Abstract A080: An analysis of outcomes in patients (pts) with advanced pancreatic cancer (PDAC) whose tumors harbor pathogenic BRCA1 or BRCA2 mutations based on gene mutation location
Authors: Hur Jamie , McPhaul Thomas , Cunningham Dea , Zheng Lei , Pishvaian Christopher J , Laheru Daniel , De Jesus-Acosta Ana , Le Dung , Zaidi Neeha , Azad Nilo , Browner Ilene , Burns William R , Burkhart Richard , Lafaro Kelly , Narang Amol , He Jin , Lee Valerie , Brody Jonathan R , Pishvaian Michael J 
Published: September 2024

Abstract
Introduction: BRCA1/2 mutations in pts with PDAC predict for an improved tumor response, higher median time to progression (TTP), and longer median overall survival (mOS) with platinum-based therapy (tx) as compared to non-platinum-based tx. We examined whether mutations within specific regions of the BRCA1/2 genes correlate to any differences in mTTP or mOS in this pt population. Methods: An established database of PDAC pts seen at Johns Hopkins University from 2018 to 2023, whose tumors underwent next-generation DNA sequencing was queried for the presence of a path/likely path BRCA1/2 mutation. The pathogenicity of each BRCA1/2 mutation was confirmed using the NCI Clinvar database. Pt disease characteristics and tx information was captured from the electronic medical record. OS was defined from the time of diagnosis of advanced/metastatic disease until death. First line platinum-treated mTTP was defined from tx initiation until disease progression. Results: We identified 258 pts with BRCA1/2 mutations, 56 with path/likely mutations, of which 41% were male, 80% were Caucasian and 10% African American, with a median age at diagnosis of 66 (range 42-85). Consistent with our previously published data, the mOS for pts with BRCA1/2 mutations was greater with platinum tx at any time during their PDAC survival compared to never having any platinum tx (BRCA 1: 20.5 months vs 10.2 months n=16; BRCA 2: 15.7 months vs 5 months n=40). mTTP and mOS were analyzed based on where along the gene the BRCA mutations occurred. For BRCA1, mutations clustered in 3 groups (G1 BARD1-binding; G2 Exon11/Check2 binding; and G3 BRCT region). For BRCA2, mutations clustered in 3 groups (G1 N-terminal; G2 BRC repeats/RAD51 binding; and G3 DNA Binding). For pts with BRCA1 mutations, pts in Group 2 had the worst mOS and mTTP. For example, mOS (months) was: G1=39.9, G2=13.3; G3=26.5. For pts with BRCA2 mutations, pts in Group 2 had the worst mOS (months): G1=34.1, G2=14.9; G3= 20.2. However, for BRCA2, there were no differences in mTTP. Conclusions: Evaluation of survival in pts with BRCA1/2 mutated PDAC reveals differences in mOS and mTTP as a function of the location of the mutation along the gene. In particular, pts with BRCA 1 exon 11 mutations had the worst mOS, consistent with previous in vivo studies in which Brca1Δ11/Δ11 mouse mammary tumors were resistant to cisplatin. By contrast, mutations in the C-terminal DNA binding domain of BRCA2 had better mOS, also consistent with previous studies. Interestingly, we did not observe prolonged survival in pts with BRCA2 exon 11 mutations, as has been observed in ovarian cancer, likely reflecting a difference in platinum sensitivity between the two diseases. Further evaluation of the relevance of the specific mutation location as it relates to interaction with other elements of the homologous recombination repair machinery, other genetic lesions, and the tumor microenvironment, are warranted to help understand what specifically mediates sensitivity to platinums in a BRCA1/2-mutated PDAC.
Citation Format: Jamie Hur, Thomas McPhaul, Dea Cunningham, Lei Zheng, Christopher J Pishvaian, Daniel Laheru, Ana De Jesus-Acosta, Dung Le, Neeha Zaidi, Nilo Azad, Ilene Browner, William R Burns, Richard Burkhart, Kelly Lafaro, Amol Narang, Jin He, Valerie Lee, Jonathan R Brody, Michael J Pishvaian. An analysis of outcomes in patients (pts) with advanced pancreatic cancer (PDAC) whose tumors harbor pathogenic BRCA1 or BRCA2 mutations based on gene mutation location [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A080.