De Mattia Elena, Polesel Jerry, Roncato Rossana, Labriet Adrien, Bignucolo Alessia, Gagno Sara, Buonadonna Angela, D'Andrea Mario, Lévesque Eric, Jonker Derek, Couture Félix, Guillemette Chantal, Cecchin Erika, Toffoli Giuseppe
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano, Italy.
Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini n. 2, 33081 Aviano, Italy.
Cancers (Basel). 2021 Apr 3;13(7):1705. doi: 10.3390/cancers13071705.
A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient's immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients' immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, = 0.0327, Bootstrap -value = 0.0280) and replication (HR: 1.71, = 0.0411) cohorts. Conversely, rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, = 0.0202, Bootstrap -value = 0.0203) and replication (HR: 0.61, = 0.0216) cohorts. A genetic prognostic score was generated integrating -rs7910212 and -rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR []-rs1054190, -rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities ( < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as and markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.
癌症化疗的一种新范式源于包括伊立替康和5-氟尿嘧啶（5-FU）在内的化疗药物与免疫系统之间的相互作用。患者的免疫反应可调节化疗效果，另一方面，化疗药物可促进肿瘤细胞的免疫原性。基于这些原因，分析癌症患者的免疫遗传特征及其对化疗后生存的影响成为一个新的研究领域。本研究旨在确定免疫相关途径中预测FOLFIRI（伊立替康、5-FU、亚叶酸钙）治疗后总生存期（OS）的遗传决定因素。该研究纳入了两个独立队列，共335例接受一线FOLFIRI同质治疗的转移性结直肠癌（mCRC）患者。使用微珠阵列技术评估了34个免疫相关基因中192个标签基因多态性的预后作用。rs7910212-C等位基因在发现队列（HR：1.57，P = 0.0327，Bootstrap -值 = 0.0280）和验证队列（HR：1.71，P = 0.0411）中均与较差的OS相关。相反，rs7179840-C等位基因在发现队列（HR：0.65，P = 0.0202，Bootstrap -值 = 0.0203）和验证队列（HR：0.61，P = 0.0216）中均与较好的OS相关。整合了-rs7910212和-rs7179840标记以及我们先前在同一研究人群中确定的炎症相关预后多态性（即PXR []-rs1054190、-rs7299460）生成了一个遗传预后评分。计算出的遗传评分成功区分了具有不同生存概率的患者（对数秩检验P < 0.0001）。这些发现为诸如 和 标记等遗传决定因素的预后价值提供了新的见解，并可能提供一种新的决策工具，以改善接受FOLFIRI治疗的mCRC患者的临床管理。
