n.a.

Inclusion criteria:

Peer-reviewed and possesses primary data relating specifically to the population of interest Population: persons that identify as transgender Exposures (investigation, experience or discussion of):

a) A positive diagnosis by a medical professional of one or more of: breast cancer, cervical cancer, uterine cancer, ovarian cancer, (neo)vaginal cancer, prostate cancer, and testicular cancer

b) Treatment for one or more of the above mentioned cancers Comparator (where available): persons that identify as non-transgender or cisgender

Outcomes: a) Rates of breast cancer, cervical cancer, uterine cancer, ovarian cancer, (neo)vaginal cancer, prostate cancer, or testicular cancer

b) Treatment regimen for one or more of: breast, cervical cancer, uterine cancer, ovarian cancer, (neo)vaginal cancer, prostate cancer, and testicular cancer Study design: randomised control trials, case-control studies, cohort studies, crosssectional studies, and case reports

Exclusion:

Does not make clear the natal sex and gender identity of participants

Study design: secondary studies, opinions, editorials, and conference abstracts Purely addresses screening of breast or reproductive cancers

Incidence

Incidence:

Evidence relating to breast cancers in the trans population is limited and insufficient to estimate cancer prevalence.

A small number of studies and consisting of incidence rates and histopathological findings does not suggest that there is an increased risk of breast cancers associated with the use of gender-affirming hormones.

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: 1 critical flaw (items 2)

Overall quality of evidence: low

Additional concerns about quality:

The review was limited by a lack of clinical and epidemiological data for prevalence estimation or for further analysis investigating an association between gender-affirming hormones and breast/reproductive cancer.

A unique limitation was the varying language used to describe the trans population.

Articles were often excluded because they lacked data relating specifically to trans people.

The results of some studies were presented without  distinction between trans and cis people, as all participants were represented by the LGBT acronym.

Quality of included studies: GRADE

The overall evidence quality was very low to low.

Planned included studies: /

Due to the small study population we propose to downgrade the level of evidence from 3a to 3b

Sources of funding:

No funding was received.

Abbreviations:

n.a. = not Available, not Applicable

LGBT = Lesbian, Gay, Bisexual, and Transgender

Source: Stone JP, Hartley RL, Temple-Oberle C. Breast cancer in transgender patients: A systematic review. Part 2: Female to Male. Eur J Surg Oncol. 2018 Oct;44(10):1463-1468. doi: 10.1016/j.ejso.2018.06.021. Epub 2018 Jul 5. PMID: 30037639.

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: The aim is to perform a systematic review of the literature and document all reported cases of FtM breast cancer as well as provide research recommendations

Design: Systematic Review

Search date: from inception

to 01. April 2018

Searched databases:

MEDLINE, ProQuest, PubMed, Cochrane Database of Systematic Reviews, Google Scholar

Included study designs:

Case Report, Cross-sectional, Case series, Retrospective Cohort

Number of included studies: 8

Number of included patients: n.a.

Mean/median age: n.a.

Inclusion criteria:

Both MtF and FtM studies were included in level one and

two screening to encompass all possible cases.

Exclusion:

Articles were excluded, if they have no transgender patients, no confirmed breast cancer events in transgender patients or no breast cancer screening in transgender patients were excluded. 

Incidence

Incidence:

The predominant screening recommendations

for transgender men are conservative, recommending screening as per natal females with mammograms every two years between the ages of 50 and 69, regardless of CSH.

While FtM patients appear to have a decreased risk of breast cancer than natal females after top surgery, there is limited research to determine at which risk threshold is it acceptable to withhold breast cancer screening in this population.

AMSTAR II critical appraisal tool

Overall confidence in the results of the review: 3 critical flaws (items 2, 7,  13)

Overall quality of evidence: critically low

Additional concerns about quality: However, because transgender recognition and transgender literature are relatively new, this may reflect a latent period, where the disease has been initiated but the presence of symptoms not yet manifested.

Quality of included studies: Overall, study quality was low.

Level of evidence (Oxford 2011: 3)

Sources of funding:

The authors have no financial disclosures.

Abbreviations:

FtM = Female-to-Male 

MtF = Male-to-Female 

CSH = Cross-Sex Hormone

n.a. = not Available, not Applicable

Shen, Z, Sun, J, Yu, Y, Chiu, C, Zhang, Z, Zhang, Y, et.al. Oncological safety and complication risks of mastectomy with or without breast reconstruction: A Bayesian analysis.. J Plast Reconstr Aesthet Surg, 2021. 74 (2)(2): p. 290-299., https://pubmed.ncbi.nlm.nih.gov/33093010/.

Source and Purpose

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: ““..surgeons and researchers remain uncertain about the oncological safety of breast reconstruction. 13 Which surgical choice offers the greatest balance of benefits and risks is still unclear. Therefore, a systematic review of the current literature with a Bayesian network meta-analysis was con- ducted to compare data on oncological safety and compli- cation risks among the MA, IBR, and DBR groups.

