Mutation Profiles May Aid in Treatment of Non–Clear-Cell Renal Cell Carcinoma

Somatic mutation profiles of metastatic non–clear-cell renal cell carcinoma (nccRCC) vary by subtype, and analyzing somatic and germline mutations and microsatellite instability (MSI) may reveal clinically actionable mutations in a proportion of patients with advanced disease, according to a recent report published in JCO Precision Oncology.

Among all RCC cases, approximately 20% are nccRCC, which includes subtypes that are highly heterogeneous. Since nccRCC has limited sensitivity to conventional agents targeting vascular endothelial growth factor and mammalian target of rapamycin, a strong need for better therapies exists, and characterizing genomic variations may aid in this quest.

Carlo and colleagues retrospectively analyzed tumor tissue from 116 patients with metastatic nccRCC. Among these patients, 57 had de novo metastatic disease (49%), and 59 had localized disease that later metastasized (51%). The subtype classifications were highly varied (35% unclassified, 22% papillary, 15% chromophobe, 11% translocation associated, and 16% other).

The team used OncoKB classification to annotate individual mutations for their therapeutic potential and found that 13% of all tumors harbored potentially actionable somatic mutations. They also explored the efficacy of targeted therapies in patients who received treatment, and found that 33% of patients had an objective response and an additional 25% achieved stable disease. These are very promising findings and point toward more personalized medicine in these subtypes of nccRCC, the authors noted.

The  identified alterations included ALK translocation, MET amplifications, and TSC1 or TSC2 alterations. A total of 5 patients had tumors with level 3 alterations; most alterations were level 4, which are hypothetical biomarkers based on preclinical data. “Although these are not considered clinically actionable, they may be biomarkers and may be used as eligibility criteria for early-phase clinical trials,” wrote the authors.

Among 45 patients who had germline testing, the researchers found 11 (24%) harbored mutations (24%). Among the 115 available tumors for analysis, the investigators found 2 tumors (1.7%) had high MSI status and 6 tumors (5%) had intermediate MSI status.

The study is limited because it is a single-institution experience, and prevalence of RCC subtypes may vary by geography or ancestry. “There may also be referral bias to a specialized cancer center. The analysis was limited to targeted exome sequencing, and this approach could have missed other nonexonic as well as epigenetic changes,” wrote the authors.

Simpa Salami, MD, an assistant professor of urology at the University of Michigan, Ann Arbor, Michigan, said these initial findings are an important first step. High MSI may affect clinical management, and this study suggests this may be an issue in only a small percentage of patients, he said.

“Understanding the biology of nccRCC is an important area of research given the limited data available in this space. While it is unclear how the current findings will impact patient management, it certainly paves the way for additional investigations into the role of the identified alterations in the pathogenesis of this disease and the development of targeted therapeutic strategies,” Salami told Cancer Network.