Exceptional Responders May Be Key to New Cancer Treatments.

Abstract

Patients with cancer who respond exceptionally well to therapy may have molecular changes in their tumors that explain their response. A comprehensive analysis of this group that identified these changes may help to contribute to the development of potential new treatments according to a study in Cancer Cell.1 According to the authors, their research indicates that genomic characterizations of cancer could help to uncover genetic alterations that lead to unexpected and long-term treatment responses. The work was conducted by the National Cancer Institute (NCI) in collaboration with other institutions. The majority of the patients in the retrospective study had difficult-to-treat metastatic cancers. The research involved 111 patients identified through the national NCI Exceptional Responders Initiative who had various cancer types and had received standard treatments. The Exceptional Responders Initiative was launched in 2014 to explore the feasibility of collecting and analyzing exceptional responders' data and biospecimens to better understand their responses to cancer therapies. Exceptional responders were defined as those who had a partial or complete response to a treatment that would be effective in less than 10% of similar patients. In addition, the response duration was defined as one that lasts at least 3 times longer than the median response time. The Exceptional Responders Initiative has led to the review of medical histories of more than 500 patients recommended by physicians. The vast majority had exceptional responses to chemotherapy. These molecular profiling results and clinical data are publicly available through the NCI's Genomic Data Commons. In 23% of the patients (26 of 111) reviewed as part of the Cancer Cell study, researchers were able to identify molecular features that could potentially explain their exceptional treatment responses. These included the co-occurrence of multiple rare genetic changes in the tumor genome and/or the infiltration of the tumor with certain types of immune cells. Investigators used multiple genomic approaches to analyze the tumor and, where available, normal tissue, including analyses of DNA mutations, RNA expression levels, DNA copy number alterations, and DNA methylation. They also analyzed the immune cells in the tumor microenvironment. Among the broad mechanisms underlying exceptional responses in the study were the body's ability to repair DNA damage and the immune system's response to tumors as well as synthetic lethality—a rare combination of genomic alterations that led to tumor cell death during treatment. The research highlights the importance of testing patients for tumor alterations that may indicate available treatments, says study coleader Louis M. Staudt, MD, PhD, National Institutes of Health Distinguished Investigator and director of the NCI Center for Cancer Genomics. Findings also pointed to increased levels of certain immune cells—specifically, B lymphocytes—in tumors associated with exceptional responses. Future studies will need to confirm this retrospective analysis, but they could lead to future work in the area of developing treatments that exploit the vulnerabilities found in the tumor cells of exceptional responders.