ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 17 Two studies illustrating the failures and prospective dangers of targeted therapies are provided below. In the first study, results that were published in 2014 from the PALOMA-1 clinical trial showed that MBC patients with mutations that could be targeted fared no better than patients without them. PALOMA-1 had been split into two parts. The first part included 66 patients with ER+, HER2− advanced breast cancer. The second part consisted of 99 patients with ER+, HER2− disease and specific biomarkers, including cyclin D1 amplification, p16 loss, or both. Although preclinical data had suggested that ER+ patients with cyclin D1 amplification and p16 loss may be predicted to respond, this was not observed in the clinical trial [23]. In the second study, researchers found that at least in some cases, targeting single genetic mutations through drugs can occasionally backfire. In a study that targeted the phosphatidylinositol 3-kinase (PI3K) mutation, monotherapy treatment aimed at PI3K inhibition caused mitochondria to migrate to the peripheral cytoskeleton of the tumor cells, whereas the mitochondria of untreated cells were seen clustered around the cell nucleus [24]. The net result was that PI3K inhibition diverted the mitochondria to specialized regions of the cell membrane that are implicated in cell motility, and the cells could move spontaneously, thus permitting invasion. Molecular profiling of a patient’s tumor often allows identification of the biological mechanism of a response to therapy, including an exceptionally favorable or poor response [11, 16-18, 25]. However, the contribution of molecular aberrations must be carefully considered, because focusing on molecular aberrations to the exclusion of other potentially contributing factors can, at least in some instances, prove problematic. In addition, non-genetic attributes, including those occurring at the RNA or protein level as described by Dr. Mills, also influence therapeutic responses. Although genomic factors are often clearly important, a genomic explanation for an atypical response is not always identified [26]. Furthermore, factors not directly involving the tumor likely also play a role in therapeutic responses, as described below. Moving Beyond Analysis of Molecular Aberrations in Tumors The studies below that analyze factors other than genetic mutations provide sufficiently intriguing preliminary results that warrant further study in both normally and atypically responding patients, a necessary step toward adopting these practices into the standard of care.