The Demanding Patient Revisited.

patients with CUP are needed. We thank Varghese and Saltz from Memorial Sloan Kettering Cancer Center for their comments concerning the definition of “actionability” in the setting of cancer presenting as CUP. Also, inresponsetoVargheseandSaltz,TTF1-positivetumors withEML4-ALK fusionscharacteristicofnon–small-cell lungcancerwerenot includedinourseries.Onecase inourseriesdidfeatureaTMPRSS-ERG fusiondiagnosticofmetastaticprostaticcarcinoma. This casewas listed as a CUP in that the tumor did not markby IHCanalysis asbeingofprostaticoriginandtheclinical workupdidnot suggest that thepatienthadprostatecancer.Althoughnot a focus of our present study,we believe that hybrid capture–basedcomprehensivegenomicprofilingcandefinitively identify the site of origin in approximately 10% to 15% of CUP cases.ThecaseexampleinourarticleofanEML4-ALKfusioncancer respondingdramatically tocrizotinib therapycannot, inour opinion,bedesignatedasa lungcancerbycurrentdiagnosticcriteriabecause IHCanalysiswasnegative forTTF1,positive forvimentin,andfeaturedapoorlydifferentiated,nonmucinous,sarcomatoidmorphologicappearance.Finally,wethankWhangand HayesfromtheUniversityofNorthCarolinafortheirletterdescribingtheprolongedresponseofapatient toananti-humanepidermalgrowth factor receptor2pluschemotherapyregimenforan ERBB2-amplifiedCUP.Finally,ourarticle1 andall 3Letters to the Editor have in common the desire to see the development of mechanism-drivenprospective clinical trials inwhichgenomic profilingisusedtosearchfor“druggable”alterationsinCUPcases toachieveacomparisonoftheresultsoftheuseoftargetedtherapies when possible with generic chemotherapy and testing whether thisapproachcanimprovetheclinicaloutcomesforpatientswith this devastating formof cancer.