Circulating Tumor DNA Reveals Array of Genomic Alterations in mRCC

Circulating Tumor DNA Reveals Array of Genomic Alterations in mRCC

Dr. Sumanta K. Pal
In the largest study of its kind to date, most patients with metastatic renal cell carcinoma (mRCC) had detectable circulating tumor DNA (ctDNA). Differences in specific genomic alterations were seen between receipt of first-line therapies and subsequent therapies, potentially illustrating mechanisms of resistance (Abstract 434), but much work remains before ctDNA detection might offer clinical utility.

There may be an evolution of tumor biology as [disease] progresses toward metastasis,” said Sumanta K. Pal, MD, of the City of Hope Comprehensive Cancer Center, during an Oral Abstract Session on Feb. 18. “We really have no predictive biomarkers in the clinic today,” he said, either to help guide therapy or inform prognosis.

Circulating biomarkers represent a practical means to assess tumor biology because advanced tumors are known to shed DNA into the blood. Dr. Pal and colleagues used the Guardant360 assay, which assesses 70 or more cancer-related genes in ctDNA, to try to determine the mutational landscape of advanced RCC.

The study included a total of 224 patients who had advanced RCC. Patients who received sunitinib, pazopanib, bevacizumab, or temsirolimus were in the first-line group, and those who received cabozantinib, nivolumab, lenvatinib, everolimus, axitinib, or other therapies were in the post–first-line group. Patients were an average age of 61 years; most (149 of 224 patients) were men; and, of the 128 occurrences with specified histology, 71% were clear cell disease. Most patients on first-line therapy (63%) received sunitinib, followed by pazopanib (34%) and bevacizumab (3%). Patients on post–first-line therapy most frequently received nivolumab (38%), followed by everolimus (19%), axitinib (17%), and cabozantinib (9%); 17% received other post­–first-line therapies.

The assay detected ctDNA in 79% of patients, and there was an average of 3.3 genomic alterations per patient. Most of the alterations identified (89%) were single nucleotide variants and small insertions/deletions.

In the full cohort, the most common alterations were in TP53, VHL, NF1, and EGFR. In a subset of just the 89 patients with clear cell RCC, TP53 was again the most common altered gene, followed by VHL, ARID1A, NF1, and PIK3CA.

There were several differences between patients in the first-line and post–first-line groups. TP53 alterations were seen in 49% of patients on post–first-line therapy compared with only 24% of patients on first-line therapy (p = 0.02). NF1 also was more commonly altered in the post–first-line than first-line setting (21% vs. 3%; p = 0.01). There were more alterations of VHL, EGFR, ARID1A, and PIK3CA in the post–first-line than first-line setting also, but these differences did not reach significance. Dr. Pal said that these differences could represent potential mechanisms of resistance.

He also noted that the frequencies of some of these alterations differed substantially from those seen in published databases. VHL, for example, is more frequently altered in earlier data sets than in this study, whereas TP53 and ARID1A were altered far more often in this study than in previous data sets. This could reflect the advanced disease state seen in patients in the new study.

“My question is, are these new genomic alterations? Or are we seeing noise?” asked Primo N. Lara Jr., MD, of the University of California, Davis, who was the Discussant for the abstract. He said that the inherent genomic instability of cancer, including RCC, means that, with regard to genomic alterations, tumors “tend to accumulate a lot of passengers, not drivers. There is still only one driver.”

Other work on this topic has found a variety of common alterations, but their functional utility is debatable. “I really believe this is important work. It gives us a landscape of an emerging new field, but this is but a 30,000-foot view,” Dr. Lara said, adding that establishing the functional role of the detected genomic alterations will require “bedside-to-bench translation. We must sort those passengers from the drivers, because the passengers just represent noise.”

– David Levitan