A Postpartum Breast Cancer Diagnosis Reduces Survival in GermlineBRCApathogenic 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 >0-0-<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 >0-0-<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. Key Points 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 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.