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

Article

Analyzing somatic and germline mutations and MSI may reveal clinically actionable mutations in a proportion of patients with advanced RCC.

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.

Recent Videos
One of the largest obstacles to tackle in the kidney cancer landscape will be translating the research on rare kidney cancer subtypes into clinical trials.
Zanzalitinib exhibited favorable data when evaluated alone or in combination with anti-PD-1 immune checkpoint inhibition in phase 1 RCC trials.
The investigational agent exhibited superior efficacy vs pembrolizumab in patients with lung cancer, suggesting potential efficacy in kidney cancer.
“As a community, if we’re looking to help enroll and advocate for patients with rare [kidney cancers], we need to be aware of what is out there,” said A. Ari Hakimi, MD.
Treatment with the dual inhibitor displayed a short half-life and a manageable toxicity profile in patients with clear cell renal cell carcinoma.
The annual Kidney Cancer Research Summit was born from congressional funding for kidney cancer research, according to KidneyCAN president Bryan Lewis.
Combining renal vaccines with immune therapy may better target tumor cells while limiting harm to healthy tissue, according to David A. Braun, MD, PhD.
Improving data collection and biomarker development across institutions may represent areas of expansion in kidney cancer research.
KIM-1 is a biomarker in the blood that may help noninvasively detect kidney cancer, according to Wenxin (Vincent) Xu, MD.
A phase 0 trial is seeking to assess the feasibility of aiding anti-cancer cells with cytokines to restore their function.
Related Content