Number of nonsynonymous genomic variants may correlate with prognosis in advanced pancreatic cancer.

Abstract

432 Background: Pancreatic cancer is associated with poor outcomes at any stage. A very small number of patients - approximately 3% of those with metastatic disease - experience long-term survival through 5 years but the biologic mechanisms underlying the benefit observed with these “exceptional responders” are incompletely understood. We explored potential genomic differences between exceptional responders and typical responders to treatment for advanced pancreatic cancer that could confer a more favorable biology. Methods: We included consecutive exceptional responders and matched controls (MCs) with advanced pancreatic cancer in a 1:3 ratio from the Cleveland Clinic from April, 2013 – August, 2017. ERs were defined as patients with overall survival (OS) > 18 months for metastatic disease and > 24 months for locally advanced disease. Controls were matched by age, gender, stage and type of chemotherapy given and experienced OS at or below median survival for their stages. Clinical variables including demographics, comorbidities, stage, histology and treatment history were collected. Next generation sequencing (NGS) was performed for DNA sequencing of 648 genes and tumor mutation burden (TMB) on available tissue. The study population initially comprised of 14 exceptional responders and 42 MCs. However, only 4 exceptional responders and 6 MCs were included for analysis due to insufficient tissue for NGS for the remaining patients. Descriptive statistics were used for statistical analysis. Differences in survival outcomes were assessed using the Kaplan-Meier method and log-rank test. Results: The median ages for the exceptional responders and MCs were 69 and 67.5 years, respectively. Both groups were at least 75% male and white. Of the exceptional responders, 50% had pancreatic tail primaries compared to 0% of the MCs. There were no differences between groups in first-line chemotherapy used. Exceptional responders had significantly fewer non-synonymous mutations compared to MCs (2.25 vs. 5.17, p = 0.014). Mutation count < 3 was associated with significantly better progression-free survival (PFS) and OS as shown in the Table. TMB did not differ between exceptional responders and MCs (4.88 vs. 5.70 Muts/Mb, p = 0.39). Of the exceptional responders, 50% had alterations in BAGE2 versus 0% of MCs. Conversely, 50% of MCs had alterations in LRP1B, CUL4B or APC vs. 0% of exceptional responders. Conclusions: Having a lower number of non-synonymous mutations may correlate with exceptional response to systemic therapy and therefore with improved survival in pancreatic cancer. Pancreatic tail primary may also be associated with improved outcomes. These findings, though limited by small sample size, should encourage future study into genomic signatures of exceptional response. [Table: see text]