Background Patients 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 methods We 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. Results Mutant 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). Conclusion ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy. Clinical trial number ISRCTN 81261306.

中文翻译：

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循环肿瘤 DNA 可预测切除高危 II/III 期黑色素瘤患者的存活率。

背景 高危 II/III 期切除的黑色素瘤患者通常会发生远处转移。目前，我们无法区分会复发的患者和手术治愈的患者。我们调查了循环肿瘤 DNA (ctDNA) 是否可以预测切除黑色素瘤患者的复发和存活率。患者和方法 我们进行了液滴数字聚合酶链反应，以检测 161 名参加 AVAST-M 辅助试验的 II/III 期高危黑色素瘤患者术后血浆中的 BRAF 和 NRAS 突变。结果 在 15/132 (11%) BRAF 突变患者样本和 4/29 (14%) NRAS 突变患者样本中检测到突变 BRAF 或 NRAS ctDNA（≥1 份突变 ctDNA）。可检测到 ctDNA 的患者无病间隔时间缩短 [DFI；风险比（HR）3.12；95% 置信区间 (CI) 1.79-5.47；P < 0.0001] 和无远处转移间隔（DMFI；HR 3.22；95% CI 1.80-5.79；P < 0.0001）与 ctDNA 检测不到的患者相比。在调整体能状态和疾病阶段后，可检测的 ctDNA 仍然是一个重要的预测因子（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）。可检测到 ctDNA 的患者的 5 年总生存率为 33%（95% CI 14%-55%），而无法检测到 ctDNA 的患者为 65%（95% CI 56%-72%）。可检测到 ctDNA 的患者的总生存期明显更差（HR 2.63；95% CI 1.40-4.96）；P = 0.003）并且在调整性能状态后仍然显着（HR 2.50, 95% CI 1.32-4.74, P = 0.005）。结论 ctDNA 可预测高危切除黑色素瘤的复发和生存，并有助于选择患者进行辅助治疗。临床试验编号 ISRCTN 81261306。