Background: Signaling via the Insulin-like Growth Factor type 1 Receptor (IGF1R) plays a crucial role in cancer development. In breast cancer (BC), IGF1R and estrogen receptor expression are correlated. In this current study we explored the hypothesis that postmenopausal hormone receptor positive (HR+ve) BC patients with high IGF1R tumor expression still have estrogen driven IGF1R stimulated tumor growth when treated with tamoxifen, resulting in detrimental clinical outcome compared to patients treated with exemestane. Additionally, we assessed the added value of metformin as this drug may lower IGF1R stimulation. Methods: Of 2,446 Dutch TEAM patients, randomized to either exemestane for 5 years or sequential treatment (tamoxifen for 2-3 years followed by exemestane for another 3-2 years) tumor tissue microarray sections were immunohistochemically stained for IGF1R. Overall Survival (OS), Breast Cancer specific Survival (BCSS) and Relapse-Free Survival (RFS) were assessed in patient subgroups with low and high IGF1R expression, and in patients with or without metformin use. Results: High IGF1R tumor expression was significantly associated with exemestane therapy for RFS (Hazard Ratio (HR) 0.74, 95% Confidence Interval (CI) 0.58-0.95, p = 0.02). In addition, the combination of metformin with exemestane resulted in improved efficacy, yielding a 5-yrs RFS of 95% (HR 0.32, 95% CI 0.10-1.00, p = 0.02, compared to sequential treatment). No relation was observed in tumors with low IGF-1R expression. Conclusion: This study suggests IGF1R as a potential biomarker of improved clinical outcome in HR+ve BC patients treated with exemestane. Adding metformin to exemestane treatment may add to this effect.

Breast cancer, Clinical outcome, Endocrine treatment, Hormone receptor, IGF1 receptor, Metformin
dx.doi.org/10.1016/j.molonc.2015.10.010, hdl.handle.net/1765/90779
Molecular Oncology
Department of Medical Oncology

Engels, C.C, de Glas, N.A, Sajet, A, Bastiaannet, E, Smit, V.T.H.B.M, Kuppen, P.J.K, … Liefers, G.-J. (2016). The influence of insulin-like Growth Factor-1-Receptor expression and endocrine treatment on clinical outcome of postmenopausal hormone receptor positive breast cancer patients: A Dutch TEAM substudy analysis. Molecular Oncology, 10(4), 509–516. doi:10.1016/j.molonc.2015.10.010