Patients with advanced non-clear cell renal cell carcinoma have a high prevalence of germline mutations, including some that could be used to guide therapy.
Patients with advanced non-clear cell renal cell carcinoma (RCC) have a high prevalence of germline mutations, including some that could be used to guide therapy, researchers have reported in JAMA Oncology (2018; 4:1228-35).
More than 20% of the non-clear cell RCC patients had a hereditary mutation, and about half of those were in specific genes, FH and MET, that could be used to direct systemic treatment or to indicate eligibility for clinical trials, said researcher Maria I. Carlo, MD, of Memorial Sloan Kettering Cancer, New York.
These findings suggest that regardless of family history, patients with advanced non-clear cell RCC should be referred to a cancer geneticist to at least consider germline testing, Dr. Carlo said in an interview with Urology Times.
"There is still more research to be done to clarify which subgroups of non-clear cell should be referred,” she said in the interview, “but I think it's definitely reasonable to have a discussion with all patients with non-clear cell RCC, knowing you'll have a higher prevalence of mutations."
The study, believed to be the first to evaluate prevalence of germline mutations in a large cohort of patients with advanced RCC, included 254 patients seen in medical oncology or urology clinics who agreed to testing and disclosure of the results.
Top-line results showed that 41 of those patients (16.1%) had any germline mutation, and of those, 14 (5.5%) were mutations in RCC-associated genes, Dr. Carlo and co-investigators reported.
Next: High prevalence of germline mutations in non-clear cell subsetThe more interesting finding of the study, however, was the high prevalence of germline mutations in the non-clear cell subset, including some RCC-associated mutations that are potentially actionable, Dr. Carlo said.
Out of 74 patients with non-clear cell RCC, nine (12.2%) had RCC-associated germline mutations, while in the 177 patients with clear cell RCC, only three (1.7%) had such mutations (p=.001), according to the report.
Eight out of nine of those germline mutations in the non-clear cell RCC subset were potentially actionable. Those included including seven mutations in FH, which is diagnostic of the hereditary syndrome hereditary leiomyomatosis and RCC (HLRCC), and one in MET.
For patients with FHmutations diagnostic of HLRCC, clinical practice guidelines now recommend treatment with bevacizumab (Avastin) plus everolimus (Afinitor) or erlotinib (Tarceva), and in a phase II biomarker study, presence of a germline METmutation was associated with response to MET/VEGFR2 inhibitor treatment in patients with papillary RCC, Dr. Carlo and co-authors noted in their report.
According to co-author Robert Motzer, MD, those results suggest all non-clear cell RCC patients should be referred for genetic counseling.
“Beyond a rare inherited condition called von Hippel-Lindau syndrome, as well as a few other uncommon disorders, we haven’t previously known that kidney cancer had this strong hereditary component,” Dr. Motzer said in an article on the Memorial Sloan Kettering blog, On Cancer.
Testing should include not only RCC genes, but also consideration of a broader set of genes, according to authors of a commentary on the study published in JAMA Oncology (2018; 4:1235-6).
“In the modern era of oncology, with near-ubiquitous sequencing of tumor DNA, increasing numbers of germline variants in cancer-related genes may be found,” wrote Patrick G. PiliÃ©, MD, and Kathleen A. Cooney, MD, in the commentary.
However, a team approach that includes genetic counseling, treatment planning, and cancer prevention will be needed to interpret the genetic findings ethically and appropriately, wrote Dr. PiliÃ©, of the University of Texas MD Anderson Cancer Center in Houston, and Dr. Cooney, of the Huntsman Cancer Institute in Salt Lake City.
Dr. Carlo reported a consulting or advisory role with Pfizer.