Exceptional Responders

Abstract

Anecdotes of patients who experience unexpectedly profound and/or durable responses to a specific cancer treatment, inconsistent with the experience of the vast majority of patients who receive that same treatment, are replete within the scientific literature [1]. The relevance of such outlier responses has usually not been well defined; however, in the context of clinical trials of anti-cancer therapies in which only a minority of patients (or even a single patient) achieves a substantial response, durable responses can often have significant repercussions. The efficacy of such drugs is by definition interpreted based upon the response of the overall study population, frequently leading to a failure of further drug development. Before the advent of Next Generation Sequencing (NGS), detailed analysis of patient responders was extremely challenging. Moreover, clinical trials of targeted therapies in large part initially adopted traditional histology-based eligibility criteria, leading to the accrual of patients whose tumors did not harbor the putative target inhibited by targeted agents. The phenotype of enhanced sensitivity to a drug observed within outlier cases or “exceptional responders” can now be interrogated using NGS to define their genomic underpinnings and ultimately to use this information to inform the design of future clinical trials. Additionally, outlier responders represent a unique opportunity to identify new predictive biomarkers of exquisite sensitivity to targeted therapy (or traditional chemotherapy), delineating a subset of patients that could significantly benefit from these drugs as compared to the overall population. In contrast to other strategies to identify actionable targets, such as the large-scale analyses of The Cancer Genome Atlas (TCGA) [2], examination of exceptional responders represents a phenotype-to-genotype approach in an individual, outcome-driven context that has the potential to enhance our understanding of tumor biology, inform clinical trial design, identify novel therapeutic targets, salvage drugs deemed ineffective within a genetically undefined patient population, and define more precise subgroups of patients who may benefit from new or existing drugs. In this chapter, we will describe examples of how detailed genomic analysis of extreme responses to a variety of treatments has resulted in improved insight into the molecular pathogenesis of a specific disease subtype or uncovered putative therapeutic targets for further investigation.