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

2017; Impact Journals LLC; Volume: 8; Issue: 45 Linguagem: Inglês

10.18632/oncotarget.20239

1949-2553

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

Cancer Genomics and Diagnostics

// Manuela Milani 1, * , Sergio Venturini 2, * , Simone Bonardi 1 , Giovanni Allevi 1 , Carla Strina 1 , Maria Rosa Cappelletti 1 , Silvia Paola Corona 3 , Sergio Aguggini 1 , Alberto Bottini 1 , Alfredo Berruti 4 , Adrian Jubb 5 , Leticia Campo 5 , Adrian L. Harris 5 , Kevin Gatter 5 , Stephen B. Fox 6 , Daniele Generali 1, 7 and Giandomenico Roviello 7, 8 1 U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, ASST Cremona, Viale Concordia 1, Cremona, Italy 2 CE.R.G.A.S., Università Bocconi, Milano, Italy 3 Peter MacCallum Cancer Centre, Bentleigh East VIC, Australia 4 U.O. Oncologia Medica, Spedali Civili si Brescia, University of Brescia, Brescia, Italy 5 Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK 6 Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia 7 Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, Trieste, Italy 8 Department of Oncology, Medical Oncology Unit, San Donato Hospital, Italy * Manuela Milani and Sergio Venturini contributed equally to the study Correspondence to: Daniele Generali, email: daniele.generali@gmail.com Keywords: epirubicin resistance, haemoglobin, hypoxia-inducible factor, neoadjuvant, breast cancer Received: September 21, 2015 Accepted: July 18, 2017 Published: August 14, 2017 ABSTRACT 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.