Cell-Free DNA Assay Can Help Monitor Melanoma for Metastasis

The presence and burden of single nucleotide variants (SNVs) as measured in cell-free DNA (cfDNA) may have substantial prognostic utility in patients with melanoma who have regional and/or distant metastases, according to a new study.

“Blood cfDNA biomarkers are minimally invasive and potentially allow routine monitoring of molecular changes in patients’ cancer over the course of therapy and follow-up,” wrote study authors led by Dave S. B. Hoon, PhD, of the John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California. “Unfortunately, no blood-based melanoma biomarker is available for early detection of recurrence, particularly in patients with stage III melanoma rendered clinically disease free upon surgery, except the problematic surrogate biomarker, serum lactate dehydrogenase (LDH).”

The authors conducted a study of whether a 54 cancer gene assay that monitors SNVs in cfDNA might provide useful information in metastatic melanoma patients. The study included two cohorts: cohort 1 included 44 patients with stage II, III, or IV disease with matched tumor DNA at the time of surgery or of distant organ metastasis; and cohort 2 included 12 patients who were monitored longitudinally after complete lymph node dissection. The results were published in JCO: Precision Oncology.

The cfDNA assay analyzed variations in genes known to be melanoma driver genes. In cohort 1, cfDNA SNVs were found in 75% of patients. The variant allele fraction (VAF), representing the number of cfDNA molecules with specific variants divided by the total number of unique cfDNA molecules at that nucleotide position, ranged from 0.1% to 33.6%.

The number of SNVs and the total SNV burden were associated with outcomes. Patients with more than two SNVs had a median overall survival (OS) of 8.6 months, while those with two or fewer had a median OS of 17.5 months (P = .026). Those with an SNV burden > 0.5% had a median OS of 9.2 months, compared with 16.4 months in those with a lower burden (P = .049). A multivariate analysis showed that higher SNV load and burden were both independent prognostic factors for both poorer OS and disease-free survival, after adjustments for baseline factors.

Cohort 2 showed similar results, and moreover, monitoring cfDNA allowed for earlier detection of distant organ metastasis than either clinical or radiologic detection, by a median of 7.5 months (P < .01). Detection by cfDNA was also significantly earlier than with LDH monitoring (P = .01).

“Overall, our cfDNA analysis reveals informative SNV and CNV [copy number variation] profiles, potentially precluding the need for invasive tumor biopsies,” the authors wrote. “This approach allows for real-time monitoring of tumor progression and evolution, earlier recurrence detection, and discovery of new SNVs and CNVs indicative of therapy resistance.”