Germline Mutations in Non-Clear Cell Renal Cell Carcinoma May Direct Systemic Therapy

Renal cell carcinoma (RCC), the most common type of kidney cancer, will affect about 64,000 people this year in the United States, of which approximately 30 percent will learn of their disease after it has advanced.

What if there was a way to determine which of these patients could benefit from systemic treatment, such as immunotherapy or targeted therapy? Could it help them live longer with better quality of life?

Researchers from Memorial Sloan Kettering Cancer Center in New York City examined cancer-related germline mutations — those passed onto people from their parents — in patients with advanced RCC. The study, published in JAMA Oncology, was conducted from October 2015 to July 2017 and included 254 patients with advanced RCC (177 had clear cell RCC, 74 had non—clear cell RCC and three had both). The median age of participants was 56 years.

In addition, 33 patients had a history of a second malignant tumor, including prostate and breast cancer, and melanoma. A family history of RCC was seen in 24 patients.

“Our aims were to examine the prevalence of germline mutations in known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations,” the researchers wrote.

They found that 41 patients had germline mutations in 17 different cancer-predisposition genes, but none of them had more than one germline mutation. Most (14 patients) had mutations in RCC-associated genes; seven in FH; three in BAP1; and one each in VHL, MET, SDHA and SDHB. The most frequent mutations were CHEK2, which was found in nine patients, and FH, found in seven patients.

Of the 177 patients with clear cell RCC, 25 had a germline mutation and three in an RCC-associated gene. Of the 74 patients with non—clear cell RCC, 13 had a germline mutation, with nine in an RCC-associated gene. Of the three patients with both, all had germline mutations, two in BAP1 and one in CHEK2.

Patients with non—clear cell RCC, which makes up about 20-25 percent of all RCC cases, were significantly more likely to have an RCC-associated gene mutation, noted researchers. Eight patients had a mutation that could guide therapy.

“Recent studies suggest that germline mutations may be more frequent in patients with advanced cancer compared with those with early-stage disease,” the researchers wrote. “Identifying patients with inherited mutations has become particularly relevant because mutations in certain genes, such as FH and MET, can guide systemic therapy or clinical trial eligibility.”

Researchers concluded that more than 20 percent of patients with non—clear cell RCC had a germline mutation, of which half had the potential to direct systemic therapy.

However, they noted that current referral criteria for genetic testing did not identify a substantial portion of patients with mutations. “Phenotype-directed or tumor-only testing would have failed to identify most patients with actionable mutations,” the researchers wrote.

“A broader approach to tumor-normal sequencing of all patients with advanced RCC, especially those with non—clear cell RCC, might help identify individual patients for whom targeted therapies are indicated, as well as family members who may benefit from preventive interventions tailored to their increased cancer risk,” they added.