A Postpartum Breast Cancer Diagnosis Reduces Survival in Germline BRCA pathogenic variant Carriers

IMPORTANCE In young-onset breast cancer, a diagnosis within 5-10 years of childbirth associates with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with breast cancer at younger ages, but the impact of childbirth on mortality is unknown. OBJECTIVE Determine whether time between recent childbirth and breast cancer diagnosis impacts mortality among young-onset breast cancer patients with germline BRCA1/2 PVs. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study includes 903 women with germline BRCA1/2 PVs diagnosed with stage I-III breast cancer at ≤45 years of age, between 1950-2021 in the UK. MAIN OUTCOMES AND MEASURES The primary outcome is all-cause mortality, censored at 20 years post-diagnosis. The primary exposure is time between most recent childbirth and breast cancer diagnosis, with recent childbirth defined as >0-<10 years post childbirth (n=419)], further delineated to >0-<5 years (n=228) and 5-<10 years (n=191). Mortality of nulliparous cases (n=224) was compared to the recent postpartum groups and the ≥10 years postpartum (n=260) group. Cox proportional hazards regression analyses were adjusted for patient age, tumor stage, further stratified by tumor estrogen receptor (ER) and BRCA gene status. RESULTS For all BRCA PV carriers, increased all-cause mortality was observed in women diagnosed >0-<10 years postpartum, compared to nulliparous and ≥10 years groups, demonstrating the transient duration of postpartum risk. Risk of mortality was greater for ER-positive cases in the >0-<5 group [HR=2.35 (95% CI, 1.02-5.42)] and ER-negative cases in the 5-<10 group [HR=3.12 (95% CI, 1.22-7.97)] compared to the nulliparous group. Delineated by BRCA1 or BRCA2 , mortality in the 5-<10 group was significantly increased, but only for BRCA1 carriers [HR=2.03 (95% CI, 1.15-3.58)]. CONCLUSIONS AND RELEVANCE Young-onset breast cancer with germline BRCA PVs confers increased risk for all-cause mortality if diagnosed within 10 years of childbirth, with risk highest for ER+ cases at >0-<5 years postpartum, and for ER-cases at 5-<10 years postpartum. BRCA1 carriers are at highest risk for poor prognosis when diagnosed at 5-10 years postpartum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers. Question Is a postpartum diagnosis an independent risk factor for mortality among young-onset breast cancer patients with germline BRCA1/2 PVs? Findings A diagnosis <10 years postpartum associates with higher risk of mortality compared to nulliparous and ≥10 years postpartum cases. Peak risk after childbirth varies for ER-positive (>0-<5 years) vs. ER-negative cases (5-<10 years). BRCA1 carriers had peak risk of mortality 5-10 years postpartum, with no associations observed for BRCA2 carriers. Meaning A breast cancer diagnosis within 10 years of childbirth independently associates with increased risk for mortality in patients with germline BRCA1/2 PVs, especially for carriers of BRCA1 PVs. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was supported by funding from the Oregon Health & Science University's Knight Cancer Institute (Z. Zhang), the National Institute of Health (NIH) Office of Research on Women's Health and the National Institute of Child Health and Human Development K12HD043488 (Building Interdisciplinary Research Careers in Women's Health, BIRCWH) (Z. Zhang), the International Alliance for Cancer Early Detection (ACED) Grant, the NIH/National Cancer Institute R01CA169175 (P Schedin), the Prevent Cancer Foundation Fellowship (S. Bernhardt), and the resources to P Schedin from the Willard L. and Ruth P. Eccles and Leonard Schnitzer Family Foundations. We also thank the Knight Cancer Institute's Cancer Center Support Grant P30CA69533. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The parent study was approved by the University of Manchester ethics review board. Oregon Health & Science University (OHSU) received de-identified data and the research was approved as exempt for the secondary-data analyses study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors