Long-Term Breastfeeding is associated with Improved Pathological Response and Reduced Oncogenic Mutations in Triple Negative Breast Cancer

Breastfeeding has been associated with a reduced risk of developing triple-negative breast cancer (TNBC), but its impact on tumor biology and treatment response remains unclear. We analyzed 43 patients with TNBC treated with taxane-based neoadjuvant chemotherapy (NAC), integrating detailed reproductive histories with clinicopathological features and targeted next-generation sequencing of pre- and post-treatment tumor samples. Long-term breastfeeding (≥ 6 months) was significantly associated with higher pathological complete response (pCR) rates (57% vs. 27%), as well as a lower mutational burden and reduced prevalence of alterations in KIT, NOTCH1, CDKN2A, and KDR. Non-responding tumors were enriched in KDR mutations suggesting a potential role in chemoresistance. NOTCH1 and CDKN2A mutations correlated with increased mutational burden, indicating enhanced genomic instability These findings suggest that extended breastfeeding may imprint lasting biological effects that shape mammary epithelial stability, immune surveillance, and subsequent chemosensitivity. Recent mechanistic evidence supports this concept, showing durable T-cell–mediated immunoprotection and epigenetic/metabolic programming induced by lactation. Although limited by sample size, our results provide the first clinical and genomic evidence linking breastfeeding duration with therapy response in TNBC and underscore the relevance of reproductive history in shaping tumor behavior and treatment outcomes.