Premenopausal women with breast cancer in the early postpartum period show molecular profiles of invasion and are associated with poor prognosis

Abstract

Background Though pregnancy and lactation are considered as protective factors against development of breast cancer (BC), small proportion of young premenopausal women develop tumors within 5 to 10 years of last childbirth presenting with aggressive disease. The exact mechanisms that lead to poor prognosis in these postpartum breast cancers (PPBC) is largely unknown. Methods We have evaluated the association of clinical and reproductive factors with BC in a cohort of women ≤ 45 years (N = 155) with long term follow up. Based on duration since last childbirth (LCB), they were grouped into PPBC1 (LCB ≤ 5 years), PPBC2 (LCB between 6–10 years), PPBC3 (LCB > 10 years) and NPBC (age matched nulliparous BC patients). Disease free survival and hazard associated with recurrence/metastasis were compared between the groups. RNA sequencing of tumor samples from three different parous groups (n = 10) was performed and transcriptomic data was analyzed for differentially expressed genes and altered pathways. Results Women in the PPBC1 group had an early menarche and late first and last childbirth compared to other groups. Survival analysis within lymph node positive tumors showed that PPBC1 tumors had a worse prognosis compared to PPBC2 and NPBC tumors (p = 0.015, and p = 0.026 respectively with a higher hazard both by univariate and multivariate analysis). Clustering of the differentially expressed genes between the groups showed distinct expression in early PPBC (PPBC1) tumors. Pathway analysis revealed upregulation of invasive signature along with T cell exhaustion, extracellular matrix remodeling, angiogenesis and epithelial to mesenchymal transition within early PPBC tumors. Conclusion PPBC diagnosis may represent a unique subtype of cancer that requires distinct clinical and translational research to understand altered pathways. Clinical parameters and biologic subtyping alone may be insufficient to accurately project the risk of recurrence and optimal treatment strategies in young patients who develop BC in the early postpartum period.