[Abstract] Association of BRCA1/2 pathogenic variants with primary tumor location and metastatic organotropism in pancreatic adenocarcinoma

Abstract

Background: Pancreatic cancers (PDACs) with BRCA1/2 pathogenic variants (PVs) are prognostically favorable and predict response to platinum-based treatment. Recent data suggest that these mutations may be more strongly associated with cancers arising from the body/tail (B/T) compared to the head of the pancreas (HOP). Primary tumors of the B/T are known to frequently metastasize to the peritoneum, which is thought to be largely due to anatomic location. We hypothesized that BRCA1/2 PVs may interact with tumor location in determining sites of metastatic spread.

Methods: We conducted a retrospective study using a database of patients with BRCA1/2 PVs and PDAC as well as wildtype (WT) control patients matched for age, sex, year and stage at diagnosis. Demographic and clinical data were compared by Fisher’s exact test. Adjusted odds ratios for each site of metastasis or somatic variant were estimated using logistic regression with backwards stepwise AIC minimization. Cases with diagnosed metastases and available next generation somatic sequencing were included in the respective logistic regression models.

Results: Patients with BRCA1/2 PVs were more likely to have masses in the B/T compared to control patients [51.6% vs 31.0%; p-value < 0.001]. After adjusting for age, sex, platinum-based chemotherapy, curative-intent surgical resection, and primary location, patients with BRCA1/2 PVs were less likely to develop peritoneal metastases compared to control patients (see table, row 3). Additionally, for patients with B/T masses, the rate of peritoneal spread was significantly lower in those with BRCA1/2PVs compared to those without (OR: 0.41 [0.20, 0.83]). We did not observe a significant association between BRCA1/2 PV and peritoneal spread in patients with HOP masses (OR: 1.09 [0.48, 2.5]). Furthermore, patients with BRCA1/2PVs were significantly less likely to have a TP53 mutation compared to controls (51% vs 71%; p = 0.038). This association persisted after adjusting for the variables described above (see table, row 3). No significant differences were found for mutations in KRAS (83% vs 86%; p = 0.60), SMAD4 (16% vs 13%; p = 0.59), or CDKN2A (19% vs 29%; p = 0.13).

Conclusions: Our data suggest that patients with BRCA1/2-related PDAC are more likely to present with B/T masses compared to WT patients, are less likely to have TP53 mutations and are less likely to have peritoneal spread of disease. These data support that the prognostic benefit of BRCA-related PDAC may be linked to a favorable somatic mutation profile.

Nicholas J. Seewald

Assistant Professor of Biostatistics

Assistant Professor of Biostatistics at the University of Pennsyvlania Perelman School of Medicine