Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Melanoma Institute Australia, Sydney, New South Wales, Australia.
JAMA Oncol. 2018 May 1;4(5):717-721. doi: 10.1001/jamaoncol.2017.5332.
Longitudinal circulating tumor DNA (ctDNA) has been shown to predict response and survival in patients with metastatic melanoma treated with anti-programmed cell death 1 (PD-1) antibodies. Pseudoprogression, defined as radiologic finding of disease progression prior to response, has been a challenge to clinicians.
To establish whether ctDNA at baseline and up to week 12 of treatment can differentiate between the radiologic findings of pseudoprogression and true progression in patients with metastatic melanoma.
DESIGN, SETTING, AND PARTICIPANTS: This explorative biomarker study examined circulating BRAF and NRAS mutations in a cohort of 125 patients with melanoma receiving PD-1 antibodies alone or in combination with ipilimumab between July 3, 2014, and May 24, 2016. Pseudoprogression was defined retrospectively as radiologic progression not confirmed as progressive disease at the next radiologic assessment. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favorable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by >10-fold decrease) and unfavorable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis.
Early differentiation of pseudoprogression from true progression using longitudinal ctDNA profile.
According to guidelines by Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 of the 125 patients (23.2%). Of the 29 patients, 17 (59%) were 65 years or younger, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the 9 patients (7%) with confirmed pseudoprogression, all patients had a favorable ctDNA profile. At a median follow-up of 110 weeks, 7 of 9 patients (78%) were alive. All but 2 patients with true progression had an unfavorable ctDNA profile. Sensitivity of ctDNA for predicting pseudoprogression was 90% (95% CI, 68%-99%) and specificity was 100% (95% CI, 60%-100%). The 1-year survival for patients with RECIST-defined progressive disease and favorable ctDNA was 82% vs 39% for unfavorable ctDNA (hazard ratio [HR], 4.8; 95% CI, 1.6-14.3; P = .02). Overall survival was longer in patients with a partial response (54 of 125 patients [43%]) compared with patients with progressive disease and a favorable ctDNA profile (11 of 125 patients [9%]; HR, 0.09; 95% CI, 0.01-0.80; P < .01).
The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival.
已有研究表明，转移性黑色素瘤患者在接受抗程序性细胞死亡 1（PD-1）抗体治疗时，循环肿瘤 DNA（ctDNA）的纵向变化可预测其对治疗的反应和生存情况。影像学表现为疾病进展前的假进展，这给临床医生带来了挑战。
确定基线和治疗第 12 周的 ctDNA 是否可以区分转移性黑色素瘤患者的影像学假进展和真正进展。
设计、地点和参与者：本探索性生物标志物研究分析了 2014 年 7 月 3 日至 2016 年 5 月 24 日期间接受 PD-1 抗体单药或联合伊匹单抗治疗的 125 例黑色素瘤患者的循环 BRAF 和 NRAS 突变。回顾性定义假进展为影像学进展，但在下一次影像学评估时未确认为进展性疾病。在治疗的前 12 周内，前瞻性地采集基线和治疗期间的 ctDNA 血浆样本进行分析。有利的 ctDNA 谱（基线时无法检测到 ctDNA 或基线时可检测到 ctDNA 但随后降低了>10 倍）和不利的 ctDNA 谱（基线时可检测到 ctDNA，且稳定或增加）与反应和预后相关。
使用纵向 ctDNA 谱来早期区分假进展和真正的进展。
根据实体瘤反应评价标准（RECIST），125 例患者中有 29 例（23.2%）出现疾病进展。在 29 例患者中，17 例（59%）患者年龄在 65 岁或以下，18 例（62%）为男性，9 例（31%）有假进展，20 例（69%）有真进展。在 9 例（7%）经证实的假进展患者中，所有患者均具有有利的 ctDNA 谱。中位随访 110 周时，9 例患者（78%）存活。所有真进展患者均有不利的 ctDNA 谱。ctDNA 预测假进展的敏感性为 90%（95%CI，68%-99%），特异性为 100%（95%CI，60%-100%）。RECIST 定义的疾病进展和有利 ctDNA 患者的 1 年生存率为 82%，而不利 ctDNA 患者为 39%（HR，4.8；95%CI，1.6-14.3；P=0.02）。与疾病进展且 ctDNA 谱有利的患者相比，有部分反应（125 例患者中的 54 例[43%]）的患者总生存时间更长（HR，0.09；95%CI，0.01-0.80；P<0.01）。
结果表明，ctDNA 谱可准确区分黑色素瘤患者接受 PD-1 抗体治疗时的疾病假进展和真进展。在系统性治疗期间定期进行的这种血液检测结果反映了肿瘤生物学，有可能成为预测长期反应和生存的有力生物标志物。
