Originally published as JCO Early Release 10.1200/JCO.2007.13.7083 on December 8 2008

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Phosphorylated ER, HIF-1, and MAPK Signaling As Predictors of Primary Endocrine Treatment Response and Resistance in Patients With Breast Cancer

Daniele Generali, Francesca M. Buffa, Alfredo Berruti, Maria P. Brizzi, Leticia Campo, Simone Bonardi, Alessandra Bersiga, Giovanni Allevi, Manuela Milani, Sergio Aguggini, Mauro Papotti, Luigi Dogliotti, Alberto Bottini, Adrian L. Harris, Stephen B. Fox

From the Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine; Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Unità di Patologia Mammaria –Breast Cancer Unit and Anatomia Patologica, Azienda Instituti Ospitalieri di Cremona, Cremona; Anatomia Patologica; Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino Azienda Ospedaliera San Luigi di Orbassano, Orbassano, Italy; Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria; and the Department of Pathology, University of Melbourne, Melbourne, Australia

Corresponding author: Stephen B. Fox, MD, Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, 3002, Australia; e-mail: stephen.fox{at}petermac.org

Purpose We aimed to identify signaling pathways involved in the response and resistance to aromatase inhibitor therapy in patients with breast cancer.

Patients and Methods One hundred fourteen women with T2-4 N0-1, estrogen receptor (ER) –positive tumors were randomly assigned to neoadjuvant letrozole or letrozole plus metronomic cyclophosphamide. Twenty-four tumor proteins involved in apoptosis, cell survival, hypoxia, angiogenesis, growth factor, and hormone signaling were assessed by immunohistochemistry in pretreatment samples (eg, caspase 3, phospho- mammalian target of rapamycin, hypoxia-inducible factor 1 [HIF-1], vascular endothelial growth factor, mitogen-activated protein kinase [MAPK], phosphorylated epidermal growth factor receptor, phosphorylated ER [pER]). A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization. Ten-fold cross-validation and iterative leave-one-out were employed to validate and test the model, respectively. Tumor size, nodal status, age, tumor grade, histological type, and treatment were included in the analysis.

Results Ninety-one patients (81%) attained a disease response, 48 achieved a complete clinical response (43%) whereas 22 did not respond (19%). Increased pER and decreased p44/42 MAPK were significant factors for complete response to treatment in all leave-one-out iterations. Increased p44/42 MAPK and HIF-1 were significant factors for treatment resistance in all leave-one-out iterations. There was no significant interaction between these variables and treatment.

Conclusion Activated ER form was an independent factor for sensitivity to chemoendocrine treatment, whereas HIF-1 and p44/42 MAPK were independent factors for resistance. Although further confirmatory analyses are needed, these findings have clear potential implications for future strategies in the management of clinical trials with aromatase inhibitors in the breast cancer.

published online ahead of print at www.jco.org on December 8, 2008

Supported in part by the Associazione Patologia Oncologica Mammaria, Cremona, Italy, Cancer Research UK, and the European Union via the Euroxy Grant.

D.G. and F.M.B. contributed equally to this study.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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