NEW YORK – A team led by investigators in the UK and Canada has unearthed somatic tumor mutations with ties to disease recurrence risk in individuals with clear-cell renal cell carcinoma (ccRCC).
The genomic classifier, described in a paper in Clinical Cancer Research on Thursday, may ultimately help identify ccRCC patients who would benefit the most from adjuvant treatment after surgery.
"[W]e believe that current criteria for selecting high-risk patients are not accurate, and our genomic classifier can refine risk stratification and personalized selection of patients for adjuvant therapies," co-senior and co-corresponding author Yasser Riazalhosseini, a human geneticist at McGill University and head of cancer genomics at McGill's Victor Phillip Dahdaleh Institute of Genomic Medicine, explained in an email.
While immune checkpoint inhibitors and tyrosine kinase inhibitors are being explored as a first-line treatment for advanced ccRCC, Riazalhosseini noted, the use of immune checkpoint inhibitors in an adjuvant treatment setting has been complicated by the low rates of disease recurrence found in patients not receiving the treatment, including patients assigned to the placebo group in related clinical trials.
Using targeted sequencing, he and his team profiled a dozen cancer-related genes in tumor samples from 943 individuals with ccRCC, including 469 patients in a discovery cohort and 474 for the validation stage of the study. Their analyses focused on ccRCC patients with tumor alterations in the von Hippel-Lindau tumor suppressor gene VHL, which is typically affected in around 80 percent of sporadic ccRCC cases.
The 12-gene panel was informed by a combination of published exome sequence data from the Cancer Genome Atlas and other studies, together with the team's own clinical association studies and a whole-genome sequencing study of ccRCC that Riazalhosseini and others published in Nature Communications in 2014.
Findings from the current study suggested that the number of somatic mutations found in combination with mutated VHL may coincide with increased risk of ccRCC recurrence. The team's analyses of disease-free survival at the five-year mark demonstrated that patients with somatic VHL alterations alone fared better than those with somatic mutations in the other genes profiled, showing a disease-free survival of nearly 91 percent.
In contrast, five-year disease-free survival dipped to just over 80 percent in cases with one other mutation, and further declined in individuals with VHL mutations in combination with two or three additional mutations, coming in at around 68 percent and below 51 percent, respectively.
The team saw a similar pattern in the validation group and in an analysis focused on the subset of ccRCC patients classified as eligible for adjuvant therapy based on clinical features such as tumor grade. Disease-free survival across the full group of ccRCC patients in the study who would be recommended for adjuvant treatment under current classification criteria was not quite 64 percent, compared to nearly 91 percent in individuals who would not currently be recommended for adjuvant therapy.
When the researchers brought in their genomic classifier approach, they refined the view of survival in this patient group, demonstrating that adjuvant therapy-eligible individuals with zero, one, two, or three somatic mutations other than VHL had disease-free survival rates reaching 79.3 percent, 69.4 percent, 45.6 percent, and 35.3 percent, respectively.
"[We] are excited about our findings and are very interested in testing our classifier in additional and independent patient cohorts," Riazalhosseini said, noting that the team is continuing to search for other informative alterations, including copy number changes, that may coincide with ccRCC recurrence risk.
The researchers are also exploring testing for the genomic classifier in the clinic using circulating tumor DNA-based liquid biopsy, he said, adding that larger studies will be needed to come up with similar classification approaches in the smaller subset of ccRCC cases lacking VHL mutations.