Abstract 5379: Stratification of colorectal cancer patients based on various sequencing platforms and tumor mutational burden
Authors: Lo Fang Yin , Olson Claire , Deutsch Kerry , Saloranta Tuuli , Golez Inah , Yeatman Timothy , Anderson Steven , Madan Anup 
Published: August 2018

Colorectal cancer (CRC) is the third most common type of cancer in the United States. Although chemotherapy, radiation and targeted therapies can improve survival rates, recent studies have shown the potential benefit of immunotherapies to improve outcomes for patients with advanced CRC. Targeted therapies that use monoclonal antibodies (mAbs) to EGFR have been shown to benefit some CRC patients. Until recently, KRAS has been the only predictive biomarker for anti-EGFR therapy for metastatic CRC. However, 40% to 60% of patients with wild-type KRAS do not respond to anti-EGFR therapy. Therefore, to accurately predict patients' response to treatments and improve clinical outcomes, additional prediction and treatment methods are imperative. One of the many efforts to improve prediction for CRC patient's response to the anti-EGFR therapy is the development of gene expression based RAS signature scores for identification of RAS activated tumors independent of mutations in the KRAS gene. There is also considerable effort being placed on combinations of targeted therapy and immunotherapies to improve responses for these cancers. Previously, we have stratified 55 CRC samples by applying a RAS gene signature score which measures MEK pathway functional output independent of tumor genotype. We showed that samples that have RAS activating mutations such as KRAS and BRAF have significant higher RAS scores (p&lt;0.001). Here we investigate 120 colorectal cancer patients using exome sequencing, targeted panel sequencing, and RNA sequencing. Specifically, we acquired 40 normal-tumor pair samples and performed GATK tumor-normal pair mutation calling. Among these 120 samples, 65 of them are from patients treated with either cetuximab or panitumumab. Continued from our previous study, we stratified these samples based on calculated RAS scores, and showed how the results correlate with clinical outcome. Tumor mutational burden (TMB) can help predict the likelihood that a patient will benefit from certain immunotherapies; however, clinical applicability is limited due to cost and computing requirements of whole-exome sequencing to detect variants with high degree of accuracy. Therefore it would be helpful if TMB can be identified based on targeted sequencing. Here we investigate how TMB calculated based on different sequencing platform correlates with each other and whether targeted sequencing panel can be used instead of exome sequencing for stratifying patients. In addition, we investigated if Illumina's global screening array can be used for TMB analysis. Furthermore, to investigate the potential immune reactivity in these CRC samples, and thereby the potential benefit of immunotherapy, we performed in-silico prediction of neo-antigens and peptide binding affinity between tumor antigens derived from mutations and human HLA alleles.

Citation Format: Fang Yin Lo, Claire Olson, Kerry Deutsch, Tuuli Saloranta, Inah Golez, Timothy Yeatman, Steven Anderson, Anup Madan. Stratification of colorectal cancer patients based on various sequencing platforms and tumor mutational burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5379.