BRCA1/2 reversion mutations in pancreatobiliary cancer identified from patient biopsies.

Abstract

4130 Background: Germline genomic alterations (GA) in BRCA1 or BRCA2 ( BRCA) are associated with increased risk of pancreatic cancer. Tumors with BRCA GA may be more sensitive to platinum (Pt) therapies or PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) that may restore BRCA function and underlie reduced sensitivity to Pt compounds or PARPi can arise. Methods: DNA extracted from FFPE tumor tissue obtained during routine clinical care for 7077 patients with predominantly relapsed, refractory or metastatic pancreatobiliary carcinoma was analyzed using comprehensive genomic profiling (CGP) for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Tumor tissue only was used to predict germline (g BRCA) or somatic status by an algorithm with a call rate of 85% and > 95% accuracy. Results: 417/7077 (5.9% ± 0.5%) tumors had ≥1 deleterious BRCA GA; 205 (2.9% ± 0.4%) had a predicted g BRCA GA. Significantly fewer women had deleterious BRCA GA (182/417; 43.6%)(p = 0.02); g BRCA GA frequency did not differ significantly (96/205; 46.8%)(p = NS). Overall, 49.1% of patients were women. 12 samples harbored potential revGA: pancreatic ductal adenocarcinoma (ACa) (7) or acinar cell carcinoma (Ca) (2), gallbladder ACa (2), and pancreatobiliary Ca NOS (1). 10/12 samples with revGA were metastases. Potential revGA were of 3 types: overlapping indel (7), compensatory fs (4), and missense (2). One case harbored 2 indels, both with potential to excise a fs GA. Apparent g BRCA were present in 7 cases, only somatic BRCA GA in 3 cases, and g BRCA/somatic status was ambiguous in 2 cases. For 2 patients, testing of multiple samples reveals the acquisition of revGA over time. KRAS mutation frequencies were similar for all samples (57.1%), BRCA-mutated samples (58.8%) and revGA-positive samples (58.3%). Clinical histories for patients with revGA will be presented. Conclusions: CGP of 7077 pancreatobiliary carcinomas reveals 5.9% had ≥1 deleterious BRCA GA, nearly 50% of which were g BRCA. Although rare, revGA can be acquired over time and potentially compensatory missense, fs and indel mutations were observed.