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

IMPORTANCEIn 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. OBJECTIVEDetermine 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 PARTICIPANTSThis prospective cohort study includes 903 women with germline BRCA1/2 PVs diagnosed with stage I-III breast cancer at [&le;]45 years of age, between 1950-2021 in the UK. MAIN OUTCOMES AND MEASURESThe 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 [&ge;]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. RESULTSFor all BRCA PV carriers, increased all-cause mortality was observed in women diagnosed >0-<10 years postpartum, compared to nulliparous and [&ge;]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 RELEVANCEYoung-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 PointsO_ST_ABSQuestionC_ST_ABSIs a postpartum diagnosis an independent risk factor for mortality among young-onset breast cancer patients with germline BRCA1/2 PVs? FindingsA diagnosis <10 years postpartum associates with higher risk of mortality compared to nulliparous and [&ge;]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. MeaningA 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.