Hilmi Marc, Cros Jérôme, Puleo Francesco, Augustin Jeremy, Emile Jean-Francois, Svrcek Magali, Hammel Pascal, Arsenijevic Tatjana, Van Laethem Jean-Luc, Bachet Jean-Baptiste, Nicolle Remy
Programme Cartes D'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France.
Department of Pathology, Assistance Publique Hopitaux de Paris, Beaujon Hopsital, INSERM U1149, Université de Paris, Clichy, France.
Eur J Cancer. 2021 May;148:171-180. doi: 10.1016/j.ejca.2021.01.042. Epub 2021 Mar 18.
Few patients with pancreatic adenocarcinoma (PAC) are eligible for surgery. Patients with early relapse have a poor prognosis and might be better candidates for a medical approach. Clinical and pathological parameters only partially predict recurrence and are only obtained after surgery. PAC subtypes based on gene expression were proposed, and we assessed if they could predict the risk and type of recurrence independently of clinicopathological parameters.
Patients with curative-intent surgery for PAC without pretreatment were selected and divided into two independent cohorts defined as discovery (n = 381) and validation (n = 149) cohorts. Transcriptomic analyses were performed on formalin-fixed paraffin-embedded surgical samples to characterise tumour and stroma compartments using previously defined signatures. We associated molecular and clinicopathological characteristics with general, distant, and local recurrences using Cox regression analyses.
We found that tumour biology predicted distant recurrence contrary to local recurrence, which was directly related to resection margin status. Pure basal-like and stroma-activated subtypes were strongly associated with distant recurrence, independently of clinicopathological factors (hazard ratios [HRs] = 5.85, p < 0.001 and HR = 1.75, p = 0.007, respectively). By dissecting tumoural and stromal compartments, we demonstrated that the basal-like tumour component positively correlated with distant recurrence in both cohorts (HR = 1.45, p < 0.001 and HR = 1.90, p < 0.001), whereas the inactive structural stroma component was protective against distant recurrence (HR = 0.68, p < 0.001 and HR = 0.72, p < 0.001).
In addition to suggesting a different mechanism for local and distant relapse (incomplete resection and high metastatic potential, respectively), our results show the potency of molecular phenotype to predict patient outcome regarding distant recurrences.
很少有胰腺腺癌（PAC）患者适合手术。早期复发的患者预后较差，可能更适合采用药物治疗。临床和病理参数只能部分预测复发，且只能在手术后获得。基于基因表达的PAC亚型已被提出，我们评估了它们是否能独立于临床病理参数预测复发风险和类型。
选择接受了根治性手术且未进行预处理的PAC患者，并将其分为两个独立队列，即发现队列（n = 381）和验证队列（n = 149）。对福尔马林固定石蜡包埋的手术样本进行转录组分析，使用先前定义的特征来表征肿瘤和基质成分。我们使用Cox回归分析将分子和临床病理特征与总体复发、远处复发和局部复发相关联。
我们发现肿瘤生物学可预测远处复发，与局部复发相反，局部复发与手术切缘状态直接相关。纯基底样和基质激活亚型与远处复发密切相关，独立于临床病理因素（风险比[HRs]分别为5.85，p < 0.001和HR = 1.75，p = 0.007）。通过剖析肿瘤和基质成分，我们证明基底样肿瘤成分在两个队列中均与远处复发呈正相关（HR = 1.45，p < 0.001和HR = 1.90，p < 0.001），而无活性的结构基质成分可预防远处复发（HR = 0.68，p < 0.001和HR = 0.72，p < 0.001）。
除了提示局部和远处复发的不同机制（分别为切除不完全和高转移潜能）外，我们的结果还显示了分子表型在预测患者远处复发结局方面的效力。
