Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
Inivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UK.
Ann Oncol. 2022 May;33(5):500-510. doi: 10.1016/j.annonc.2022.02.007. Epub 2022 Mar 17.
Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use.
We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient.
ctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <0.01%. ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (HR: 5.48, P <0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively).
ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention.
在接受根治性治疗的局限性非小细胞肺癌（NSCLC）患者中，识别残留疾病有望识别出有复发风险的患者。新方法可以检测到血浆中循环肿瘤 DNA（ctDNA）的分数浓度低至百万分之几，需要临床证据来告知其使用。
我们分析了 88 例早期 NSCLC（I 期/II 期/III 期分别为 48.9%/28.4%/22.7%）患者的 363 份连续血浆样本，主要为腺癌（62.5%），接受根治性手术治疗（n=61）、手术联合辅助化疗/放疗（n=8）或放化疗（n=19）。肿瘤外显子组测序鉴定了体细胞突变，并使用针对每个患者特有的肿瘤特异性变体的多达 48 个扩增子的患者特异性 RaDaR™检测分析血浆。
治疗前分别有 24%、77%和 87%的 I 期、II 期和 III 期疾病患者以及 26%的所有纵向样本中检测到 ctDNA，中位肿瘤分数为 0.042%，63%的样本<0.1%，36%的样本<0.01%。ctDNA 检测的临床特异性>98.5%，在原发性肿瘤临床复发前中位时间为 212.5 天。28 例临床原发性肿瘤复发患者中有 18 例（64.3%）治疗后检测到 ctDNA。在治疗结束后 2 周到 4 个月的标记时间点内检测到 17%的患者，与无复发生存率（风险比（HR）：14.8，P<0.00001）和总生存（HR：5.48，P<0.0003）较短相关。术后 1-3 天有 25%的患者检测到 ctDNA，但与疾病复发无关。治疗前的检测与总生存和无复发生存时间较短相关（HR：2.97 和 3.14，P 值分别为 0.01 和 0.003）。
使用敏感的患者特异性检测，在接受早期 NSCLC 初始治疗的患者中检测 ctDNA 有可能识别出可能受益于进一步治疗干预的患者。
