Coltelli Luigi, Allegrini Giacomo, Orlandi Paola, Finale Chiara, Fontana Andrea, Masini Luna Chiara, Scalese Marco, Arrighi Giada, Barletta Maria Teresa, De Maio Ermelinda, Banchi Marta, Fini Elisabetta, Guidi Patrizia, Frenzilli Giada, Donati Sara, Giovannelli Simona, Tanganelli Lucia, Salvadori Barbara, Livi Lorenzo, Meattini Icro, Pazzagli Ilaria, Di Lieto Marco, Pistelli Mirco, Casadei Virginia, Ferro Antonella, Cupini Samanta, Orlandi Francesca, Francesca Damiana, Lorenzini Giulia, Barellini Leonardo, Falcone Alfredo, Cosimi Alessandro, Bocci Guido
Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy.
Division of Medical Oncology, Livorno and Pontedera Hospitals, Azienda USL Toscana Nord Ovest, Pisa, Italy.
NPJ Breast Cancer. 2022 Mar 21;8(1):33. doi: 10.1038/s41523-022-00400-6.
To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5-0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5-1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.
研究血管内皮生长因子A（VEGF-A）、血管内皮生长因子受体2（VEGFR-2）、白细胞介素8（IL-8）、缺氧诱导因子-1α（HIF-1α）、内皮 PAS 结构域蛋白1（EPAS-1）和血小板反应蛋白1（TSP-1）单核苷酸多态性（SNP）之间的药物遗传学相互作用及其对接受贝伐单抗联合一线紫杉醇治疗或仅接受紫杉醇治疗的转移性乳腺癌（MBC）患者无进展生存期（PFS）的影响。对种系DNA进行分析，并通过实时聚合酶链反应（PCR）技术研究SNP。应用多因素降维（MDR）方法研究SNP之间的相互作用。本研究为探索性双向队列研究：对来自11个肿瘤科室的307例患者进行回顾性评估（2009年至2016年），然后进行前瞻性随访（NCT01935102）。215例患者接受紫杉醇和贝伐单抗治疗，而92例患者仅接受紫杉醇治疗。在贝伐单抗联合紫杉醇组中，MDR软件提供了两种药物遗传学相互作用谱，由特定的VEGF-A rs833061和VEGFR-2 rs1870377基因型组合而成。有利基因谱的中位PFS为16.8个月，而不利基因谱为10.6个月（p = 0.0011）。Cox比例风险模型显示调整后的风险比为0.64（95%置信区间，0.5 - 0.9；p = 0.004）。有利基因谱的中位总生存期（OS）为39.6个月，而不利基因谱为28个月（p = 0.0103）。Cox比例风险模型显示调整后的风险比为0.71（95%置信区间，0.5 - 1.01；p = 0.058）。在仅接受紫杉醇治疗的92例患者中，结果显示有利基因谱与不利基因谱相比，对PFS（p = 0.509）和OS（p = 0.732）均无影响。VEGF-A rs833061和VEGFR-2 rs1870377基因型之间的药物遗传学统计相互作用可能识别出一组接受贝伐单抗治疗且PFS较好的患者。
