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Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients

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Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients RESEARCH ARTICLE Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients Issam Makhoul1*, Valentina K. Todorova2, Eric R. Siegel3, Stephen W. Erickson3, a1111111111 Ishwori Dhakal3, Vinay R. Raj2, Jeannette Y. Lee3, Mohammed S. Orloff4, Robert J. Griffin5, a1111111111 Ronda S. Henry-Tillman6, Suzanne Klimberg6,7, Laura F. Hutchins1, Susan A. Kadlubar5 a1111111111 a1111111111 1 Division of Hematology/Oncology Division, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 2 Division of Medical Genetics, University of Arkansas for Medical a1111111111 Sciences, Little Rock, Arkansas, United States of America, 3 Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 4 Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 5 Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 6 Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America, 7 Department of Pathology, University of OPEN ACCESS Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America Citation: Makhoul I, Todorova VK, Siegel ER, Erickson SW, Dhakal I, Raj VR, et al. (2017) * [email protected] Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Abstract Bevacizumab in Breast Cancer Patients. PLoS ONE 12(1): e0168550. doi:10.1371/journal. pone.0168550 Background Editor: Ratna B. Ray, Saint Louis University, UNITED STATES We previously reported improved pathologic complete response (pCR) in a prospective Received: August 14, 2016 phase II study using neoadjuvant bevacizumab in combination with chemotherapy com- pared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this Accepted: December 2, 2016 study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis- Published: January 3, 2017 related genes for their impact on pCR and overall survival (OS). Copyright: © 2017 Makhoul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which Methods permits unrestricted use, distribution, and DNA for genotyping was available from 34 subjects who received bevacizumab in addition reproduction in any medium, provided the original to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 author and source are credited. SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related Data Availability Statement: All relevant data are genes, for their effect on pCR via logistic regression with an additive-inheritance model within the paper and its Supporting Information files. while adjusting for race and bevacizumab treatment. SNPs that showed significant associa- tions with pCR were selected for additional characterization. Funding: This work was supported by the UAMS Translational Research Institute (TRI), Award number: UL 1TR000039-05, Grant recipient: Issam Results Makhoul; and the Arkansas Breast Cancer Research Program and University of Arkansas for After adjusting for race and tumor type, patients who had bevacizumab added to their Medical Sciences, Award number: neoadjuvant therapy were found to experience a significantly improved rate of pCR PLOS ONE | DOI:10.1371/journal.pone.0168550 January 3, 2017 1 / 14 SNPs in ANGPT1, ANGPT2, and FGF2 and Response to Bevacizumab 1UL1RR029884, Grant recipient: Valentina compared to patients who did not (adjusted OR 8.40, 95% CI 1.90±37.1). When patients Todorova. The funders had no role in study design, were analyzed for SNP effects via logistic regression with race and bevacizumab treatment data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibro- received salary from the funders. blast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine Competing Interests: The authors have declared kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were that no competing interests exist. associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Conclusion Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizu- mab 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. Trial Registration ClinicalTrials.gov NCT00203502 Introduction Bevacizumab, a humanized monoclonal antibody that was designed to target vascular endo- thelial growth factor A (VEGF-A), was first approved for breast cancer in the metastatic setting in 2008 based on the results of the E2100 Intergroup phase III trial comparing paclitaxel with or without the addition of bevacizumab as first-line therapy. [1] The approval was contingent on the results of further studies, which ultimately did not demonstrate significant improve- ments in overall survival. Thus, FDA approval of bevacizumab for breast cancer was officially withdrawn in 2010 [2], although additional studies of bevacizumab in the adjuvant setting were ongoing. [3] In the neoadjuvant setting, the addition of bevacizumab to chemotherapy results in increased pathologic complete response [(pCR); reviewed in [4]]. While these results are promising, it is apparent that clinical response to bevacizumab is highly variable. For this reason, biomarkers are urgently needed to identify patients most likely to benefit. Pharmacogenomics studies have reported associations between single nucleotide polymor- phisms (SNPs) in VEGF and VEGFR-2 and response in metastatic breast cancer [5±7], but studies of the impact of SNPs on pCR in the neoadjuvant setting have just started being per- formed. A recent analysis of the randomized phase III GeparQuinto study examined genetic variants within the VEGF pathway genes in relation to response to neoadjuvant bevacizumab. [8] In that study, a total of 15 genes were examined, but the only two common genes investi- gated in both that study and the current report were KDR and VEGFA. However, a compre- hensive examination of germline SNPs in other genes involved in angiogenesis is lacking. We have previously conducted and reported on a Phase II neoadjuvant trial examining the combination of chemotherapy with bevacizumab. [9] In that trial, we found significant differ- ences in pCR according to tumor types (52% for ductal carcinoma compared to only 10% in non-ductal disease, p = 0.021), receptor status (59% in estrogen/progesterone receptor nega- tive compared to only 27% in patients positive for at least one receptor, p = 0.047) and race (pCR in African Americans (AA) 75% compared to 28% in European Americans (EA), PLOS ONE | DOI:10.1371/journal.pone.0168550 January 3, 2017 2 / 14 SNPs in ANGPT1, ANGPT2, and FGF2 and Response to Bevacizumab p = 0.007). Subsequent investigations in this patient population revealed that elevated serum levels of tyrosine kinase with immunoglobulin and epidermal growth factor-homology domains 2 (Tie-2) and basic fibroblast growth factor (bFGF) at baseline were seen in subjects who attained pCR. [10] In the current study, we combined two cohorts in order to assess the effects of the SNPs in the angiogenic pathway while adjusting for the effect of bevacizumab. Materials and Methods Study populations Cancer patients±Data from two independent clinical studies were combined for the analyses in this report. One was a Phase II neoadjuvant clinical trial of bevacizumab added to chemother- apy, for which the study design, sample collection, and protein analysis have been described elsewhere. [9,10] The other was a prospective observational study investigating doxorubicin tox- icity in breast-cancer patients who followed the same neoadjuvant chemotherapy regimen as the Phase II trial, but without the addition of bevacizumab; these patients were enrolled between 12/16/2010 and 9/1/2013. [11] Both studies were conducted at the University of Arkansas for Medical Sciences, and both had IRB approval. Serial blood samples were collected at baseline and at each visit from patients in both studies. From the Phase II trial, we excluded one Asian and one Hispanic to leave 37 patients who were either AA or EA. All 38 subjects from the obser- vational study were AA or EA. Healthy, cancer-free subjects±Healthy subjects were those recruited as controls in case-con- trol studies of breast, colorectal and prostate cancer conducted at UAMS from 1997±2007. These studies were approved by the IRB at UAMS. All participants have signed a written con- sent form that was approved by the IRB of UAMS. Germline DNA was isolated from buffy coat samples provided by the healthy individuals. Genotyping assays High-density genotyping±To test for the association between SNPs in candidate genes and pCR, DNA was extracted from buffy coats of 63 study participants (34 receiving bevacizumab/
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