Abstract 2771: Correlation of tumor mutation burden and chemotherapy outcomes in colorectal cancer
Authors: Pai Sachin G. , Carneiro Benedito , Kalyan Aparna , Costa Ricardo , Helenowski Irene , Radmeaker Alfred , Shah Hiral , Olson Daniel , Chae Young , Giles Francis 
Published: July 2017

Abstract
Background: The Cancer Genome Atlas (TCGA) has identified 16% of colorectal cancers (CRC) to have defects in mechanisms that repair spontaneous DNA damage, and consequently have high tumor mutation burden (TMB). Although, there is accumulating evidence for activity of immunotherapy on tumors harboring high-TMB, its impact on response to chemotherapy is unknown.
Methods: In this retrospective cohort study, we analyzed progression free survival (PFS) of 74 patients with metastatic CRC (61 colon & 13 rectal cancer) treated at tertiary care oncology clinics and underwent next-generation sequencing (NGS) of their tumor sample using FoundationOne® (Foundation Medicine Inc., Cambridge, MA). Most recent available specimen was analyzed at the time of diagnosis of metastatic disease. TMB was calculated by counting all synonymous and nonsynonymous variants as well as indels across a 1.25 megabase coding region spanning 315 genes. Low TMB (TMB-L) and Intermediate/High TMB (TMB- I/H) were defined as ≤ 5 mutations per base (MB) or ≥ 6/MB respectively. Demographic and clinical information (including imaging results, chemotherapy treatment) were obtained by chart review. Treatment was captured as ‘oxaliplatin-based’ if the chemotherapy regimen contained oxaliplatin (i.e., FOLFOX, XELOX) or ‘irinotecan-based’ if the regimen contained irinotecan (i.e., FOLFIRI). Subsequent modifications of dose or omission of the drug due to toxicity were not captured. Continuous variables were reported as medians and inter-quartile ranges and compared between groups via the Wilcoxon rank-sum test. Categorical variables were reported as frequencies and percentages and compared between groups via Fisher’s exact test. Survival estimates were compared between groups via the log-rank test.
Results: There was no statistically different PFS in TMB-L (n=39) compared to TMB- I/H (n=26). (10.0 vs. 5.9 months, P = 0.18). In the TMB-L cohort, irinotecan-based chemotherapy (n=25) treated patients had improved PFS compared to oxaliplatin-based chemotherapy (n=10) treated CRC patients (11.9 vs. 6.5 months, P= &lt;0.001). No difference in PFS was observed between the two treatment cohorts in TMB-I/H group. In stage 2 and 3 colon cancer patients, there was no difference in time to recurrence in the TMB-L and TMB-I/H cohorts, when patients were treated with oxaliplatin-based therapy in peri-operative setting (detailed statistics including survival curves will accompany final presentation).
Conclusion: TMB status may be a predictive biomarker in a subset of patients treated with chemotherapy, specifically in TMB-L cohort. Confirming these findings in a larger repository of tissue from studies comparing irinotecan vs. oxaliplatin-based regimen is recommended.
Citation Format: Sachin G. Pai, Benedito Carneiro, Aparna Kalyan, Ricardo Costa, Irene Helenowski, Alfred Radmeaker, Hiral Shah, Daniel Olson, Young Chae, Francis Giles. Correlation of tumor mutation burden and chemotherapy outcomes in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2771. doi:10.1158/1538-7445.AM2017-2771