Division of Systems Biology and Personalised Medicine, Walter & Eliza Hall Institute (WEHI), Melbourne; Department of Medical Oncology, Royal Melbourne Hospital, Melbourne; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne.
Department of Medical Oncology, Royal Melbourne Hospital, Melbourne; Department of Medical Oncology, Western Health, Melbourne; Department of Medical Oncology, Cabrini Health, Malvern, Australia.
Ann Oncol. 2019 Sep 1;30(9):1472-1478. doi: 10.1093/annonc/mdz200.
In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making.
Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data.
Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy.
ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.
在早期胰腺癌中，目前尚无生物标志物可指导治疗方案的选择。本前瞻性生物标志物试验评估了循环肿瘤 DNA（ctDNA）分析指导辅助治疗决策的可行性和潜在临床应用价值。
多学科团队认为可切除的胰腺腺癌患者入组。采集术前和术后的 ctDNA 分析样本。使用基于 PCR 的 SafeSeqS 检测方法，在原发胰腺肿瘤中鉴定 12、13 和 61 密码子 KRAS 突变，并检测 ctDNA。ctDNA 分析结果与 CA19-9、无复发生存率和总生存率（OS）相关。患者管理按标准护理进行，ctDNA 数据设盲。
112 例患者术前同意，81 例（72%）接受手术。91%（38/42）可获得的肿瘤样本中鉴定出 KRAS 突变。在可获得的血浆样本（N=42）中，术前检测到 62%（23/37）和术后 37%（13/35）存在 KRAS 突变 ctDNA。中位随访 38.4 个月时，术前检测到 ctDNA 与无复发生存率（RFS）[风险比（HR）4.1；P=0.002]和 OS（HR 4.1；P=0.015）较差相关。根治性切除术后可检测到 ctDNA 与 RFS（HR 5.4；P<0.0001）和 OS（HR 4.0；P=0.003）较差相关。术后可检测到 ctDNA 的 13 例患者（100%）均发生复发，其中 7 例接受吉西他滨为基础的辅助化疗。
局限性胰腺癌的 ctDNA 研究具有挑战性，许多患者无法接受手术，没有足够的肿瘤组织进行分析，或未按方案完成样本采集。术前和/或术后 ctDNA 分析是一种很有前途的预后标志物。ctDNA 指导治疗的研究是合理的，包括对术后可检测到 ctDNA 的患者进行强化治疗策略的研究，这些患者尽管接受了吉西他滨为基础的辅助治疗，但复发风险极高。
