Circulating Tumor DNA May Hold the Key to Metastatic Renal Cell Carcinoma Treatment

TP53 alteration seen among 49% of patients receiving first-line treatment for renal cell carcinoma.

In a new study, investigators discovered that a majority of patients with metastatic renal cell carcinoma (RCC) had circulating tumor DNA (ctNDA).

Between first- and second-line treatments, the ctDNA was observed to be altered, which suggests unknown mechanisms of treatment resistance may be involved, according to a study presented at the American Society of Clinical Oncology 2017 Genitourinary Cancers Symposium.

“There may be an evolution of tumor biology as [disease] progresses toward metastasis,” said researcher Sumanta K. Pal, MD. “We really have no predictive biomarkers in the clinic today.”

Circulating tumor biomarkers could offer a practical method to determine tumor biology since cancers are known to leave DNA in the blood, according to the study. The investigators used the Guardant360 assay to analyze 70 or more genes linked to cancer in the ctDNA to better understand metastatic RCC.

Included in the study were 224 patients with metastatic RCC. Patients were either treated with first-line therapy - sunitinib, pazopanib, bevacizumab, or temsirolimus - or were treated with post-first-line therapy, such as cabozantinib, nivolumab, lenvatinib, everolimus, or axitinib.

The assay detected ctDNA in 79% of patients, with an average of 3.3 mutations per patient. Approximately 89% of the patients were observed to have single nucleotide variants and small insertions or deletions, according to the study.

The investigators reported that the most common mutations were in TP53, VHL, NF1, and EGFR. In patients with clear cell RCC, TP53 was the most commonly altered gene.

Interestingly, the TP53 alteration was seen among 49% of post-first-line treatment patients, but only seen among 24% of patients in the other cohort, according to the study. The NF1 alteration was also significantly more common among patients in the post-first-line treatment group.

The researchers believe that these differences in alterations may point to mechanisms behind treatment resistant.

Additionally, the investigators noted that the alterations were significantly different than those seen in databases. The VHL mutation was previously observed to occur more frequently, while TP53 and ARID1A were more frequently altered in the current study. These changes may indicate the advanced disease state of the patients, according to the 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 at the conference.

Dr Lara said that genomic instability of cancer means that tumors tend to have multiple alterations, but typically only 1 drives the disease.

“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. “We must sort those passengers from the drivers, because the passengers just represent noise.”