Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response

Abstract

High-throughput next-generation sequencing has provided enormous insight into the genomic landscape of several tumor types, illuminating molecularly defined tumor subtypes, identifying new druggable targets, and providing insights into the heterogeneity of many tumors.¹ Metastatic tumors often undergo genomic evolution during progression and resistance, and therefore genomic drivers may not always be evident in the primary tumor. Furthermore, no specific guidelines exist to help clinicians interpret and contextualize individual patients’ genomic information when making therapeutic decisions. Herein, we describe an evidence-based precision medicine trial for patients with metastatic or treatment-resistant disease using a whole-exome sequencing (WES) clinical test called EXaCT-1, developed and validated by our group. Unique aspects include analysis of more than 21 000 genes of the cancer exome rather than a targeted hot-spot gene approach, complete disclosure of results through a WES clinical report, incorporation of metastatic and serial biopsies, use of fresh/frozen and formalin-fixed tissue, and development of patient-derived organoids and xenografts for co-clinical trials. Integral to the study are a comprehensive computational pipeline capable of categorizing mutations and generating a report for discussion in a multidisciplinary precision medicine tumor board and clinical follow-up to determine the clinical impact of mutations on subsequent response to therapies and patient outcomes. The overarching goals of our trial are to understand how WES affects therapeutic decision making in the context of advanced cancer care and to identify novel biomarkers of response.