title: Endothelin-1 genetic polymorphism as predictive marker for bevacizumab in metastatic breast cancer.
abstract: Biomarkers for bevacizumab efficacy in metastatic breast cancer (MBC) are of urgent need. The genetic variability of genes involved in angiogenesis could explain the interpatient variability of drug effects. For this biomarker study DNA was extracted from tumor blocks or blood samples of patients with human epidermal growth factor receptor 2 (HER2)-negative MBC treated with bevacizumab in combination with chemotherapy (bevacizumab cohort, 163 patients) or chemotherapy only (control cohort, 105 patients). We assessed the correlation of 10 single-nucleotide polymorphisms (SNPs) in genes modulating angiogenesis (vascular endothelial growth factor-A (VEGF-A), VEGF receptor 1 (VEGFR-1), serine threonine kinase 39 (STK39)) or hypertension (endothelin-1 and uromodulin) with outcome and toxicity. In the bevacizumab cohort, the SNP rs5370-TT in endothelin-1 (EDN1) showed a significantly shorter median overall survival (OS, 6.3 vs 21.3 months; hazard ratio (HR) 2.89, 95% confidence interval (CI) 1.34-6.26; log-rank P=0.0069) and a trend toward worse median progression-free survival (3.5 vs 7.9 months; HR 2.05, 95% CI 0.96-4.39; log-rank P=0.065) compared with the alternate genotypes combined. Similarly, patients harboring the VEGF-936 (rs3025039) TT alleles showed a significantly shorter median OS than patients with VEGF-936 CC or CT (14.9 vs 21.3 months; HR 2.37, 95% CI 1.09-5.13; P=0.0286). In multivariate analysis including important clinical parameters like disease-free survival (DFS), adjuvant chemotherapy, ECOG (Eastern Cooperative Oncology Group) performance score, histologic subtype, grade, hormone receptor status, visceral metastases and treatment line, only the association of rs5370 (EDN1) with OS was still statistically significant (P=0.012). In the control cohort, no association of the EDN1 genotype with outcome was seen, suggesting a predictive value for bevacizumab. In conclusion, the SNP rs5370 in endothelin-1 could help identifying patients who unlikely gain any benefit from bevacizumab.
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: S P
authors.initials: SP
authors.lastname: Gampenrieder
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Hufnagl
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Brechelmacher
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Huemer
authors.affiliation: Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: H
authors.identifier: 0000-0003-4055-3841
authors.initials: H
authors.lastname: Hackl
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Rinnerthaler
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Romeder
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Monzo Fuentes
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Morre
authors.affiliation: Department of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Hauser-Kronberger
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Mlineritsch
authors.affiliation: IIIrd Medical Department with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Greil
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D019332:Endothelin-1 / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D019332:Endothelin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1