VEGF Gene Amplification/Haplotype as Biomarkers for Bevacizumab in Breast Cancer

描述（由申请人提供）：在关键性III期试验E2100中，与单独化疗相比，在标准化疗中添加贝伐珠单抗延长了既往未经治疗的转移性乳腺癌女性的中位无进展生存期（PFS）。这些发现导致FDA加速批准贝伐单抗联合紫杉醇作为转移性疾病的初始化疗。然而，E2100的上级PFS并未转化为总生存期（OS）的改善，许多患者发生了显著的药物相关毒性。不幸的是，没有经过验证的生物标志物来帮助选择哪些患者将经历最佳的获益与毒性比。我们最近发现，血管内皮生长因子-A（VEGFA）基因（贝伐单抗的靶基因）扩增和缺失在原发性乳腺癌中相对常见。我们之前还发现了VEGFA中的两个单核苷酸多态性（SNP），这两个SNP强烈预测了中位OS的改善，另外两个SNP预测了E2100中接受贝伐单抗治疗转移性乳腺癌时对显著高血压的保护。自该发现以来，其他非VEGFA SNP与其他实施贝伐单抗的随机III期试验的结果相关。具体目标1：肿瘤VEGFA扩增或边界扩增（估计频率为14%）将预测E2100中接受贝伐珠单抗治疗的转移性乳腺癌患者的上级结局，而VEGFA缺失（估计频率为11%）将预测较差结局。我们还假设VEGFA扩增/缺失不能预测E2100对照组的结果。具体目标#2：证明VEGFA单倍型和其他候选SNP将预测E2100中接受贝伐珠单抗治疗的转移性乳腺癌患者的上级结局（但不适用于对照组）。具体目标#3：根据肿瘤特异性变异性（VEGFA扩增/缺失）和宿主特异性变异性（SNP）计算的组合算法将最佳预测贝伐珠单抗在E2100中的结局（疗效）。影响：贝伐单抗是一种治疗乳腺癌的高活性药物，但并非所有患者都能获益，而且有一些严重的毒性，包括：中风和高血压。不幸的是，没有经过验证的生物标志物来指导哪些患者应该接受这种药物。此外，贝伐单抗的非选择性实施对美国医疗保健系统具有显著的负面财务影响。这项提议有可能揭示一个预测性的签名，将选择一个亚组谁应该接受贝伐单抗。

DESCRIPTION (provided by applicant):The addition of bevacizumab to standard chemotherapy prolonged the median progression free survival (PFS) over chemotherapy alone for women with previously untreated metastatic breast cancer in the pivotal phase III trial, E2100. These findings led to the FDA accelerated approval for bevacizumab in combination with paclitaxel as initial chemotherapy for metastatic disease. The superior PFS in E2100, however, did not translate into an improvement in overall survival (OS) and many patients experienced significant drug-related toxicities. Unfortunately there are no validated biomarkers to help select which patients will experience the optimal benefit to toxicity ratio. We recently demonstrated that vascular endothelial growth factor-A (VEGFA) gene (the target for bevacizumab) amplification and deletion is relatively common in primary breast cancers. We also previously identified two single nucleotide polymorphisms (SNPs) in VEGFA which predicted strongly for an improved median OS and two additional SNPs which predicted protection from significant hypertension when receiving bevacizumab for metastatic breast cancer in E2100. Since that finding, other non-VEGFA SNPs have been correlated with outcome in other randomized phase III trials implementing bevacizumab. Specific Aim #1: Tumor VEGFA amplification or borderline amplification (estimated 14% frequency) will predict superior outcome for patients with metastatic breast cancer receiving bevacizumab in E2100 whereas those with VEGFA deletion (estimated 11% frequency) will predict inferior outcome. We also hypothesize that VEGFA amplification/deletion will not predict outcome in the control arm of E2100. Specific Aim #2: To demonstrate that VEGFA haplotypes and other candidate SNPs will predict superior outcome for patients with metastatic breast cancer receiving bevacizumab in E2100 (but not for the control arm). Specific Aim #3: A combined algorithm calculated from tumor-specific variability (VEGFA amplification/deletion) and host-specific variability (SNPs) will optimally predict outcome (efficacy) with bevacizumab in E2100. Impact: Bevacizumab is a highly active agent in breast cancer but not all patients benefit and there are some substantial toxicities including: stroke and hypertension. Unfortunately there are no validated biomarkers that direct which patients should receive this agent. Additionally, non-selective implementation of bevacizumab has significant negative financial implications on the United States health care system. This proposal has the potential to unveil a predictive signature which will select a subgroup who should receive bevacizumab.