Combined and individual tumor-specific expression of insulin-like growth factor-I receptor, insulin receptor and phospho-insulin-like growth factor-I receptor/insulin receptor in primary breast cancer: Implications for prognosis in different treatment groups

Clinical trials examining insulin-like growth factor-I receptor (IGF1R)-targeting strategies have emphasized that better predictive biomarkers are required to improve patient selection. Immunohistochemical tumor-specific protein expression of IGF1R, insulin receptor (InsR), and phosphorylated IGF1R/InsR (pIGF1R/InsR) individually and combined in relation to breast cancer prognosis was evaluated in a population-based cohort of 1,026 primary invasive breast cancer patients without preoperative treatment diagnosed in Sweden. IGF1R (n = 923), InsR (n = 900), and pIGF1R/InsR (n = 904) combined cytoplasmic and membrane staining was dichotomized. IGF1R(strong)/InsR(mod/strong)/pIGF1R/InsR(pos) tumors were borderline associated with 2-fold risk for events, HR(adj) (2.00; 95%CI 0.96-4.18). Combined IGF1R and pIGF1R/InsR status only impacted prognosis in patients with InsR(mod/strong) expressing tumors (P(interaction) = 0.041). IGF1R(strong) expression impacted endocrine treatment response differently depending on patients’ age and type of endocrine therapy. Phospho-IGF1R/InsR(pos) was associated with lower risk for events among non-endocrine-treated patients irrespective of ER status, HR(adj) (0.32; 95%CI 0.16-0.63), but not among endocrine-treated patients (P(interaction) = 0.024). In non-endocrine-treated patients, pIGF1R/InsR(pos) was associated with lower risk for events after radiotherapy, HR(adj) (0.31; 95%CI 0.12-0.80), and chemotherapy, HR(adj) (0.29; 95%CI 0.09-0.99). This study highlights the complexity of IGF hetero-and homodimer signaling network and its interplay with endocrine treatment, suggesting that combinations of involved factors may improve patient selection for IGF1R-targeted therapy.