title: Phosphorylated VEGFR2 and hypertension: potential biomarkers to indicate VEGF-dependency of advanced breast cancer in anti-angiogenic therapy.
abstract: The efficacy of anti-VEGF agents probably lies on VEGF-dependency. Apatinib, a specific tyrosine kinase inhibitor that targets VEGF receptor 2, was assessed in patients with advanced breast cancer (ABC) (ClinicalTrials.gov NCT01176669 and NCT01653561). This substudy was to explore the potential biomarkers for VEGF-dependency in apatinib-treated breast cancer. Eighty pretreated patients received apatinib 750 or 500 mg/day orally in 4-week cycles. Circulating biomarkers were measured using a multiplex assay, and tissue biomarkers were identified with immunostaining. Baseline characteristics and adverse events (AEs) were included in the analysis. Statistical confirmation of independent predictive factors for anti-tumor efficacy was performed using Cox and Logistic regression models. Median progression-free survival (PFS) was 3.8 months, and overall survival (OS) was 10.6 months, with 17.5 % of objective response rate. Prominent AEs (≥60 %) were hypertension, hand-foot skin reaction (HFSR), and proteinuria. Higher tumor phosphorylated VEGFR2 (p-VEGFR2) expressions (P = 0.001), higher baseline serum soluble VEGFR2 (P = 0.031), hypertension (P = 0.011), and HFSR (P = 0.018) were significantly related to longer PFS, whereas hypertension (P = 0.002) and HFSR (P = 0.001) were also related to OS. Based on multivariate analysis, only p-VEGFR2 (adjusted HR, 0.40; P = 0.013) and hypertension (adjusted HR, 0.58; P = 0.038) were independent predictive factors for both PFS and clinical benefit rate. Apatinib had substantial antitumor activity in ABC and manageable toxicity. p-VEGFR2 and hypertension may be surrogate predictors of VEGF-dependency of breast cancer, which may identify an anti-angiogenesis sensitive population.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Minhao
authors.initials: M
authors.lastname: Fan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Wang
authors.forename: Biyun
authors.initials: B
authors.lastname: Wang
authors.forename: Qunlin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zheng
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Ni
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.forename: Xichun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010766:Phosphorylation; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use; D012307:Risk Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C553458:apatinib; D040301:Vascular Endothelial Growth Factor Receptor-2