Abstract 3671: Associations between a polymorphic locus in the promoter region of the IGFBP-3 gene, circulating IGFs, mammographic breast density and survival in a 2×2 trial of low-dose tamoxifen and fenretinide in premenopausal women

Abstract

Abstract Background The Insulin-like Growth Factors (IGFs) pathway has been reported to play a role in breast carcinogenesis. A single nucleotide polymorphism in the promoter region of the IGFBP-3 gene (rs2854744), located at position -202 from the transcription start site, results in reduced promoter activity. Some evidence of an association between this polymorphism and circulating IGFs levels, mammographic breast density and breast cancer risk have been reported. Methods and results A total of 235 premenopausal women with intraepithelial neoplasia (IEN, n=181) or 5-year Gail risk >1,3% (n=54), were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide, a retinoic acid derivative, 200 mg/d, both agents, or placebo for 2 years. Mammography and fasting blood samples for serum IGF-I and IGFBP-3 measurements were collected at baseline and every 12 months for 3 years, within the same phase of the menstrual cycle. A total of 223 subjects were genotyped for IGFBP-3 A-202C with a Taqman real time PCR method for allelic discrimination. The IGFBP-3 A-202C genotype frequencies for AA, AC and CC were 31.4%, 52.5% and 16.1% respectively. According to baseline risk stratification, we observed a higher frequency of IGFBP-3 -202 CC genotype (92%) as compared to the AA+AC genotype group (76%, p<0.04) in the IEN group. Baseline serum IGFBP-3 (μg/ml) and IGF-I/IGFBP-3 molar ratio median values were 4.15 and 0.19 in the AA; 3.82 and 0.21 in the AC; 3.57 and 0.23 in the CC genotype group respectively. There was a significant trend for higher baseline IGFBP-3 levels and lower IGF-I/IGFBP-3 ratio with increasing number of the A allele at IGFBP-3 -202 locus (p=0.0005 and p=0.005 respectively) adjusting for risk stratification at baseline. Median baseline mammographic percent density values for IGFBP-3 AA, AC and CC genotype groups were 48.4%, 46.1% and 42.8% respectively. Interestingly, women with at least one A allele at IGFBP-3 -202 locus (AA or AC) had a 4-fold increase in the odds of having a high percentage of breast density (> 42.8%) compared to women with IGFBP-3 -202 CC genotype (OR=4.21; CI 1.17-15.18, p<0.05) adjusting for BMI and dense area. After a median follow-up of 7.5 years, 59 new breast events were observed. Subjects with IGFBP-3 -202 AA genotype had a borderline significantly greater disease free survival compared to AC+CC genotype group (p=0.06). There was no significant interaction between IGFBP-3 genotype and treatment. Conclusions Our results provide further support for an association between IGFBP-3 A-202C polymorphism and circulating IGFBP-3 levels. Moreover, our data provide first evidence of an association between IGFBP-3 genotype and disease free survival in women with breast IEN. Further studies are warranted to fully elucidate these relationships. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3671. doi:10.1158/1538-7445.AM2011-3671