Voss MH, et al. - As Memorial Sloan Kettering Cancer Center (MSKCC) risk model that integrates clinical and laboratory data is an established prognostic tool for metastatic renal-cell carcinoma, researchers investigated the influence of adding the mutation status for several candidate prognostic genes to the MSKCC model on the model's prognostic performance. Observations revealed the independent prognostic value of mutation status of BAP1, PBRM1, and TP53 in patients with advanced or metastatic renal-cell carcinoma treated with first-line tyrosine kinase inhibitors. Use of a genomically annotated model including the mutational status of these three genes seemed to enhance stratification of patients across risk groups.

Methods

• From the COMPARZ trial (training cohort; n=357) and RECORD-3 trial (validation cohort; n=258), available data regarding formalin-fixed paraffin-embedded tumour tissue and clinical outcome of patients with metastatic renal-cell carcinoma assigned to treatment with tyrosine kinase inhibitors were used for this retrospective cohort study.
• For the 2 trials, eligible patients were those who were treatment-naive; had histologically confirmed, advanced, or metastatic renal-cell carcinoma; and a Karnofsky performance status score of at least 70.
• For this analysis, researchers pooled data from patients in all treatment groups (sunitinib and pazopanib in the training cohort, and everolimus and sunitinib in the validation cohort) for each cohort.
• In the training cohort, they used tumour tissue to evaluate somatic mutations by next-generation sequencing, and tested the association between cancer-specific outcomes (overall survival, progression-free survival, and overall response) and the mutation status of six genes of interest (BAP1, PBRM1, TP53, TERT, KDM5C, and SETD2).
• They added only those genes which had prognostic value in this setting to the MSKCC risk model to create a genomically annotated version.
• Using the validation cohort, they independently tested the prognostic value of the annotated model vs the original MSKCC risk model.

Results

• The COMPARZ study had 357 (32%) of 1110 patients assigned to protocol treatment between August, 2008, and September, 2011, evaluable for mutation status and clinical outcomes in the training cohort.
• Two hundred fifty eight (55%) of 471 evaluable patients, enrolled between October, 2009, and June, 2011, on the RECORD-3 study comprised the independent validation cohort.
• Findings revealed prognostic significance of the presence of any mutation in BAP1 or TP53, or both, and absence of any mutation in PBRM1 in terms of overall survival in the training cohort, (TP53^wt/BAP1^mut, TP53^mut/BAP1 ^wt o TP53^mut/BAP1^mut vs TP53^wt/BAP1^wt hazard ratio [HR] 1·57, 95% CI 1·21–2·04; p=0·0008; PBRM1^wt vs PBRM^mut, HR 1·58, 1·16–2·14;p=0·0035).
• Addition of the mutation status for these three prognostic genes to the original MSKCC risk model was done to create a genomically annotated version.
• Change in the distribution of participants in the training cohort into the three risk groups of the original MSKCC model was observed from 87 (24%) of 357 patients deemed at favourable risk, 217 (61%) at intermediate risk, and 53 (15%) at poor risk, to distribution across four risk groups in the genomically annotated risk model, with 36 (10%) of 357 deemed at favourable risk, 77 (22%) at good risk, 108 (30%) at intermediate risk, and 136 (38%) at poor risk.
• Model performance improved with the addition of genomic information for predicting overall survival (C-index: original model, 0·595 [95% CI 0·557–0·634] vs new model, 0·637 [0·595–0·679]) and progression-free survival (0·567 [95% CI 0·529–0·604] vs 0·602 [0·560–0·643]) with adequate discrimination of the proportion of patients who achieved an objective response (Cochran-Armitage one-sided p=0·0014).
• The genomically annotated risk model was confirmed to be superior to the original version in the analyses in the validation cohort.