Tumour Identity Card Program (CIT), French League Against Cancer, Paris, France.
Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille, France.
Ann Oncol. 2021 Feb;32(2):250-260. doi: 10.1016/j.annonc.2020.10.601. Epub 2020 Nov 12.
Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments.
Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated.
The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value.
The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.
化疗是唯一被批准用于胰腺导管腺癌（PDAC）的全身治疗方法，根据患者的体能状态和预期疗效选择方案。建立与化疗疗效相关的有效分层方法，通过量身定制治疗方法，有可能改善预后。
在 PaCaOmics 计划中纳入的 PDAC 患者的临床前模型（原代细胞培养物和患者来源的异种移植物）上进行了同时的化疗敏感性和全基因组 RNA 谱分析（NCT01692873）。在单中心队列中进行了基于 RNA 的分层测试，并在回顾性收集的切除 PDAC 样本的多中心队列中进行了验证（分别为 67 例和 368 例）。在单中心和多中心队列中，分别有 43（65%）和 203（55%）例患者接受了辅助 gemcitabine 治疗。研究了预测 gemcitabine 敏感性与患者总生存期（OS）和无病生存期之间的关系。
GemPred RNA 特征来自临床前模型，将 gemcitabine 敏感的 PDAC 定义为 GemPred+。在接受测试和验证队列中 gemcitabine 治疗的患者中，GemPred+患者的 OS 高于 GemPred-（P=0.046 和 P=0.00216）。在两个队列中，在未接受 gemcitabine 治疗的患者中，GemPred 分层与 OS 无关。在接受 gemcitabine 治疗的患者中，GemPred+患者的 OS 显著高于 GemPred-：91.3 个月[95%置信区间（CI）：61.2-未达到]与 33 个月（95%CI：24-35.2）；风险比 0.403（95%CI：0.221-0.735，P=0.00216）。gemcitabine 和 GemPred+分层的交互检验具有统计学意义（P=0.0245）。在接受 gemcitabine 治疗的人群中，多变量分析保留了独立的预测价值。
基于 RNA 的 GemPred 分层预测了辅助 gemcitabine 在 PDAC 患者中的获益。
