32P Genomic risk classification and whole transcriptome analysis of HR+/HER2- post-partum breast cancers: A FLEX sub study

Women diagnosed under the age 45 and within 5-10 years of a childbirth have increased risk of metastasis. These high-risk cancers, defined as post-partum breast cancer (PPBC), have significantly worse prognosis independent of clinical-pathologic features and demonstrate treatment resistance. We hypothesized that PPBC exhibits high risk molecular profile and sought to define the genomic patterns of PPBC. The prospective, observational FLEX Study (NCT03053193) includes stage I-III early BC patients who received MammaPrint®(MP) and/or BluePrint®(BP) testing and consented to full transcriptome and clinical data collection. We identified 377 HR positive and HER2-negative patients, age ≤50, grouped as PP 0-5 years n=33; PP 6-10 years n=51. Two control groups PP >10 years n=175 and nulliparous n=118 were used for comparison. Median age, clinical characteristics, metabolic factors, and genomic test results (MP and BP) were compared between PP groups and nulliparous. Limma R package was used for differential gene expression analysis in age-matched cohorts. Pathway analysis was conducted using Metascape. PPBC 0-5 had a significantly higher frequency of MP High 2 and lower frequency of MP Low Risk compared to nulliparous women (p=0.02). PP 0-5 had higher frequency of Luminal B and Basal compared to PP >10 years (p=0.01). In gene expression analysis, PP 0-5 cohort had 25 genes with 2-fold higher expression compared to nulliparous including genes like MUCL1, CLEC3A, CXCL9. Pathway analysis demonstrated increased adaptive immune-mediated and humoral- response pathways in PP 0-5 years. In this study, PPBC 0-5 years of childbirth demonstrates significantly higher risk of recurrence (MP High 2) and increased immune gene expression, other unique genes/pathways related to PPBC biology compared to BC occurring >10 years after childbirth or in nulliparous women. These findings are consistent with the poor clinical outcomes previously reported for PPBC. Increased frequency of MP High 2 tumors and immune biology indicate that PPBC might benefit from adding immunotherapy, to be explored in future trials.