Tao Qing, Zhu Wen, Zhao Xiaohui, Li Mei, Shu Yongqian, Wang Deqiang, Li Xiaoqin
Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Front Oncol. 2020 Apr 21;10:530. doi: 10.3389/fonc.2020.00530. eCollection 2020.
There is currently a lack of validated predictors for adjuvant chemotherapy efficacy in patients with gastric cancer (GC). Perineural invasion (PNI) is the process of neoplastic invasion of the nerves, accompanied by tumor microenvironment (TME) changes. TME can determine treatment outcome while the impact of PNI on chemotherapy efficacy remains unknown in GC. We investigated the association between PNI and the efficacy of postoperative adjuvant chemotherapy in patients with resected GC. Patients who underwent radical resection of stage IB-III GC with or without fluoropyrimidine (FU)-based adjuvant chemotherapy were retrospectively selected from two separate patient cohorts. PNI was confirmed with S100 immunohistochemistry (IHC). Tumor hypoxia and activity of selected pathways were quantified by mRNA-based signature scoring based on publicly available data. A hypoxia biomarker, ERO1A, and a FU resistance biomarker, thymidylate synthase (TS), were assessed by IHC, respectively. Two cohorts included 223 and 599 patients, respectively. Adjuvant chemotherapy significantly improved overall survival (OS) and disease-free survival (DFS) in PNI-positive but not in PNI-negative patients, which was not impacted by stages. Multivariate models showed that adjuvant chemotherapy was an independent predictor for OS and DFS in PNI-positive patients in both cohorts. For TME, PNI-negative tumors were more hypoxic than were PNI-positive tumors, and displayed relative up-regulation of signaling along the pathways that are important in FU metabolism or resistance. Expressions of ERO1A and TS significantly decreased in PNI-positive compared to PNI-negative tumors. PNI might help predict adjuvant chemotherapy benefit in patients with resected GC. Validation in prospective studies is required. Novel treatment strategies need to be developed in PNI-negative patients.
目前，胃癌（GC）患者辅助化疗疗效缺乏经过验证的预测指标。神经周围侵犯（PNI）是肿瘤侵袭神经的过程，伴有肿瘤微环境（TME）变化。TME可决定治疗结果，而PNI对GC化疗疗效的影响尚不清楚。我们研究了PNI与接受手术切除的GC患者术后辅助化疗疗效之间的关联。从两个独立的患者队列中回顾性选取了接受IB-III期GC根治性切除且接受或未接受基于氟嘧啶（FU）辅助化疗的患者。通过S100免疫组织化学（IHC）确认PNI。基于公开数据，通过基于mRNA的特征评分对肿瘤缺氧和选定通路的活性进行量化。分别通过IHC评估缺氧生物标志物ERO1A和FU耐药生物标志物胸苷酸合成酶（TS）。两个队列分别包括223例和599例患者。辅助化疗显著改善了PNI阳性患者的总生存期（OS）和无病生存期（DFS），但对PNI阴性患者无效，且不受分期影响。多变量模型显示，在两个队列中，辅助化疗都是PNI阳性患者OS和DFS的独立预测指标。对于TME，PNI阴性肿瘤比PNI阳性肿瘤缺氧程度更高，并且在FU代谢或耐药中重要的通路沿线信号显示相对上调。与PNI阴性肿瘤相比，ERO1A和TS的表达在PNI阳性肿瘤中显著降低。PNI可能有助于预测接受手术切除的GC患者辅助化疗的获益情况。需要在前瞻性研究中进行验证。对于PNI阴性患者，需要制定新的治疗策略。