Design: Systematic review with Metaanalysis

Study design

Cohort studies, case control studies

Search dates

November 2019

Databases:

Cochrane library

PubMed/MEDLINE

EMBASE

China National Knowledge Infrastructure

Inclusion criteria

prospective or retrospective studies that enrolled breast cancer patients with MA alone or breast re- construction (IBR and DBR) after MA

comparisons of any two or three surgical options (MA, IBR, or DBR)

report on at least one of the outcomes for oncological safety (disease- free survival (DFS), overall survival, local recurrence, and distant metastases) and complication risks (overall compli- cations, surgical site infection, and lymphedema)

Exclusion criteria:

studies enrolling participants with prophylactic MA or primary breast augmentation or the ones published be- fore 2000

Intervention

A: IBR

B: DBR

C: No reconstruction (Mastectomy only)

Complications

Complications

IBR vs. no reconstruction (A vs. C)

• 6 studies
• Effect: OR: 0.78 (95%-CI: 0.43 – 1.44); I²:97.6%

Risk of bias assessment of studies: not assessed, reassessed for the current clinical guideline

Overall confidence in results of SR (AMSTAR-2): moderate

PICO elements: yes

A priori design: partial yes

Justification for design: no

Literature search >= 2 databases, search strategy + other sources:

• 3 databases

• String for PubMed provided

• No further resources searched

Selection in duplicate: yes

Data extraction in duplicate: yes

List of excluded studies: no

sufficient detail on studies: partial yes

RoB assessed: no (NOS was used to assess the quality of the cohorts, but no results reported on each study included)

Funding of incl. studies: no

MA appropriate: yes

RoB considered in MA: no

RoB in interpretation: no

Heterogeneity explained: no

Publication bias investigated: yes

Sources of CoI: The authors report no conflicts of interest.

Sources of funding

NR

Broyles, JM, Balk, EM, Adam, GP, Cao, W, Bhuma, MR, Mehta, S, et.al. Implant-based versus Autologous Reconstruction after Mastectomy for Breast Cancer: A Systematic Review and Meta-analysis.. Plast Reconstr Surg Glob Open, 2022. 10 (3)(3): p. e4180., https://pubmed.ncbi.nlm.nih.gov/35291333/.

Source and Purpose

Design and participants

Intervention

Outcomes

Results

Quality and comment

Aim: This “Given the preference sensitive nature of breast reconstruction, the evolving nature of the evidence, and the lack of an agreed-upon preferred surgical modality, we conducted a systematic review (SR) with meta-analysis to assess the benefits and surgical complications of IBR versus AR after mastectomy for breast cancer (or prophylaxis).”

Sources of funding: The authors have no financial interest to declare in relation to the content of this article. This project was funded under Contract No. HHSA 75Q80120D00001 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services.

Design: Systematic review with Metaanalysis

Search dates

From database inception through March 23, 2021

Databases:

Medline (via PubMed)

Embase

Cochrane Central Register of Controlled Trials (CENTRAL)

CINAHL

ClinicalTrials.gov

Inclusion criteria:

NR

Exclusion criteria:

Does not address any Key Question (n=313)

>=10% of patients underwent breast augmentation (n = 7)

>=10% of patients underwent revision reconstruction (n=3)

Does not address breast reconstruction (n = 17)

Does not address mastectomy for breast cancer (n = 5)

Does not report any outcome of interest (n=28)

 Protocol/methods only with no results (n = 20)

NRCS, N<30 participants per arm (n = 103)

NRCS without adequate adjustment (n = 234)

 Single group studies, N<500 participants (n = 187)

 Single group studies, N> 500 participants, no surgical complications data (n=26)

Case report or series of case reports (n = 7)

Narrative review/commentary (n=55)

Systematic review (n = 20)

Copublication of included study with no new data (n=35)

Unable to retrieve article (n = 20)

Duplicates (n = 70)

Did not address any key question addressed in current review (n = 61)

Single-group studies (n = 86)

Intervention vs. Comparator

A: Autologous

B: Implant

1) BREAST-Q QoL

2) Mortality

3) Surgical complications

4) Reconstructive failure

BREAST-Q QoL outcomes

Satisfaction with breasts

7 studies reportedthis outcome

3 studies (pooled data)

Overall Mean difference: 8.08 (95% CI 6.11 to 10.05) in favor of autologous breast reconstruction

Physical well-being

 6 studies reported this outcome, no pooled data

Overall Mean difference: NR

“Results were inconsistent across studies.”

General Quality of Life

3 studies reported this outcome, no pooled data

Overall Mean difference: NR

“For each instrument in each study, differences in general quality of life between IBR and AR were not statistically significant.”

Psychosocial well-being

5 studies reported this outcome

3 studies (pooled data)

Overall Mean difference 3.14 (95% CI 1.26 to 5.02) 

Sexual well-being

4 studies reported this outcome

3 studies (pooled data)

Overall Mean difference 5.83 (95% CI 3.44 to 8.23) in favor of autologous breast reconstruction

Mortality

1 study reported this outcome

Overall: adjusted OR 0.96, 95% CI 0.89–1.04

Surgical complications

3 studies reported this outcome

No pooled data

Reconstructive failure

4 studies reported this outcome

No pooled data

Risk of bias assessment of studies: 25 of the 38 NRCSs had a high risk of bias (mostly due to critical or serious risk of confounding and lack of blinding) and 13 had a moderate risk (mostly due to lack of blinding). RCTs had moderate risk of bias.

Overall confidence in results of SR (AMSTAR-2):

PICO elements: partially described

A priori design: no

Justification for design: no

Literature search >= 2 databases, search strategy + other sources:

• 3 databases

• String for PubMed provided

• No further resources searched

Selection in duplicate: yes

w Data extraction in duplicate:

• “All extracted data were confirmed by a second, independent researcher.”

•  List of excluded studies: no

sufficient detail on studies: no

RoB assessed: yes

Funding of incl. studies: no

RoB considered in MA: no

RoB in interpretation: yes

Heterogeneity explained: no

Publication bias investigated: no

Sources of CoI: yes (see Sources of funding)

Sources of funding

The authors have no financial interest to declare in relation to the content of this article. This project was funded under Contract No. HHSA 75Q80120D00001 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services.