Timing of breast cancer diagnosis postpartum and survival in women with germline pathogenic variants.

Parity and breastfeeding reduce lifetime breast cancer (BC) risk, but the postpartum period is associated with transiently increased risk and poor outcomes. The prognostic significance of reproductive timing in women with germline pathogenic susceptibility variants (PVs) remains unclear. We evaluated the association between time since last childbirth, breastfeeding, and other reproductive variables and overall survival (OS) in a large Australian hereditary BC cohort. We conducted a retrospective cohort study of 1200 female PV carriers with invasive BC enrolled in the Kathleen Cuningham Foundation Consortium (1980-2022). Eligible participants carried class 4-5 PVs in high- or moderate-penetrance BC susceptibility genes and had no pregnancies after BC diagnosis. Time since last childbirth was categorised as nulliparous, <10 years, or ≥10 years, with further analyses using five postpartum intervals. Cox proportional hazards models, adjusted for age, oestrogen receptor (ER) status, chemotherapy, surgery, and radiotherapy, were used to assess associations with OS. Of 1200 women (median follow-up, 13 years), 52% were diagnosed ≥10 years postpartum, 32% were diagnosed <10 years, and 16% were nulliparous. Women diagnosed <10 years postpartum were younger (median 36 compared with 48 years, P < 0.001), more likely to carry BRCA1 PVs, and had more ER-negative disease. Diagnosis ≥10 years postpartum was associated with improved OS compared with nulliparity [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.43-0.92, P = 0.02]. In parous women, breastfeeding compared with no breastfeeding (HR 0.49, 95% CI 0.33-0.73, P < 0.001) and diagnosis ≥10 vs <10 years since last childbirth (HR 0.48, 95% CI 0.31-0.74, P < 0.001) independently predicted better OS. In women with PVs, longer time since last childbirth and breastfeeding were independently associated with improved survival following BC diagnosis. These findings identify reproductive timing and lactation as important prognostic modifiers in hereditary BC and may inform risk stratification and survivorship care.