Use of insulin-like growth factor (IGF) pathway polymorphism IGF1R_rs2016347 to predict tumor recurrence in estrogen receptor-positive breast cancer patients

Background: Accumulating evidence suggests that insulin-like growth factor (IGF) signaling is an important pathway for breast cancer pathogenesis which regulates both cellular proliferation and apoptosis. Recently, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling in breast cancer. We tested whether functional germline variations in the IGF-pathway are associated with clinical outcome in ER positive primary invasive breast cancer patients, who were treated with surgery and adjuvant hormone treatment. Methods: Tissue samples of 222 patients with ER positive primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. gDNA was extracted from formalin fixed paraffin embedded (FFPE) tissue samples and six (IGF1_rs6214, IGF1_rs2946834, IGF1_rs7136446, IGF1R_rs2016347, IGFBP3_rs2854744, IRS1_rs1801123) functional IGF1-pathway polymorphisms were analyzed using direct DNA-sequencing and PCR-RFLP. Results: In univariate analysis patients with primary invasive breast cancer carrying at least one T allele (GT or TT) of IGF1R_rs2016347 polymorphism had a significant better disease free survival (DFS) than patients with GG genotype (DFS 5.3 years versus 7.6 years; p=0.02). This association remained significant in multivariate analysis adjusting for tumor size, lymph node involvement, and c-erbB2 status [HR=0.57 (CI 95%; 0.36-0.9); adjusted p=0.01). The other tested IGF-pathway polymorphisms did not show significant associations for DFS. Conclusions: These results indicate functional IGF1R_rs2016347 polymorphism as independent prognostic marker for tumor recurrence suggesting that co-targeting both ER and IGF1R holds promise for the treatment of patients with ER positive breast cancer.