Background: The insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal breast epithelial cells and breast carcinomas. A number of studies have examined the over-expression of IGF-1R in breast cancer with the range of between 39% to 93%. However, many of these studies were carried out using ELISAs, radioimmunoassay with small patient cohorts. Phosphorylation of IGF-1R results in the activation of the MAPK and PI3K/Akt pathway. Activation of the PI3K/Akt pathway under the influence of IGF-1R plays an important role in maintaining the proliferation of breast cancer cells that are resistant to gefitnib, trastuzumab or chemoradiotherapy in vitro and in vivo. In the present study, we examined the expression of IGF-1R in early breast cancer and investigated the clinicopathological implications using immunohistochemistry and FISH.Methods: TMAs from a consecutive series (1981-98) of 1,812 women managed by wide local excision and postoperative radiotherapy (45Gy in 20-25 fractions) were collected following appropriate ethical review. Of 1686 cases stained, 198 received no adjuvant hormonal or chemotherapy, 1106 received tamoxifen only as adjuvant therapy and 144 received a combination of hormonal and chemotherapy. Median age at diagnosis was 56, 72% were post-menopausal, 23.9% node positive, median size was 1.5 cm. Samples were stained, using triplicate 0.6mm2 TMA cores for IGF-1R.Results: FISH for IGF1R gene amplification was successful in 343/408 cases (84%). Only 7 cases of IGF1R amplification were observed (2%). IGF1R expression was successfully evaluated in 1597 of 1686 (94.7%) cases. High levels of IGF-1R expression was weakly associated with tumour ER-a (correlation coefficient, 0.108; p=2.2 x 10-5) and PgR levels (correlation coefficient 0.162; p=1.86x10-10) and inversely correlated with EGFR expression (correlation coefficient -0.189; p=6.33x10-6). No association was noted between IGF1R expression and other molecular or clinical markers, such as tumour size. There was a trend for over-expression of IGF-1R to link with increased distant relapse free survival, particularly in ER positive breast cancers. This trend is time dependent, such that no difference in outcome is observed at 15 years.Conclusions: We have demonstrated in a large cohort of patients that IGF-1R gene amplification is a rare event, and over-expression is weakly associated with good prognostic features (ERa and PgR, lack of EGFR and better outcome).

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2128.