Abstract 3254: Dissecting genomic determinants of response to platinum-based chemotherapy in advanced NSCLC and colorectal cancer
Authors: Mo Shirley S. , Liu David , Gray Stacy W. , Joffe Steven , Wagle Nikhil , Garber Judy , Garraway Levi A. , Sholl Lynette , Janne Pasi A. , Allen Eliezer M. Van 
Published: August 2018

Background: Despite the advent of new targeted- and immuno-therapies, chemotherapy continues to be a mainstay in most tumor types. In lung and colorectal cancer, platinum-based regimens are the standard of care as part of front-line systemic, neoadjuvant, or adjuvant chemotherapy regimens. Response to these agents varies widely among patients, and currently there are no mature or reliable biomarkers of clinical response to platinum therapies for these cancer types. We hypothesized that a systematic integrated genomic analysis of pre-treatment tumors from a large cohort of platinum-treated cancer patients would reveal genomic determinants of resistance and response, which may guide a precision medicine-based approach to choosing effective treatments. Methods: 238 metastatic lung and colorectal adenocarcinoma patients were enrolled in the CanSeq study from February 2013 to July 2015. We performed whole-exome sequencing (WES) on pre-treatment tumors, and called variants including single nucleotide variants (SNVs), small insertions and deletions, copy-number alterations, purity and ploidy of tumors, and inferred clonality and subclonality of individual mutations. Clinical records were reviewed to determine response to therapy, progression-free (PFS), and overall survival. Patients were characterized as having clinical benefit (CB), intermediate benefit (IB), and no clinical benefit (NCB) based on the best radiologic response to therapy and PFS. CB included all patients with complete response or partial response + a long PFS in the top quartile of responders, while NCB experienced progressive disease. IB included all other patients. We evaluated associations between genomic features and response using standard statistical methods. Results: 119 patients received platinum-based systemic chemotherapy and had pre-treatment tumors. Our initial analysis comparing CB vs. NCB suggests that mutations in PTPRD, a receptor protein tyrosine phosphatase previously associated with platinum resistance in cancer cell lines, may be significantly associated with chemoresistance (3/9 NCB, 0/23 CB, p &lt; 0.05, Fisher's Exact) and shorter progression-free survival (p &lt; 0.001, Log-Rank). Further, we found that lower mutational burden is associated with response to platinum chemotherapy (p &lt; 0.05, Wilcoxon Rank Sum). Conclusion: Our approach demonstrates the power and potential of harmonizing genomic and clinical data in an unbiased way to identify biomarkers of platinum chemosensitivity. Our findings suggest that lower mutational burden correlates with CB from platinum therapy, while specific gene alterations potentially offer additional predictive value.

Citation Format: Shirley S. Mo, David Liu, Stacy W. Gray, Steven Joffe, Nikhil Wagle, Judy Garber, Levi A. Garraway, Lynette Sholl, Pasi A. Janne, Eliezer M. Van Allen. Dissecting genomic determinants of response to platinum-based chemotherapy in advanced NSCLC and colorectal cancer [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 3254.