Interaction of BRCA1 vs BRCA2 pathogenic variants with primary tumor location in pancreatic cancer.

Abstract

e16326 Background: BRCA1/2 germline or somatic pathogenic variants (PVs) are found in 5-10% of pancreatic adenocarcinoma (PDAC) patients. Recent data suggest that BRCA2 PVs may be associated with increased overall survival (OS) compared to BRCA1 PVs after adjusting for treatment and clinical characteristics. Additionally, pancreatic tail PDAC was found to harbor PVs in BRCA1/2 more frequently compared to PDAC within the pancreatic head (HOP). We hypothesized that tumor location in patients with BRCA1 and BRCA2 PVs would associate with overall survival and somatic mutation profile. Methods: We conducted a retrospective cohort study using a database of patients with PDAC and BRCA1/2 PVs at an academic center. Demographic and clinical data were compared by Fisher’s exact test. OS was measured using date of death or last follow-up and compared by Cox proportional hazards regression adjusting for treatment with platinum-based chemotherapy and curative-intent surgical resection. Cases with available next generation somatic sequencing were reviewed. Results: There were no significant differences in age, sex, stage at diagnosis, ECOG status at diagnosis, tumor location, treatments, or sites of metastasis between patients with BRCA1 vs BRCA2 PVs. In the overall cohort, we observed no significant difference in OS between patients with BRCA1 vs BRCA2 (17.0 vs 20.2 months). However, survival analysis stratified by tumor location demonstrated that BRCA1 patients with HOP tumors had significantly worse OS compared to BRCA2 patients with HOP tumors (13.1 vs 25.7 months, p = 0.014) and had a significantly higher rate of TP53 mutations (100% vs 50%, p = 0.032). No significant differences in OS or rates of TP53 mutations were observed in the body/tail of the pancreas. Conclusions: These results suggest that there may be differences in rates of somatic variants between BRCA1- and BRCA2-related HOP PDAC and suggest an interaction between BRCA1/2 tumor biology and anatomical location. [Table: see text]