Homologous recombination repair gene mutations in Chinese pancreatic ductal adenocarcinoma patients.
Authors: Nengwen Ke, Maolin Yan, Xu Che, Yu Cheng, Zheng Wang, Zheng Wu, RongFeng Song, Guohui Xu, Yan Wang, Junwei Wang, Juan Zhao
Journal: Journal of Clinical Oncology (2021)

e16234 Background: Pancreatic cancer (PC) is a highly malignant tumor with poor prognosis. Among them, pancreatic ductal adenocarcinoma (PDAC) accounts for 80-90% of pancreatic cancer. While, the treatment of PDAC has always been a clinical challenge. PDAC with mutations in homologous recombination repair (HRR) genes such as BRCA are particularly sensitive to platinum agents. The POLO study has shown that Olaparib was efficient and well-tolerated as maintenance therapy in patients with germline BRCA1/2 mutation and a metastatic PDAC controlled after a platinum-based induction chemotherapy. However, investigation of prevalence of HRR gene mutations in Chinese PDAC patients need to be well defined. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from PDAC patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations and tumor mutational burden (TMB) values were assessed. The association of HRR gene mutations with TMB was assessed. The testing was carried out by OrigiMed (Shanghai, China) witch a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Using targeted capture genomic sequencing, we assessed 98 PDAC patients for germline and somatic loss-of-function mutations in 14 genes, including BRCA1, BRCA2, and 12 other genes in the HR pathway. Results: In total, 98 PDAC patients were recruited including 48 females and 50 males with a median age of 58 (range 35-84). The most frequently mutated genes were KRAS (94%), TP53 (74%), CDKN2A (36%), SMAD4 (27%), GATA6 (9%) and ATM (5%). Mutation rates varied in pancreatic cancer signaling pathway: WNT (35.71%), PI3K (11.22%), HRR (11.22%), NOTCH (3.06%), FGF (2.04%). 2.04% (2/98) patients had high TMB (defined as ≥10 muts/Mb) with a median of 2.2 muts/Mb (0-47 mus/Mb). 34.69% (34/98) of the patients had one or more actionable genetic mutations. We identified that 11.2% (11/98) patients had at least one mutation in HRR genes. The most frequently mutated HRR genes were ATM (50%), BRCA1 (16.7%), BRCA2 (25%) and PALB2 (8.3%). The most common mutation type in HRR-related gene was truncation (75%, 9/12). HRR-related germline mutations in BRCA (71.43%, 5/7), ATM (28.57%, 2/7) were detected in seven patients, six of them with cancer related family history. We confirmed that patients with HRR mutations were younger than wild type HRR (52.6 years vs. 59.3 years, p &lt; 0. 05). We demonstrated that patients with HRR mutations had a significantly higher TMB than patients with wild type HRR (median TMB: 3.4 vs. 1.8 muts/Mb, p &lt; 0. 05). Conclusions: HRR gene alterations occurred in 11.2% of Chinese PDAC patients HRR pathway alterations are relatively frequent in PDAC patients and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.