Exploiting The Spectrum of BRCA-associated PDAC

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype, as it is a most studied PDAC subpopulation. A portion of these patients is highly susceptible to DNA damaging therapeutics (DDR) including PARP inhibition (PARPi), however, responses are heterogeneous and clinical resistance evolves. This differential response among germline (GL) BRCA mutations carriers is suggestive of additional features underlying the nature of response/resistance to treatment. In the whole genome sequence (WGS) analysis on patient-derived xenografts (PDX) established from BRCA-associated PDAC patients, we have shown correlation between genomic subtype and response to treatment in pre-clinical model and patients’ clinical scenario. Recent studies in ovarian carcinoma patients have suggested that the absence of locus-specific loss of heterozygosity (LOH) may be a biomarker of primary resistance to DDR/PARPi.The goal of this study was to verify the established genomic classification of BRCA-associated PDAC tumors and to investigate additional genomic features predictive of response.

Methods: We have performed an analysis on clinical data of PDAC patients with GL/somatic mutations in BRCA1/2 genes diagnosed at Sheba (Israel) and OICR (Canada) in conjunction with comprehensive WGS analysis of corresponding tumor/PDX samples. We analyzed both primary resected tumors along with PDXs established from primary/metastatic lesions and performed classification into genomic subtypes. Additionally, loss of heterozygosity (LOH) was tested.

Results: Overall, 63 cases of BRCA-associated PDAC were identified in both institutions (July 2008 - Feb 2018). Sixty-two were carriers of GL BRCA1/2 mutations and one harbored somatic mutation in BRCA2. Stage at diagnosis was I/II (n=16) and III/IV (n=47); a recurrence of disease was observed in the majority (10/16) of patients with early stage. More than 30% are alive with disease and responding to platinum/PARPi for >12 months, three patients demonstrate a complete response >3 years. A subset of patients (~25%) demonstrated resistance and limited response and died ≤9 month from diagnosis/progression.

Preliminary WGS data analysis of 5 PDXs and 13 primary resected tumors showed strong correlation between genomic subtype and overall survival. LOH status showed correlation with unstable genomes in 9/12 cases. Additionally, 4/6 stage I/II patients who did not recur, display the unstable genome subtype.

Conclusion: Analysis of 18 BRCA-associated PDAC cases analyzed by WGS presented here, demonstrated correlation between unstable genomic subtype and response to treatment with DDR agents/PARPi. Genomic data to be extracted from WGS and LOH analyses of additional samples will provide more insight into understanding the spectrum of response to treatment.