ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 34 TABLE 3 SUMMARY OF PUBLISHED STUDIES EXAMINING ATYPICAL RESPONSES CANCERTYPE DRUG(S)PROVIDINGAN ATYPICALRESPONSE(TARGET) MOLECULAR ABERRATION(S) IDENTIFIED COMMENTS REFERENCE(S) ER-positive, HER2-negative MBC Xeloda® (capecitabine)(DNA synthesis) VariousDNA repairand/or chromatin remodeling genes Studyincludedsix superior exceptional responders; mechanismoftheatypical responsesuggested: identification ofclassesof mutatedgenes [10] Ewing’s sarcoma IGFR1inhibitor Mutationsin PTPRDand GRB10 (germline) KRASmutation developedin a resistant tumor; individualized combination therapymaybe useful [86,87] Metastatic bladder cancer Afinitor® (everolimus)(mTOR) TSC1loss-of-function mutation ~8% ofbladdercancershavethis mutation[9];TSC1mutationmay beabiomarkerforeverolimus sensitivity: 3/4ofpatientswith themutation respondedto everolimus, and8/9patients whosetumorprogressedon everolimusdidnot havethe mutation [17] Thyroid cancer Afinitor® (everolimus) TSC2 mutation, secondary mutation in MTOR Identification ofthemechanism ofacquiredresistance [11] Small-cell cancerofthe ureter AZD7762(CHK1inhibitor) +Camptosar® (irinotecan) (TopoisomeraseIinhibitor) RAD50 Thisdrug combination maybe useful in thecontext ofRAD50 mutation. [15] Head and neck squamouscell carcinoma Tarceva® (erlotinib)(EGFR) Activating MAPK1mutation Paradoxical activating mutation predictedresistancetoerlotinib; precision oncologymaypredict indication forerlotinibuse [88]