多态性可能预测转移性黑色素瘤患者对 PD-1 阻断治疗的反应。
Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma.
机构信息
Medical Oncology Unit, Austin Health, Melbourne, VIC, Australia.
Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
出版信息
Front Immunol. 2021 Jun 9;12:672521. doi: 10.3389/fimmu.2021.672521. eCollection 2021.
A significant number of patients (pts) with metastatic melanoma do not respond to anti-programmed cell death 1 (PD1) therapies. Identifying predictive biomarkers therefore remains an urgent need. We retrospectively analyzed plasma DNA of pts with advanced melanoma treated with PD-1 antibodies, nivolumab or pembrolizumab, for five PD-1 genotype single nucleotide polymorphisms (SNPs): PD1.1 (rs36084323, G>A), PD1.3 (rs11568821, G>A), PD1.5 (rs2227981, C>T) PD1.6 (rs10204225, G>A) and PD1.9 (rs2227982, C>T). Clinico-pathological and treatment parameters were collected, and presence of SNPs correlated with response, progression free survival (PFS) and overall survival (OS). 115 patients were identified with a median follow up of 18.7 months (range 0.26 - 52.0 months). All were Caucasian; 27% BRAF V600 mutation positive. At PD-1 antibody commencement, 36% were treatment-naïve and 52% had prior ipilimumab. The overall response rate was 43%, 19% achieving a complete response. Overall median PFS was 11.0 months (95% CI 5.4 - 17.3) and median OS was 31.1 months (95% CI 23.2 - NA). Patients with the G/G genotype had more complete responses than with A/G genotype (16.5% 2.6% respectively) and the G allele of PD1.3 rs11568821 was significantly associated with a longer median PFS than the AG allele, 14.1 7.0 months compared to the A allele (p=0.04; 95% CI 0.14 - 0.94). No significant association between the remaining SNPs and responses, PFS or OS were observed. Despite limitations in sample size, this is the first study to demonstrate an association of a germline PD-1 polymorphism and PFS in response to anti-PD-1 therapy in pts with metastatic melanoma. Extrinsic factors like host germline polymorphisms should be considered with tumor intrinsic factors as predictive biomarkers for immune checkpoint regulators.
相当数量的转移性黑色素瘤患者(pts)对抗程序性细胞死亡 1(PD1)治疗无反应。因此,确定预测性生物标志物仍然是当务之急。我们回顾性分析了接受 PD-1 抗体纳武单抗或派姆单抗治疗的晚期黑色素瘤患者的血浆 DNA,用于分析五个 PD-1 基因型单核苷酸多态性(SNP):PD1.1(rs36084323,G>A)、PD1.3(rs11568821,G>A)、PD1.5(rs2227981,C>T)、PD1.6(rs10204225,G>A)和 PD1.9(rs2227982,C>T)。收集了临床病理和治疗参数,并将 SNP 的存在与反应、无进展生存期(PFS)和总生存期(OS)相关联。确定了 115 名患者,中位随访时间为 18.7 个月(范围为 0.26-52.0 个月)。所有患者均为白种人;27%存在 BRAF V600 突变。在开始使用 PD-1 抗体时,36%为治疗初治,52%曾接受过伊匹单抗治疗。总体缓解率为 43%,19%达到完全缓解。总体中位 PFS 为 11.0 个月(95%CI 5.4-17.3),中位 OS 为 31.1 个月(95%CI 23.2-NA)。与 A/G 基因型相比,GG 基因型患者的完全缓解率更高(16.5% 2.6%),与 AG 基因型相比,PD1.3 rs11568821 的 G 等位基因与更长的中位 PFS 显著相关,14.1 7.0 个月与 A 等位基因相比(p=0.04;95%CI 0.14-0.94)。未观察到其余 SNP 与反应、PFS 或 OS 之间存在显著相关性。尽管样本量有限,但这是第一项证明在转移性黑色素瘤患者中,种系 PD-1 多态性与抗 PD-1 治疗的 PFS 相关的研究。除了肿瘤内在因素外,还应考虑宿主种系多态性等外在因素作为免疫检查点调节剂的预测性生物标志物。
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