Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma

Abstract

BackgroundPatients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma.Patients and methodsWe carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial.ResultsMutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79–5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80–5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83–5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88–6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%–55%) versus 65% (95% CI 56%–72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40–4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32–4.74, P = 0.005).ConclusionctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy.Clinical trial numberISRCTN 81261306

Detection of cell‐free circulating BRAF V 600E by droplet digital polymerase chain reaction in patients with and without melanoma under dermatological surveillance

“…In addition, we expressed the results as the variant allele frequency (VAF), meaning the percentage of mutant copies in the total amount of BRAF molecules in cfDNA (cf BRAF ), containing both wild‐type and p.V600E alleles. The limit of detection was established as 1 copy of mutant DNA per mL, based on previous studies focused on cf BRAF V600E detection in patients with melanoma by ddPCR …”

“…The limit of detection was established as 1 copy of mutant DNA per mL, based on previous studies focused on cfBRAF V600E detection in patients with melanoma by ddPCR. [26][27][28]…”

From validity to clinical utility: the influence of circulating tumorDNAon melanoma patient management in a real‐world setting

“…Our group and others have demonstrated the analytical and clinical validity of ctDNA testing as a method for monitoring tumor burden and predicting outcomes in patients receiving immune checkpoint blockade therapy (Bettegowda et al ., ; Lee et al ., ; Lipson et al ., ). Intrapatient trends observed among serial ctDNA measurements were shown to differentiate progressive disease from an immune‐related tumor response (Lee et al ., ,b). In addition, patients with advanced melanoma receiving inhibitors of the mitogen‐activated protein kinase (MAPK) pathway showed marked increases in ctDNA that preceded the radiographic appearance of progressive disease, suggesting genomic changes linked to acquired drug resistance (Gray et al ., ; Wong et al ., ).…”

“…In addition, patients with advanced melanoma receiving inhibitors of the mitogen‐activated protein kinase (MAPK) pathway showed marked increases in ctDNA that preceded the radiographic appearance of progressive disease, suggesting genomic changes linked to acquired drug resistance (Gray et al ., ; Wong et al ., ). Among patients with high‐risk resected melanoma, ctDNA levels have been shown to predict disease relapse (Lee et al ., ,b). Taken together, these findings suggest that incorporation of ctDNA as a melanoma biomarker into the clinical setting could improve the current standard of care by providing early information about neoplastic growth and complementing radiographic imaging as an accurate gauge of treatment efficacy.…”

Considering adjuvant therapy for stage II melanoma

“…In addition to genetic analysis for molecular risk stratification of melanoma, other techniques in development may help identify patients at greatest risk of relapse. Circulating tumor DNA (ctDNA) is emerging as a prognostic marker in stage IV melanoma and is now under investigation for patients with stage II and III melanoma . As part of the AVAST‐M adjuvant trial (Adjuvant Bevacizumab in Patients with Melanoma at High Risk of Recurrence), which evaluated 1 year of bevacizumab versus observation in patients with stage IIB, IIC, and III (AJCCv6 and AJCCv7) cutaneous melanoma, a subgroup of 161 randomly selected patients from both arms of the study with known BRAF or NRAS mutations had ctDNA analyzed within 12 weeks after surgical clearance of their disease (median, 8.3 weeks; range, 2.4‐12 weeks).…”