ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 6 1. Primarily examine a response to individual treatment regimens, focus on exceptional responders, and do not examine rapid progressors, with the exception of the AURORA trial and the MBC Project 2. Do not investigate the sub-population of patients (“exceptional survivors”) who considerably outlive their prognosis, irrespective of the type and quantity of therapies received, with the exception of the Broad Institute’s MBC Project and the recently initiated University of Wisconsin-Madison Exceptional Survivors study. 3. Develop their own terminology, definitions, and metrics associated with exceptional responders, rapid progressors, and exceptional survivors because no current guidelines exist 4. Focus on the genetic characteristics of tumor cells with limited consideration of inherited polymorphisms, the host and tumor environments, lifestyle factors, use of complementary/ integrative medicine (CIM), co-morbidities, and other factors that may influence tumor chemosensitivityandresponsetotherapy,aswellastheinterplayamongthesecomponents 5. Tend not to have stated plans to share de-identified data derived from their investigations that could be leveraged by other researchers in the future In an effort to address these issues, this analysis examines various ongoing and published studies regarding exceptional responders, rapid progressors, and exceptional survivors, the multiple definitions applied to these patient groups, the possible reasons precipitating an atypical response, and the potential benefits of these studies to metastatic breast cancer (MBC) and other seriously ill patients. This analysis will also address the strengths and limitations of these initiatives while delineating potential action items to be considered by the Metastatic Breast Cancer Alliance and the research community. Our contention is that studying and sharing information on a common platform about exceptional responders, rapid progressors, and exceptional survivors—and utilizing a standard framework to categorize these populations—will enable the field of personalized medicine to become considerably more precise in developing and utilizing effective protocols for treating patients with cancer and other serious illnesses. In summary, we suggest that 1. clear categorization of atypical responses is needed, and 2. atypical responses may be due to not only tumor genomic factors but also to germline-derived anomalies in normal tissue, the host and tumor environments, lifestyle factors, use of CIM, factors that determine chemosensitivity and chemoresistance, co-morbidities, and the interplay among these factors.