ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 16 performing the analysis and the method used. As an example, a recent study comparing genetic alterations in patients who underwent testing using two platforms, FoundationOne and Guardant 360, developed by two companies revealed 22% concordance between the two platforms among 45 alterations in eight patients. Although 36 drugs were recommended for these patients, only nine (25%) were recommended for the same patients by both platforms [20] (read more). FACTORS CONTRIBUTING TO ATYPICAL RESPONSES Molecular Aberrations in Tumors As described in Table 3 and seen within the aforementioned initiatives studying atypical responses, most researchers focus on identifying molecular aberrations but do not examine other possible contributing factors. Many institutions have developed molecular tumor boards that are collecting molecular information from patients studied at their facilities. Certainly, spectacular successes have occurred in which an identified molecular aberration and a corresponding targeted therapy substantially changed the outcome. An excellent example is the BCR-ABL mutation in chronic myelogenous leukemia (CML) and the drug Gleevec® (imatinib) that targets this mutant enzyme. Prior to 2001, less than one in three CML patients survived past 5 years. Now, most cases of CML can be controlled with Gleevec® , and researchers have developed new medications to counter resistance to Gleevec® when it arises. A 2011 study concluded that CML patients whose disease is in remission after 2 years of Gleevec® treatment have the same life expectancy as those who never had this disease [21]. As a result of targeted therapy with Gleevec® , a substantial number of CML patients have been transformed into “exceptional survivors” who are able to manage their disease as a chronic instead of a terminal illness. Gleevec® ’s stunning patient outcomes, coupled with successes in other areas, have inspired a multitude of additional efforts to identify and target molecular-based therapies for other cancers and serious diseases. Unfortunately, not all attempts at therapeutically targeting genetic aberrations have been successful. Although molecular testing of tumors is important, it does not represent the full breadth of reasons governing atypical responses across multiple cancer types. In a presentation at the 2015 San Antonio Breast Cancer Symposium, Gordon B. Mills, PhD, at the University of Texas MD Anderson Cancer Center referred to the “unexpected high rate of failure of targeted therapeutics [22].” He indicated that “For most of our patients with a biomarker, only a sub-population of patients benefit, and that’s usually short-term.” He contended that the reasons for this outcome include genetics, the therapy selected, and tumor adaptive resistance. Specifically regarding tumor adaptive resistance, Dr. Mills stated that, “Tumor cells adapt to the targeted therapeutic in a way that allows them to bypass that stress. And that adaptation is almost always mediated at an RNA or protein level rather than a genomic level, and cannot be ascertained by solely studying DNA.”