MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Ann Oncol. 2021 Apr;32(4):522-532. doi: 10.1016/j.annonc.2020.12.010. Epub 2021 Jan 7.
The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumor-node-metastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP).
A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082× (range 2196-28 524) and ctDNA results correlated with survival.
Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cN+. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P = 0.0003). Similar outcomes were observed for disease-free survival.
We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high- and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.
食管腺癌（EAC）的发病率正在迅速上升，其 5 年生存率<20%。除了 TNM（肿瘤-淋巴结-转移）分期外，目前尚无可靠的风险分层工具，也没有大型研究对 EAC 复发时的循环肿瘤 DNA（ctDNA）进行分析。在这里，我们分析了 EAC 中 ctDNA 动态的预后潜力，并考虑了不确定潜能的克隆性造血（CHIP）。
从英国前瞻性 Oesophageal Cancer Clinical and Molecular Stratification（OCCAMS）联盟数据集中确定了 97 例接受新辅助化疗和手术治疗的患者的 245 个样本。使用了包含 77 个基因的泛癌 ctDNA 面板。对血浆和外周血样本进行测序，平均深度为 7082×（范围 2196-28524），ctDNA 结果与生存相关。
97 例患者的特征如下：83/97（86%）为男性，中位年龄 68 岁（标准差 9.5 岁），100%为 cT3/T4，75%为 cN+。EAC 特异性驱动因素的变异等位基因分数高于乘客突变。使用严格的质量标准，16/79（20%）例患者在切除后 ctDNA 呈阳性；这些患者中有 12/16（75%）出现复发。多达 78/97（80%）例患者进行了 CHIP 分析，可筛选 CHIP 变体，在 78 例患者中有 18 例（23%）发现了 CHIP 变体。排除 CHIP 后，63 例患者中有 10 例（16%）ctDNA 阳性，其中 9 例（90%）复发。校正 CHIP 后，ctDNA 阳性患者的癌症特异性生存率为 10.0 个月，而 ctDNA 阴性患者为 29.9 个月（风险比 5.55，95%置信区间 2.42-12.71；P=0.0003）。无病生存率也观察到类似的结果。
我们在一个大型的、全国性的、前瞻性的数据集证明，EAC 手术后血浆中的 ctDNA 与复发有关。包括外周血样本可以减少或消除 CHIP 的假阳性。在未来，术后 ctDNA 可用于将患者分为高危和低危组，以加强或减轻辅助化疗的强度。
