Effect of germline mutations in homologous recombination repair genes on overall survival of patients with pancreatic adenocarcinoma

Effect of germline mutations in homologous recombination repair genes on overall survival of patients with pancreatic adenocarcinoma:

Purpose: To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and non-carriers with pancreatic ductal adenocarcinoma (PDAC). Methods: Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in 8 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared to patients testing negative for mutations in all 37 genes. Results: The 175 HRR mutation carriers and 2,730 non-carriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (Median age at diagnosis: 63 vs. 66 years, p<0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, p=0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared to non-carriers (HR: 0.83, 95% CI: 0.70 to 0.97, p= 0.02). Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared to patients without germline mutations in any of the 37 HRR genes (HR: 0.72, 95% CI: 0.55 - 0.94, p=0.01). Conclusions: This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared to non-carriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.