Insulin growth factor-1 receptor (IGF-1R) expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: a case-control study

Purpose: The IGF-1R is a glycoprotein receptor that consists of a heterodimer of two alpha and two beta subunits which are processed from a single precursor transmembrane polypeptide and has been found to be overexpressed in a variety of tumors. IGF-1R has been shown to play a critical role in malignant transformation and to influence apoptosis. We have recently shown in gene transfer studies that overexpression of the IGF-1R confers relative radioresistance on mouse fibroblasts in culture. To test the significance of this finding in a clinical setting, we have sought to determine the prognostic significance of overexpression of IGF-1R with respect to ipsilateral breast tumor recurrence (IBTR) in the conservatively treated breast cancer patient. Materials and Methods: Over 1,000 breast cancer patients treated with conservative surgery followed by radiation therapy to the intact breast served as the patient population for this study. Twenty-five patients with a diagnosis of invasive ductal carcinoma who had an IBTR as the first site of failure comprised the index case population base of this study. Following the identification of 25 patients with IBTR, the breast database was searched for 25 matching control patients who did not have an IBTR. The control patients were matched to the index case with respect to age (within 5 years), menopausal status, approximate date of radiation therapy, primary histology, axillary dissection, nodal status, primary tumor size, estrogen/progesterone receptor (ER/PR) status, and adjuvant chemotherapy/hormonal therapy. Both index cases and the matched control group received radiation therapy to a total dose of 64 Gy to the tumor bed. Following identification of index and control cases, the individual paraffin-embedded blocks (PEB) were evaluated for invasive ductal carcinoma with H and E staining by the pathologist. All PEB were then processed for immunohistochemical staining with a polyclonal antibody to the beta-chain of IGF-1R (Oncogene Science). The pathologist processing, staining, and grading the specimens was blinded as to the clinical information. Each slide was rated on a four point scale; 0-no stain, 1 + - light, 2 + - moderate, 3 + - heavy, and 4 + - intense staining, and % distribution of staining within the invasive ductal carcinoma component. A value of ≥ 2 + intensity was considered positive and a distribution of ≥ 40% was considered positive. An H-score (defined as the product of intensity x distribution) of ≥ 100 was used as a cutoff for positive IGF-1R overexpression. Results: The index case group and control group had similar age, histology, menopausal status, follow-up, ER/PR status, adjuvant treatment, and rate of distant metastasis is determined by Chi Square Analysis. The 10-year actuarial survival for the index and control group was 69% and 51%, respectively (p=N.S.). A total of 18 index cases (72%) exhibited high immunoreactivity (≥2+), while only five control cases (20%) demonstrated high immunoreactivity (p=.001). A total of 14 index cases (56%) demonstrated ≥40% distribution of staining, while only one control case (4%) showed a ≥40% distribution staining pattern (p<.001). There was a highly statistiaally significant difference in H-score values between the two groups with 14 index cases (56%) having an H-score ≥100, as compared to only one control case (4%) (p=.001). Conclusion: In a matched case control study, overexpression of the IGF-1R has strong prognostic significance with respect to local relapse in the conservatively treated breast. We now have laboratory and clinical evidence implicating IGF-1R in relatively radioresistant tumors. The mechanism responsible for IGF-1R radioresistance is currently being investigated in our laboratories