Makhoul Issam, Todorova Valentina K, Siegel Eric R, Erickson Stephen W, Dhakal Ishwori, Raj Vinay R, Lee Jeannette Y, Orloff Mohammed S, Griffin Robert J, Henry-Tillman Ronda S, Klimberg Suzanne, Hutchins Laura F, Kadlubar Susan A
Division of Hematology/Oncology Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
PLoS One. 2017 Jan 3;12(1):e0168550. doi: 10.1371/journal.pone.0168550. eCollection 2017.
We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS).
DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization.
After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes.
Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population.
ClinicalTrials.gov NCT00203502.
我们之前在一项前瞻性II期研究中报告，与单纯化疗相比，在乳腺癌患者中使用新辅助贝伐单抗联合化疗可提高病理完全缓解率（pCR）（41%对25%，p = 0.0291）。在本研究中，我们探究了血管生成相关基因中的种系单核苷酸多态性（SNP）对pCR和总生存期（OS）的影响。
可获得34名接受化疗加贝伐单抗治疗的受试者以及29名未接受贝伐单抗治疗的受试者的基因分型DNA。使用Illumina®技术，我们探究了位于10个血管生成相关基因中、次要等位基因频率（MAF）至少为5%的504个SNP，通过加性遗传模型的逻辑回归分析其对pCR的影响，同时对种族和贝伐单抗治疗进行校正。选择与pCR有显著关联的SNP进行进一步特征分析。
校正种族和肿瘤类型后，发现新辅助治疗中添加贝伐单抗的患者与未添加贝伐单抗的患者相比，pCR率显著提高（校正比值比8.40，95%可信区间1.90 - 37.1）。当将种族和贝伐单抗治疗作为协变量纳入逻辑回归分析患者的SNP效应时，血管生成素1（ANGPT1）中的两个SNP、血管生成素2（ANGPT2）中的六个SNP、成纤维细胞生长因子2（FGF2）中的三个SNP、基质金属蛋白酶9（MMP9）中的四个SNP、酪氨酸激酶内皮（TEK）中的三个SNP以及血管内皮生长因子A（VEGFA）中的两个SNP与pCR相关（P<0.05）。然而，在考虑总生存期时，治疗组之间或基因型之间没有差异。
TEK（酪氨酸激酶内皮）、ANGPT1（血管生成素1）、ANGPT2（血管生成素2）、FGF2（成纤维细胞生长因子2）、MMP9（基质金属蛋白酶9）和VEGFA（血管内皮生长因子A）的基因变异性与接受贝伐单抗治疗患者的pCR相关。与其他研究一致，在标准化疗中添加贝伐单抗并未影响总生存期，可能是由于其他因素，因此，虽然TEK、ANGPT1、ANGPT2、FGF2、MMP9和VEGFA中的SNP与pCR相关，但它们并不能预测该患者群体的总生存期。
ClinicalTrials.gov NCT00203502
