Blood Test Predicts Melanoma Recurrence

TOPLINE:

Droplet digital polymerase chain reaction (PCR) measurements of circulating tumor DNA (ctDNA) identify patients with stage III melanoma who are at high risk for early recurrence during adjuvant targeted therapy. The blood-based biomarker outperforms traditional prognostic indicators including tumor mutational burden and interferon gamma gene expression.

METHODOLOGY:

• Cell-free ctDNA is an established measure of minimal residual disease but has not been utilized in melanoma management.
• Researchers utilized analytically validated mutation-specific droplet digital PCR assays to measure BRAF V600E or BRAF V600K ctDNA in patients aged ≥ 18 years enrolled in the COMBI-AD trial.
• A total of 597 of 870 patients (331 men, 266 women) had baseline plasma samples available, with follow-up samples collected from 118 patients.
• Participants received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) combination therapy vs two matched placebos in resected BRAF V600E–mutant stage III melanoma.
• Median follow-up duration reached 60 months (interquartile range [IQR], 39-66) in the combination therapy group and 58 months (IQR, 21-66) for the placebo group.

TAKEAWAY:

• ctDNA was detectable in 79 (13%) of 597 baseline samples, with positivity rate and mutant copies per mL plasma significantly higher in patients with higher disease substages.
• Detection of ctDNA was associated with worse recurrence-free survival in both placebo group (median, 3.71 months; 95% CI, 2.39-6.89 vs median, 24.41 months; 95% CI, 17.28-43.13; hazard ratio [HR], 2.91; 95% CI, 1.99-4.25; P < .001) and combination therapy group (median, 16.59 months; 95% CI, 12.02-26.80 vs median, 68.11 months; 95% CI, 50.36 to not reached; HR, 2.98; 95% CI, 1.95-4.54; P < .001).
• Baseline ctDNA demonstrated stronger associations with survival outcomes than interferon gamma gene expression or tumor mutational burden.
• Patients with adverse longitudinal ctDNA kinetics showed markedly shorter median recurrence-free survival (molecular relapse: median, 8.31 months; 95% CI, 5.39-12.50; persistently positive: median, 5.32 months; 95% CI, 2.79 to not reached) vs those with favorable kinetics (undetectable after positive baseline: median, 19.25 months; 95% CI, 16.39 to not reached; durable undetectable: not reached; 95% CI, 38.44 to not reached; P < .001).

IN PRACTICE:

“We further demonstrated that the ctDNA assays could detect disease recurrence with moderate sensitivity and nearly 100% specificity. Additionally, pretreatment ctDNA measurements coupled with on-treatment measurements could enhance prognostication at follow-up, especially by identifying zero conversion or molecular relapse posttreatment,” wrote the authors of the study.

SOURCE:

The study was led by Mahrukh M Syeda, MS, and David Polsky, MD, PhD, Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine in New York City. It was published online in The Lancet Oncology.

LIMITATIONS:

The study included predominantly non-Hispanic White patients, which while representative of the global patient population with melanoma, limits broader demographic insights. The smaller number of samples available for longitudinal analysis compared with baseline analysis may have introduced bias in estimates of the ctDNA assay’s ability to detect minimal residual disease before clinical recurrence. Additionally, longitudinal collections were not planned beyond 12 months, restricting the ability to detect increasing burden of minimal residual disease before clinical recurrence after treatment cessation. Researchers also noted the lack of radiographic measurements of recurrent tumors to quantify associations between ctDNA copies per mL and disease burden or tumor volumes with respect to anatomic site.

DISCLOSURES:

The study was funded by Novartis. Polsky disclosed serving on advisory boards for Novartis and Merck, receiving honoraria from WebMD, Physicians’ Education Resource, and Oncology Specialty Group, and having laboratory research contracts with Novartis and Bristol Myers Squibb, along with in-kind laboratory support from BioRad. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.