Martin H. Voss|Albert Reising|Cheng Yuan|Parul Patel|Mahtab Marker|Fengshen Kuo|Timothy A. Chan|Toni K. Choueiri|James J. Hsieh|A. Ari Hakimi|Robert J. Motzer
Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study
Memorial Sloan Kettering Cancer Center|Novartis (United States)|Novartis (United States)|Novartis (United States)|Novartis (United States)|Memorial Sloan Kettering Cancer Center|Memorial Sloan Kettering Cancer Center|Dana-Farber Brigham Cancer Center|Brigham and Women's Hospital|Dana-Farber Cancer Institute|Washington University in St. Louis|Memorial Sloan Kettering Cancer Center|Memorial Sloan Kettering Cancer Center
background memorial sloan kettering cancer center mskcc risk model established prognostic tool metastatic renalcell carcinoma integrates clinical laboratory data agnostic tumour genomics several mutations including bap1 pbrm1 prognostic value renalcell carcinoma using two independent clinical trial datasets patients metastatic renalcell carcinoma aimed study whether addition mutation status several candidate prognostic genes mskcc model could improve models prognostic performance methods retrospective cohort study used available formalinfixed paraffinembedded tumour tissue clinical outcome data patients metastatic renalcell carcinoma assigned treatment tyrosine kinase inhibitors comparz trial training cohort n357 record3 trial validation cohort n258 eligible patients trials treatmentnaive histologically confirmed advanced metastatic renalcell carcinoma karnofsky performance status score least 70 cohort data patients treatment groups sunitinib pazopanib training cohort everolimus sunitinib validation cohort pooled analysis training cohort tumour tissue used evaluate somatic mutations nextgeneration sequencing association cancerspecific outcomes overall survival progressionfree survival overall response mutation status six genes interest bap1 pbrm1 tp53 tert kdm5c setd2 tested genes prognostic value setting added mskcc risk model create genomically annotated version validation cohort used independently test prognostic value annotated model compared original mskcc risk model findings 357 32 1110 patients assigned protocol treatment comparz study august 2008 september 2011 evaluable mutation status clinical outcomes training cohort independent validation cohort included 258 55 471 evaluable patients enrolled october 2009 june 2011 record3 study training cohort presence mutation bap1 tp53 absence mutation pbrm1 prognostic terms overall survival tp53wtbap1mut tp53mutbap1wt tp53mutbap1mut vs tp53wtbap1wt hazard ratio hr 157 95 ci 121204 p00008 pbrm1wt vs pbrmmut hr 158 116214 p00035 mutation status three prognostic genes added original mskcc risk model create genomically annotated version distribution participants training cohort three risk groups original mskcc model changed 87 24 357 patients deemed favourable risk 217 61 intermediate risk 53 15 poor risk distribution across four risk groups genomically annotated risk model 36 10 357 deemed favourable risk 77 22 good risk 108 30 intermediate risk 136 38 poor risk addition genomic information improved model performance predicting overall survival cindex original model 0595 95 ci 05570634 vs new model 0637 05950679 progressionfree survival 0567 95 ci 05290604 vs 0602 05600643 adequate discrimination proportion patients achieved objective response cochranarmitage onesided p00014 analyses validation cohort confirmed superiority genomically annotated risk model original version interpretation mutation status bap1 pbrm1 tp53 independent prognostic value patients advanced metastatic renalcell carcinoma treated firstline tyrosine kinase inhibitors improved stratification patients across risk groups use genomically annotated model including mutational status three genes warrants investigation prospective trials could use model stratify patients metastatic renalcell carcinoma clinical trials funding novartis pharmaceuticals corporation mskcc support grantcore grant j randall kathleen l macdonald research fund