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Phosphorylated VEGFR2 and hypertension: potential biomarkers to indicate VEGF-dependency of advanced breast cancer in anti-angiogenic therapy

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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.

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Abbreviations

PFS:

Progression-free survival

OS:

Overall survival

ORR:

Objective response rate

DCR:

Disease control rate

CBR:

Clinical benefit rate

AEs:

Adverse events

HFSR:

Hand–foot skin reaction

VEGFR2:

Vascular endothelia growth factor receptor 2

p-VEGFR2:

Phosphorylated VEGFR2

TKI:

Tyrosine kinase inhibitors

ABC:

Advanced breast cancer

RECIST:

Response evaluation criteria for solid tumors

CTCAE:

Common terminology criteria for AEs

ECOG:

Eastern Cooperative Oncology Group

TNBC:

Triple-negative breast cancer

IHC:

Immunohistochemistry

IOD:

Integrated optical density

AOD:

Average optical density

ROC:

Receiver operator characteristic

ER:

Estrogen receptor

PR:

Progesterone receptor

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Acknowledgments

The authors thank the patients, investigators, and participating institutions. We thank the pathologist Hongyu Gu for tissue biomarker analysis advice; Xiaofeng Xu for enzyme-linked immunosorbent assay; Menghong Sun, Ph.D. and Xueke Zhou for sample preservation; Zhiyu Chen, M.D. and Ka Jia for statistical advice; Zhe Zhang, M.D., for quantitative software operation; and Xiaoyu Chen, Chunmei Liao for operational support. We also thank the sponsor, Jiangsu Hengrui Medicine Co., Ltd., for providing apatinib free of charge. The financial support was provided by Science and Technology Commission of Shanghai Municipality (grant number: 114119b1800).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

This study was performed in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki (1996 version), and applicable local regulatory requirements and laws. The study was approved by Fudan University Shanghai Cancer Center Ethic Committee for Clinical Investigation.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

    Minhao Fan, Jian Zhang, Zhonghua Wang, Biyun Wang, Qunlin Zhang, Chunlei Zheng, Ting Li, Chen Ni, Zhenhua Wu & Xichun Hu

  2. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Zhimin Shao

  3. Department of Oncology, Shanghai Medical College, Fudan University, No. 270, Dong’an road, Shanghai, 200032, China

    Zhimin Shao & Xichun Hu

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  1. Minhao Fan
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  2. Jian Zhang
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Correspondence to Xichun Hu.

Additional information

Minhao Fan and Jian Zhang contributed equally to this manuscript.

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Supplementary material 1 (DOC 66 kb)

10549_2013_2793_MOESM2_ESM.eps

Supplementary Fig. 1 Kaplan–Meier curves for PFS: baseline serum sVEGFR2 (a), p-VEGFR2 (b), menstruation status (c), lines of prior chemotherapy (d), hypertension (e), and HFSR (f) (EPS 402 kb)

10549_2013_2793_MOESM3_ESM.eps

Supplementary Fig. 2 Kaplan–Meier curves for OS: p-VEGFR2 (a), number of metastatic sites (b), hypertension (c), and HFSR (d) (EPS 382 kb)

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Fan, M., Zhang, J., Wang, Z. et al. Phosphorylated VEGFR2 and hypertension: potential biomarkers to indicate VEGF-dependency of advanced breast cancer in anti-angiogenic therapy. Breast Cancer Res Treat 143, 141–151 (2014). https://doi.org/10.1007/s10549-013-2793-6

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