Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Cancer Immunol Immunother. 2023 Jun;72(6):1903-1915. doi: 10.1007/s00262-023-03367-w. Epub 2023 Feb 2.
Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC.
This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated.
A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment.
This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.
抗 PD-1 抗体被广泛用于癌症治疗，包括晚期肾细胞癌（RCC）。然而，它们在患者中的治疗效果和不良反应存在差异。本研究旨在确定预测纳武利尤单抗抗 PD-1 抗体治疗晚期 RCC 患者结局的遗传标志物。
本研究在大学医院医疗信息网络网站（协议 ID：UMIN000037739）上注册。患者招募于 2019 年 8 月 19 日至 2020 年 9 月 30 日在日本的 23 家机构进行。患者随访于 2021 年 3 月 31 日结束。患者接受纳武利尤单抗治疗晚期透明细胞 RCC。在开发组中进行全基因组关联研究，在验证组中进行目标区域的基因分型。在合并组中对感兴趣的基因 CD274、PDCD1LG2 和 PDCD1 的单核苷酸多态性（SNP）进行基因分型。主要终点是 SNP 与纳武利尤单抗治疗后的客观缓解相关。次要终点是 SNP 与放射性无进展生存期（rPFS）和治疗相关的 3 级及以上不良事件（AE）的相关性。
全基因组关联研究和验证研究表明，FARP1 中的 SNP（rs643896 和 rs685736）与纳武利尤单抗治疗后的客观缓解和 rPFS 相关，但与 AE 无关。此外，PDCD1LG2 中的 SNP（rs822339 和 rs1411262）与纳武利尤单抗治疗后的客观缓解、rPFS 和 AE 相关。根据 SNP（FARP1 中的 rs643896 和 PDCD1LG2 中的 rs4527932）中风险等位基因的数量确定的遗传风险类别，可很好地预测纳武利尤单抗治疗中的客观缓解和 rPFS。
本研究表明，FARP1 和 PDCD1LG2 中的 SNP 与纳武利尤单抗治疗的结局相关。这些 SNP 的使用可能有助于为个体患者选择合适的治疗方法，并为个性化医学做出贡献。
