Profound and durable responses are often observed in early stage clinical trials of novel cancer agents in only a small minority of patients. It has long been postulated that these responses have a definable genetic basis but until now it was not feasible to perform a comprehensive genomic analysis of such patients. Rather, at best a few candidate genes were examined. Technical feasibility thus ensured that oncology trials were designed to identify agents that have a statistically significant benefit in a genetically unselected population, a paradigm that has led to the development of many agents that have modest or no benefit in the vast majority of patients. Agents with profound activity in only a small number of patients were on the other had deemed inactive and abandoned. Our preliminary experience shows that next generation sequencing methodology can now be feasibly applied in the clinical setting to identify previously unrecognized biomarkers of response for agents that show profound responses in only a minority of patients. As an example, we explored the molecular basis of an outlier phenotype, an apparent disease cure of a 51-year old woman with recurrent metastatic small cell carcinoma. The patient was treated on a phase 1 clinical trial that combined topoisomerase I inhibition with an ATP-competitive inhibitor of checkpoint kinase 1 (Chk1). Whole genome sequencing revealed a complex but highly clonal tumor genome with a somatic, missense mutation in the Mre11 complex gene RAD50, which functions to initiate double stranded break (DSB) repair by homologous recombination or non- homologous end joining. Through modeling in yeast, we confirmed that this heterozygous RAD50 mutation, which affects a highly conserved residue and whose wild type copy was focally deleted, conferred sensitivity to topoisomerase I inhibition. Drug sensitivity was markedly enhanced upon genetic ablation of the DNA damage checkpoint pathway, suggesting a synthetic lethal interaction between checkpoint kinase inhibition and clastogenic chemotherapy. These results and additional examples to be presented demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs. The use of novel clinical trial designs to confirm genotype-phenotype associations will also be discussed.
Citation Format: David B. Solit. Clinical application of next-generation sequencing as a guide to treatment selection. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA11.