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Non-invasive quantification of tumor vascular architecture during docetaxel-chemotherapy

  • Preclinical Study
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Abstract

New ultrasound parameters, potentially predictive of tumor response to chemotherapy, were sought after analyzing details of vascular architecture of mammary tumors during chemotherapy. Tumor-bearing rats were separated into untreated or docetaxel-treated group (6 mg/kg/week). Power Doppler Index and vascular contrast-enhanced ultrasound (CEUS) reference endpoints (Peak, area under the curve (AUC), blood flow) were evaluated at the beginning (W 0), and after 2 and 6 weeks of docetaxel treatment (W +2 and W +6). An improved CEUS image analysis, taking advantage of individual pixel intensity, was developed to quantify large, medium, and small vessels of tumors. Standard immunohistochemistry validated this new methodology analyzing tumor vascular architecture. In rats, there was an enrichment of vascularization with large vessels during tumor growth indicative of a vascular adjustment to tumor size. Docetaxel stopped tumor growth, and showed a sequential effect on vascular parameters. After an initial enrichment in larger vessels (by threefold) at W +2, docetaxel led to a diminution of vascular parameters at W +6 (−46 % for peak, −55 % for AUC −31 % compared to W 0) and a vascular remodeling in favor of small vessels. One of the CEUS parameters measured before chemotherapy, the so-called global contrast-enhanced pixels density, was predictive of rat tumor response to treatment (r = 0.80; p < 0.01). The method was then applied in a clinical setting to detect changes of vascular architecture during chemotherapy of human breast carcinoma. The docetaxel chemotherapy of breast carcinomas induced a similar sequential effect, with vessel enlargement after two cycles of docetaxel treatment and an antiangiogenic effect after six cycles. Such vascular remodeling was not noticed when patients were treated with 5-fluorouracil–epirubicin–cyclophosphamide. Taken together, the sharpened analysis of CEUS pixel intensity presented here strengthened the monitoring of breast tumor vasculature with the potential to improve the prediction of docetaxel efficacy.

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Abbreviations

AUC:

Area under the curve

CEUS:

Contrast-enhanced ultrasound

CEUS-I:

Contrast-enhanced ultrasound index

GPD:

Global contrast-enhanced pixel density

HighPD:

High intensity-pixel density

MedPD:

Medium intensity-pixel density

LowPD:

Low intensity-pixel density

NMU:

N-methyl-N-nitroso-urea

PDI:

Power Doppler Index

ROI:

Region of interest

FEC:

Chemotherapeutic combination with 5-Fluorouracil, Epirubicin and Cyclosphosphamide

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Acknowledgments and Financial Support

We thank Dr Jean-François Tournamille and his team for the gift of docetaxel and their help to prepare docetaxel syringes at the Hospital “Bretonneau,” CHRU Tours. We thank Thierry Hardy for designing script under Matlab and Laura Brullé for vascular casting scan acquisition. We also thank Jérôme Montharu, Georges Roseau and Valérie Schubnel, for helping with animal care. This work was funded by “Ligue Nationale contre le Cancer” (Comités d’Indre et Loire, Loir et Cher, Indre), by “Cancéropôle Grand Ouest,” by “Institut National de la Santé et de la Recherche Médicale” (Inserm), by «Fonds Européens de Développement Régional» (FEDER), and by the “Association pour la Recherche sur le Cancer.” Sophie Vibet was the recipient of a fellowship from the “Ministère de l’Enseignement Supérieur et de la Recherche” and from the “Ligue Nationale contre le Cancer” (Comité de Charente). Caroline Goupille was supported by the University Hospital “Bretonneau,” Tours, and Sophie Serrière by a grant from INCA (Institut National du cancer, Cancéropôle Grand Ouest).

Conflicts of Interest

Authors have no financial relationship with the organization that sponsored the research. Although Dr. F. Tranquart is currently employed by Bracco (Switzerland), he was a full time employee of the Inserm/CHRU Bretonneau (Tours) in the course of the work reported in this article. The authors declare that they have no conflict of interest.

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Author notes

  1. François Tranquart

    Present address: Bracco, Plan-Les-Ouates, Geneva, Switzerland

Authors and Affiliations

  1. INSERM U1069, Nutrition Croissance et Cancer, Faculté de Médecine, Université François Rabelais, 10 Bd Tonnellé, 37032, Tours Cedex, France

    Karine Mahéo, Stephan Chevalier, Sophie Vibet, Philippe Bougnoux & Caroline Goupille

  2. UMR INSERM 930-CNRS 3106, Université François-Rabelais, Tours Cedex, France

    Sophie Serrière & François Tranquart

  3. Hôpital “Bretonneau”, CHRU, Tours Cedex, France

    Philippe Bougnoux, Aurore Bleuzen & Caroline Goupille

  4. CERB, Baugy, France

    Serge Richard

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Correspondence to Caroline Goupille.

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Mahéo, K., Chevalier, S., Vibet, S. et al. Non-invasive quantification of tumor vascular architecture during docetaxel-chemotherapy. Breast Cancer Res Treat 134, 1013–1025 (2012). https://doi.org/10.1007/s10549-012-2015-7

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  • DOI: https://doi.org/10.1007/s10549-012-2015-7

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