Abstract 5573: Nuclear IGF-1R expression as a prognostic factor in cervical cancer patients

Abstract

Abstract Background: Insulin-like growth factor-1 receptor (IGF-1R) is an unusual transmembrane receptor in that both α and β subunits, regulated by IGF-1, translocate from the membrane to the nucleus and then bind to DNA, increasing gene transcription. Insulin receptor substrate-1 (IRS-1), a docking protein for IGF-1R, also traffics to the nucleus and then activates promoters of cell cycle progression genes. We studied the prognostic significance of nuclear and membranous IGF-1R and nuclear IRS-1 in cervical cancer, previously unreported. Methods: We retrospectively reviewed all patients (pts) with stage Ib2-IIb disease who received platinum-based neoadjuvant chemotherapy (NAC) at Hyogo Cancer Center between 2002 and 2009. Age, performance status, FIGO stage, histology, tumor size, pelvic lymph nodes on MRI, squamous cell carcinoma (SCC) antigen level, hemoglobin levels before NAC, chemotherapeutic agents and chemotherapy cycles were evaluated. Paraffin-embedded pretreatment tissue was stained immunohistochemically with an anti-IGF-1Rβ (Cell signaling, MA) or anti-IRS-1 (Millipore, MA) rabbit polyclonal antibody. IGF-1R and IRS-1 expressions were scored from 0 to 3 according to frequency and intensity. All slides were reviewed by a single pathologist. We analyzed prognostic factors associated with overall survival by a Cox proportional-hazards model. Results: A total of 128 pts (median age 57 years) were identified. The majority had stage II (61%) and SCC (69%). Median tumor size was 40 mm. Overall response rate to NAC was 59%, and median follow-up was 34 months. Nuclear and membranous IGF-1R and nuclear IRS-1 expressions were scored as 0/1-2/3 in 49/60/19 pts, 97/12/19 pts, and 65/41/22 pts, respectively. Multivariate analysis revealed that nuclear IGF-1R expression (HR, 2.6; P= .035 for score 1-3 vs. 0) and age <40 (HR, 2.6; P= .026) were independently associated with worse overall survival. Neither membranous IGF-1R nor IRS-1 expression had a prognostic impact on survival. Conclusions: Nuclear IGF-1R is commonly expressed in cervical cancer and is an independent prognostic factor, unlike membranous IGF-1R or nuclear IRS-1. Approaches that block the translocation of IGF-1R from the cell membrane to nucleus might hold promise for the treatment of cervical cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5573. doi:1538-7445.AM2012-5573