Department of Clinical Oncology, Pharmacogenomics, and Palliative Medicine.
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto.
Ann Oncol. 2016 Jun;27(6):1143-1148. doi: 10.1093/annonc/mdw074. Epub 2016 Feb 18.
Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study.
Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN.
Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences.
Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.
周围感觉神经病变（PSN）是基于奥沙利铂的化疗的剂量限制毒性。已经有几项遗传标志物被证明可以预测奥沙利铂引起的 PSN；然而，这些结果仍需要在大规模的前瞻性药物基因组学研究中得到验证。
在旨在研究日本 II 期或 III 期结肠癌根治术后接受辅助改良 FOLFOX6（mFOLFOX6）治疗的患者的耐受性的 JFMC41-1001-C2（JOIN 试验）中，共有 882 名患者入组，其中 465 名患者符合这项药物基因组学分析的条件。根据已发表的数据，选择了 12 个单核苷酸多态性（SNP）。使用 Cox 比例风险模型评估每个基因型对所有患者（n=465）PSN 发病时间的影响。对于 12 个 SNP 标记物与 PSN 严重程度之间的关联分析，从 PSN 0/1 级的患者中排除了 84 名未能完成 12 个周期 mFOLFOX6 治疗的患者，因为方案治疗的终止是由于 PSN 以外的原因。
与奥沙利铂总剂量调整后，0/1 级 PSN 与 2/3 级 PSN 或 3 级 PSN 比较，与 12 个 SNP 标记物均无显著相关性。发病时间分析也未显示出任何显著差异。
我们对接受辅助 mFOLFOX6 方案治疗的日本患者进行的大规模前瞻性药物基因组学研究未能证实报告的 12 个 SNP 标记物与 PSN 显著相关的作用。考虑到本研究中观察到的 OR（范围：0.76-1.89），进一步评估这些 SNP 标记物在 L-OHP 诱导的 PSN 中的作用不太可能具有临床意义。
