Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment

• DOI: 10.1016/j.ccell.2020.10.015
• Publication Date: 2020-11-20T03:35:39Z
• Authors: David A. Wheeler; Naoko Takebe; Toshinori Hinoue; Katherine A. Hoadley; Maria F. Cardenas; Alina M. Hamilton; Peter W. Laird; Linghua Wang; Adrienne Johnson; Ninad Dewal; Vincent Miller; David Piñeyro; Manuel Castro de ...; Manel Esteller; Hui Shen; Jean Claude Zenkl...; Roy Tarnuzzer; Lisa M. McShane; James V. Tricoli; Paul M. Williams; Irina Lubensky; Geraldine O'Sulli...; Elise C. Kohn; Richard F. Little; Jeffrey White; Shakun Malik; Lyndsay Harris; Carol Weil; Alice P. Chen; Chris Karlovich; Brian Rodgers; Lalitha Shankar; Paula Jacobs; Tracy Nolan; Jianhong Hu; Donna M. Muzny; Harshavardhan Dod...; Viktoriya Korchina; Julie Gastier-Foster; Jay Bowen; Kristen Leraas; Elijah F. Edmondson; James H. Doroshow; Barbara A. Conley; S. Percy Ivy; Louis M. Staudt
• Keywords: Male; Biopsy; Genetic Variation; Antineoplastic Agents; Genomics; Prognosis; Survival Analysis; Epigenesis, Genetic; 3. Good health; Treatment Outcome; Neoplasms; Tumor Microenvironment; Humans; Female; Gene Regulatory Networks

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories—DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis—with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy. Profiling multi-platform genomics of 110 cancer patients with an exceptional therapeutic response, Wheeler et al. identify putative molecular mechanisms explaining this survival phenotype in ∼23% of cases. Therapeutic success is related to rare molecular features of responding tumors, exploiting synthetic lethality and oncogene addiction.