ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 8 The National Cancer Institute’s (NCI’s) Exceptional Responder Initiative [2].NCI has launched a clinical trial to examine the molecular basis of a favorable atypical response (NCT02243592; NCI News Note; Exceptional Responders Initiative Key Points). The aim is to collect tumor samples from 300 patients with cancer who are considered to be exceptional responders, according to their definition (see Table 1). Researchers will obtain malignant and normal tissue when possible, as well as clinical data. Whole exome sequencing and/or mRNA sequencing (targeted deep sequencing) of nucleic acids from these tissues will be performed. Samples with sufficient quantities of nucleic acids will be used for additional analyses (e.g., microRNA sequencing, promoter methylation analysis, single nucleotide polymorphism (SNP) genotyping, and/or whole genome sequencing). A potential correlation between molecular profiles and therapeutic responses will be investigated. The stated goal is to determine whether certain molecular features can predict responses to the same or similar drugs. Of note, information gathered in this study will be de-identified and placed in a controlled-access database so other investigators may use it to gain new insights. NCI has funded two Genome Characterization Centers at The Broad Institute (Boston, MA) and The University of Texas MD Anderson Cancer Center to support this initiative. The strengths of this study include the molecular testing approach, the intent to share de-identified patient data, and a working definition of exceptional responders. Limitations are that no examination of rapid progressors is included, and the study only seeks to perform molecular assessments without addressing lifestyle or other potentially contributing factors that may influence a therapeutic response. In relation to this initiative, NCI uses the following definition relative to exceptional responders: • Complete response (CR) to a regimen in which CR is expected in 6 months in a regimen in which PRs >6 months are expected in 3× the median expected PR duration (in cases where PR is expected in >10% of patients with the same disease treated with the same regimen) • CR or duration >3× the median expected CR duration (in cases where CR may be seen in >10% of patients with same disease treated with same regimen) • The observed duration of CR (or PR) is longer than expected for 90% of patients with same disease treated with same regimen The strengths of these definitions are that they are: 1) quantifiable and 2) utilize commonly measured outcomes such as CR and PR.