Abstract P6-06-52: Increased expression of insulin-like growth factor-1 receptor is associated with better prognosis in a cohort of tamoxifen treated women

Abstract

Background: Treatment resistance is a well-known problem in estrogen receptor (ER) positive breast cancer. Complementary therapies are investigated for women who do not respond or who develop resistance against standard ER targeted treatment. Insulin-like growth factor-1 receptor (IGF1R) and its signaling pathway has been suggested to cause estrogen-independent cell growth and survival. Therapy against targets within the pathway is currently investigated in clinical trials. The aim of this study was to investigate if the IGF1R/mTOR pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. Material and methods: Two patient cohorts were investigated by immunohistochemistry using tissue microarrays. The first cohort (N = 264) consisted of mainly post-menopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. The second cohort (N = 206) consisted of mainly medically untreated, pre-menopausal patients with node-negative breast cancer. The protein expression of IGF1R, p-mTOR and p-S6rp were investigated. Cytoplasmic staining was evaluated for all markers and membrane staining was additionally evaluated for IGF1R. Statistical analyses were based on the intensity (0-3) of staining. Expression of IGF1R gave similar results in the cytoplasm and membrane, and p-values for cytoplasmic staining are reported below. Distant disease free survival (DDFS) at 5 years was used as end-point. Results: IGF1R expression was positively associated with ERa (p<0.001 in Mann-Whitney ranksum test), PgR (p<0.001) and HER2 (p = 0.042) expression in cohort 1, and also with Ki67 (p = 0.006) in cohort 2. p-S6rp was positively associated with ERα in cohort 1 (p<0.001) and HER2 (p = 0.004) in cohort 2. p-mTOR was positively associated only with Ki67 (p<0.001) in cohort 1. High expression of IGF1R was associated with a significantly better prognosis in cohort 1 (HR = 0.7 per intensity step, 95% CI = 0.5-0.9, p = 0.016 using Cox regression). When stratifying for ER status the effect was found in ER negative (ER-) (N = 80, HR = 0.6, 95% CI = 0.4-1.0, p = 0.03) but not in ER positive (ER+) patients (N = 174, HR 1.2, 95% CI = 0.8-2.0, p = 0.40). Both the effect in the ER- subgroup as well as the difference between ER- and ER+ patients were confirmed in interaction analysis and remains after adjustment for age, tumor size, node status, HER2, Ki67, and menopausal status (p = 0.06 for interaction). In cohort 2, no relation to DDFS could be found for IGF1R. p-mTOR and p-S6rp showed no relationship to prognosis in either of the cohorts. Conclusion: We found that high IGF1R expression was associated with a better prognosis for tamoxifen treated women. This effect could be seen in the ER- but not in the ER+ subgroup of patients. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway shows that the prognostic effect is not due to complete activation of this pathway. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-52.