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Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis

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Abstract

The effects of breast cancer conventional chemotherapy on tumor angiogenesis need to be further characterized. Neoadjuvant chemotherapy is an ideal model to evaluate the results of chemotherapy, allowing intra-patient direct comparison of antitumor and antiangiogenic effects. We sought to analyze the effect of neoadjuvant chemotherapy on tumor angiogenesis and its clinical significance in breast cancer. Breast cancer patients (n = 108) treated with neoadjuvant sequential anthracyclines and taxanes were studied. Pre- and post-chemotherapy microvessel density (MVD) and mean vessel size (MVS) were analyzed after CD34 immunohistochemistry and correlated with tumor expression of pro- and antiangiogenic factors (VEGFA, THBS1, HIF1A, CTGF, and PDGFA) by qRT-PCR. Angiogenic measures at diagnosis varied among breast cancer subtypes. Pre-treatment higher MVS was associated with triple-negative subtype and more advanced disease. Higher MVS was correlated with higher VEGFA (p = 0.003), while higher MVD was correlated with lower antiangiogenic factors expression (THBS1, p < 0.0001; CTGF, p = 0.001). Increased angiogenesis at diagnosis (high MVS and glomeruloid microvascular proliferation) and higher VEGFA expression were associated with tumor recurrence (p = 0.048 and 0.009, respectively). Chemotherapy-induced angiogenic response (defined as decreased MVD) was present in 35.2 % of patients. This response correlated with an increase in antiangiogenic factors (THBS1) without changes in VEGFA expression, and it was associated with tumor downstaging, but not with clinical response, pathologic complete response, or prognosis. Global effects of chemotherapy mainly consisted in an increased expression of antiangiogenic factors (THBS1, CTGF), with significant changes neither of tumor VEGFA nor of MVS. Conventionally scheduled neoadjuvant chemotherapy exerts antiangiogenic effects, through an increase in antiangiogenic factors, THBS1 and CTGF, but the expression of VEGFA is maintained after treatment. Better markers of angiogenic response and a better understanding of the cooperation of chemotherapy and antiangiogenic therapy in the neoadjuvant clinical scenario are needed.

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Abbreviations

CT:

Chemotherapy

MVD:

Microvessel density

MVS:

Mean vessel size

AR:

Angiogenic response

pCR:

Pathologic complete response

HR:

Hormone receptor

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Acknowledgments

We acknowledge technical assistance provided by Rosario Martínez-Marín, Miriam Lencina Guardiola (BiobancMur, Nodo 1, IMIB-Arrixaca), Dr. Fara Sáez-Belmonte (SAI-University of Murcia), Lorena Velázquez-Olmos (CRH), and José Antonio López Oliva (HMM).

Conflict of interest

The authors declare that they do not have a financial relationship with the organization that sponsored the research. The authors declare that they have no conflict of interest.

Funding

This work was funded by Fundación Salud 2000 (Ayuda Merck Serono de Investigación en Oncología 2012) and by Instituto de Salud Carlos III (PI/1202877).

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Authors and Affiliations

  1. Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Avda. Marqués de los Vélez, s/n, 30008, Murcia, Spain

    Ginés Luengo-Gil, Enrique González-Billalabeitia, Elena García Martínez, Elisa García Garre, Vicente Vicente & Francisco Ayala de la Peña

  2. Department of Pathology, University Hospital Morales Meseguer, Murcia, Spain

    Asunción Chaves-Benito

  3. Centro Regional de Hemodonación, Murcia, Spain

    Ginés Luengo-Gil, Vicente Vicente & Francisco Ayala de la Peña

  4. University of Murcia, Murcia, Spain

    Ginés Luengo-Gil, Vicente Vicente & Francisco Ayala de la Peña

  5. IMIB-Arrixaca, Murcia, Spain

    Ginés Luengo-Gil, Enrique González-Billalabeitia, Vicente Vicente & Francisco Ayala de la Peña

Authors
  1. Ginés Luengo-Gil
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  2. Enrique González-Billalabeitia
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  3. Asunción Chaves-Benito
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  6. Vicente Vicente
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Corresponding author

Correspondence to Francisco Ayala de la Peña.

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Luengo-Gil, G., González-Billalabeitia, E., Chaves-Benito, A. et al. Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis. Breast Cancer Res Treat 151, 577–587 (2015). https://doi.org/10.1007/s10549-015-3421-4

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  • DOI: https://doi.org/10.1007/s10549-015-3421-4

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