PO.ET07.02 · 实验与分子治疗
转移性结直肠癌患者贝伐珠单抗二线化疗的药物遗传学交互作用分析：随机BEBYP试验结果
A pharmacogenetic interaction analysis of second-line chemotherapy with bevacizumab in metastatic colorectal cancer patients: Results from the randomized BEBYP trial
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摘要 Abstract
中文摘要
转移性结直肠癌（mCRC）仍是一项重大的治疗挑战，尽管贝伐珠单抗联合化疗已显示出临床获益，但其活性的经过验证的预测性生物标志物仍然缺失。此外，针对mCRC患者血管生成相关基因的药物遗传学分析未能预测治疗疗效和生存结局。基于此，我们采用了一种不同的方法开展药物遗传学研究，探讨EPAS-1、IL-8、VEGF-A和VEGFR-2单核苷酸多态性（SNP）对接受二线mFOLFOX-6或FOLFIRI（CHT）联合或不联合贝伐珠单抗治疗的mCRC患者无进展生存期（PFS）和总生存期（OS）的潜在联合效应。种系DNA取自外周血样本，SNP通过实时PCR进行基因分型。采用多因子降维（MDR）方法进行药物遗传学交互作用分析，以探索与治疗结局相关的SNP之间的潜在统计学交互作用。该分析纳入了在比萨大学医院入组随机III期BEBYP试验（clinicaltrials.gov：NCT00720512）的mCRC患者，他们接受了二线mFOLFOX-6或FOLFIRI联合（n=66）或不联合（n=66）贝伐珠单抗治疗。在贝伐珠单抗+CHT组中，MDR分析基于VEGF-A rs1570360和VEGFR-2 rs11133360基因型的特定组合识别出两种药物遗传学交互作用谱。携带有利遗传谱的患者中位PFS为8.89个月，而携带不利遗传谱者为5.23个月（p=0.001），多变量Cox风险比（HR）为0.49（95% CI，0.25-0.96；p=0.039）。有利谱与不利谱的中位OS分别为20.69个月对9.28个月（p=0.04），校正后HR为0.54（95% CI，0.3-0.98；p=0.042）。相比之下，在仅接受CHT治疗的患者中，两种遗传谱之间在PFS（5.52个月对4.85个月，p=0.642）或OS（16.31个月对16.34个月，p=0.969）方面均未观察到显著差异。总体而言，VEGF-A rs1570360和VEGFR-2 rs11133360基因型之间的交互作用识别出一种有利的药物遗传学谱，与接受贝伐珠单抗的患者PFS和OS的改善相关，而在仅CHT组中未观察到相关性。这些发现提示，血管生成相关基因的MDR分析可识别出从贝伐珠单抗为基础的治疗中获益的患者，并强化了对mCRC抗血管生成策略候选患者进行药物遗传学筛选的理论依据。
查看英文原文 English abstract
Metastatic colorectal cancer (mCRC) remains a major therapeutic challenge, and although bevacizumab combined with chemotherapy has demonstrated clinical benefit, validated predictive biomarkers of its activity are still missing. Moreover, pharmacogenetic analyses of angiogenesis-related genes in mCRC patients have failed to predict treatment efficacy and survival outcomes. Based on this rationale, we conducted a pharmacogenetic study on a different approach, investigating the potential combined effect of EPAS-1, IL-8, VEGF-A, and VEGFR-2 single nucleotide polymorphisms (SNPs) on progression-free survival (PFS) and overall survival (OS) in mCRC patients treated with second-line mFOLFOX-6 or FOLFIRI (CHT) with or without bevacizumab. Germline DNA was obtained from peripheral blood samples, and SNPs were genotyped by Real-Time PCR. Pharmacogenetic interaction analysis was performed using the Multifactor Dimensionality Reduction (MDR) approach to explore potential statistical interactions between SNPs associated with treatment outcomes. This analysis included mCRC patients enrolled in the randomized phase III BEBYP trial (clinicaltrials.gov: NCT00720512) at the University Hospital of Pisa, who received second-line mFOLFOX-6 or FOLFIRI with (n=66) or without (n=66) bevacizumab. In the bevacizumab+CHT group, the MDR analysis identified two pharmacogenetic interaction profiles based on specific combinations of VEGF-A rs1570360 and VEGFR-2 rs11133360 genotypes. Patients carrying the favorable genetic profile showed a median PFS of 8.89 months compared with 5.23 months for those with the unfavorable profile (p=0.001), with a multivariable Cox hazard ratio (HR) of 0.49 (95% CI, 0.25-0.96; p=0.039). Median OS was 20.69 vs. 9.28 months (p=0.04) for favorable vs. unfavorable profiles, respectively, with an adjusted HR of 0.54 (95% CI, 0.3-0.98; p=0.042). In contrast, among patients treated with CHT alone, no significant differences were observed in PFS (5.52 vs. 4.85 months, p=0.642) or OS (16.31 vs. 16.34 months, p=0.969) between the two genetic profiles. Overall, the interaction between VEGF-A rs1570360 and VEGFR-2 rs11133360 genotypes identified a favorable pharmacogenetic profile associated with improved PFS and OS in patients receiving bevacizumab, whereas no association was observed in the CHT-alone group. These findings suggest that MDR analysis of angiogenesis-related genes identifies patients who benefit from bevacizumab-based therapy and strengthens the rationale for a pharmacogenetic selection of candidate patients for anti-angiogenic strategies in mCRC.
利益披露 Disclosure
A. Bandini, None..
P. Orlandi, None..
M. Scalese, None..
G. Masi, None..
F. Marmorino, None..
G. Bocci, None.