Research Papers:

Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer

Manuela Milani, Sergio Venturini, Simone Bonardi, Giovanni Allevi, Carla Strina, Maria Rosa Cappelletti, Silvia Paola Corona, Sergio Aguggini, Alberto Bottini, Alfredo Berruti, Adrian Jubb, Leticia Campo, Adrian L. Harris, Kevin Gatter, Stephen B. Fox, Daniele Generali _ and Giandomenico Roviello

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Oncotarget. 2017; 8:78870-78881. https://doi.org/10.18632/oncotarget.20239

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Manuela Milani1,*, Sergio Venturini2,*, Simone Bonardi1, Giovanni Allevi1, Carla Strina1, Maria Rosa Cappelletti1, Silvia Paola Corona3, Sergio Aguggini1, Alberto Bottini1, Alfredo Berruti4, Adrian Jubb5, Leticia Campo5, Adrian L. Harris5, Kevin Gatter5, Stephen B. Fox6, Daniele Generali1,7 and Giandomenico Roviello7,8

1U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, ASST Cremona, Viale Concordia 1, Cremona, Italy

2CE.R.G.A.S., Università Bocconi, Milano, Italy

3Peter MacCallum Cancer Centre, Bentleigh East VIC, Australia

4U.O. Oncologia Medica, Spedali Civili si Brescia, University of Brescia, Brescia, Italy

5Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK

6Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia

7Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, Trieste, Italy

8Department of Oncology, Medical Oncology Unit, San Donato Hospital, Italy

*Manuela Milani and Sergio Venturini contributed equally to the study

Correspondence to:

Daniele Generali, email: [email protected]

Keywords: epirubicin resistance, haemoglobin, hypoxia-inducible factor, neoadjuvant, breast cancer

Received: September 21, 2015     Accepted: July 18, 2017     Published: August 14, 2017


Purpose: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer.

Patients and Methods: One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization.

Results: VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival.

Conclusion: Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline-based treatment outcome.

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