ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 3 Researchers in clinical oncology and other domains generally focus on results encompassing a statistical mean with little attention to patients undergoing investigational or standard therapies who respond considerably better or worse than the norm. An enormous opportunity exists to explore the reasons underlying an unusual (“atypical”) response, which would increase understanding of the mechanisms involved in cancer progression and treatment resistance, accelerate biomarker identification, and improve personalized medicine by allowing clinicians to prospectively select optimal treatments while avoiding therapies that would otherwise prove ineffective. Here we summarize published studies examining the reasons for an atypical response, new research initiatives that are exploring this topic, the strengths and limitations of these endeavors, and a call- to-action for strategic direction. Based on our review, we suggest two ways to move this field forward. FIRST, we propose that clear categorization of “atypical responders” is needed. An “atypical responder” may generally be classified as a patient who responds to a particular treatment in an unusually favorable or an unusually poor manner compared to similar patients undergoing the same regimen. Three sub-categories of patients may be considered: 1. “exceptional responders” (those with an unusually favorable treatment response), 2. “rapid progressors” (patients demonstrating an unusually poor or no therapeutic response), and 3. “exceptional survivors” (advanced stage patients who have far outlived their prognosis for their cancer subtype for reasons that are not fully understood). “Exceptional survivors” may or may not have responded unusually well to a specific therapy, or multiple lines of therapy, yet have fared far better than their counterparts. We propose all three groups of patients be studied in depth. Second, we suggest that atypical responses may be due to mutations present only in tumors (not inheritable; somatic), mutations and other genetic changes present in normal tissue (inheritable), the host and tumor environments, lifestyle factors, use of complementary/integrative medicine (CIM), factors that determine chemosensitivity and chemoresistance, co-morbidities, and the interplay among these elements. ABSTRACT