Peter MacCallum Cancer Centre, Melbourne; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester.
Ann Oncol. 2019 May 1;30(5):804-814. doi: 10.1093/annonc/mdz048.
The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma.
Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n = 29).
ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P = 0.002] and postoperatively (HR 10; 95% CI 4.3-24; P < 0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3-27; P < 0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status.
Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.
由于治疗相关的成本和毒性，有效辅助疗法的出现突显了根据复发风险对接受切除术的黑色素瘤患者进行分层的必要性。在此，我们评估了循环肿瘤 DNA（ctDNA）在预测和监测接受切除术的 III 期黑色素瘤患者复发中的作用。
通过肿瘤组织测序在 133 名患者中的 99 名（74%）患者中确定了种系突变。在来自阳性突变患者的 315 份前瞻性收集的血浆样本中，使用个性化的液滴数字 PCR（ddPCR）检测来检测已知突变。在一个前瞻性独立队列（n=29）中进行了外部验证。
在 99 名个体中的 37 名（37%）中检测到了 ctDNA。在未接受辅助治疗的 81 名患者中，基线时检测到 ctDNA 的 90%患者和术后时间点检测到 ctDNA 的 100%患者在中位随访 20 个月时复发。ctDNA 检测在基线时预测患者具有较高的复发风险[无复发生存率（RFS）风险比（HR）2.9；95%置信区间（CI）1.5-5.6；P=0.002]和术后（HR 10；95% CI 4.3-24；P<0.001）。基线时的 ctDNA 检测[HR 2.9；95% CI 1.3-5.7；P=0.003 和术后（HR 11；95% CI 4.3-27；P<0.001]也与远处无转移生存（DMFS）不良相关。在独立队列中验证了这些发现。在多变量分析中，ctDNA 检测在调整疾病分期和 BRAF 突变状态后仍然是 RFS 和 DMFS 的独立预测因子。
在两个独立的前瞻性队列中，基线和术后 ctDNA 检测确定了具有最高复发风险的 III 期黑色素瘤患者，有可能为辅助治疗决策提供信息。
