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Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell Carcinoma Risk Groups
Guillermo de Velasco1, Diana Miao2, Martin H Voss3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared with patients with favorable or intermediate risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole-exome transcriptome data in renal cell carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by the MSKCC risk group, nor was the expression of cytolytic genes-granzyme A and perforin-or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis revealed that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. Cancer Immunol Res; 4(10); 820-2. ©2016 AACR.
Insights
Metastatic renal cell carcinoma patients receiving nivolumab showed improved survival. Poor-risk patients benefited most, but tumor mutational load and immune gene expression did not correlate with risk groups.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Metastatic renal cell carcinoma (mRCC) patients demonstrate improved survival with nivolumab (anti-PD-1) compared to everolimus.
- The CheckMate-025 trial indicated superior survival in poor-risk mRCC patients treated with nivolumab.
- Prognostic factors influencing nivolumab efficacy in mRCC require further elucidation.
Purpose of the Study:
- To investigate if tumor mutational load and immune gene expression correlate with Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups in mRCC.
- To determine if these molecular factors explain the enhanced survival observed in poor-risk mRCC patients treated with nivolumab.
Main Methods:
- Analysis of whole-exome transcriptome data from 54 metastatic renal cell carcinoma patients in The Cancer Genome Atlas.
- Patients included had metastatic disease at presentation or developed it later and did not receive immune checkpoint inhibitors.
- Assessment of nonsynonymous mutational load, cytolytic gene expression (granzyme A, perforin), and immune checkpoint molecule expression across MSKCC risk strata.
Main Results:
- No significant differences in nonsynonymous mutational load were found across MSKCC risk groups.
- Expression levels of cytolytic genes (granzyme A, perforin) did not vary significantly between risk groups.
- Expression of selected immune checkpoint molecules was also not different across the MSKCC risk classifications.
Conclusions:
- Tumor mutational load does not correlate with MSKCC prognostic risk classification in mRCC.
- Expression of key immune markers within the tumor microenvironment is not associated with MSKCC risk stratification.
- These molecular features do not appear to explain the differential survival outcomes observed in poor-risk mRCC patients treated with nivolumab.
