A comparison of hormonal profiles between breast cancer and benign breast disease: a case–control study

BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low-penetrance genes, which may also modify the risk in BRCA mutation carriers. The absence of the IGF1 19-repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use. High IGF-1 levels are linked to early-onset breast cancer and larger breast volumes in the general population. The goal of this study was to elucidate the relationships between IGF1 genotype, early-onset breast cancer, breast volume, circulating IGF-1 levels and OC use in a prospective cohort of 258 healthy women ⩽40 years old from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured the height, weight, breast volumes and plasma IGF-1 levels. IGF-1 levels were similar among parous and nulliparous women not using OCs. In all, 13% had no IGF1 19-repeat allele. There was an interaction between IGF1 genotype and OC use on IGF-1 levels (P=0.026) in nulliparous women and another interaction between IGF1 genotype and parity on breast volume (P=0.01). Absence of the 19-repeat allele was associated with high IGF-1 levels in nulliparous OC users and with larger breast volumes in parous women and OC users. Incident breast cancers were also more common in women without the 19-repeat allele (log rank P=0.002). Our results suggest that lack of the IGF1 19-repeat allele modifies IGF-1 levels, breast volume and possibly early-onset breast cancer risk after hormone exposure in young high-risk women.

Purpose: We have previously reported that African American women have significantly higher IGF-1 levels, and lower IGF-2 and IGFBP-3, compared to white women. This investigation aims to determine if genetic African ancestry is associated with these racial differences in blood IGF levels. Methods: The Southern Community Cohort Study (SCCS) is a prospective cohort study of 86,000 men and women, with two-thirds African American recruitment, designed to investigate racial disparities in cancer. We randomly selected 1000 African American and 1000 non-Hispanic white female participants to support focused investigations of racial differences in biomarkers possibly related to breast cancer. Serum IGF-1, IGF-2, and IGFBP-3 levels were measured by ELISA. We estimated African and European admixture using a panel of 276 ancestry informative genetic markers. Final analyses included 821 African American women and 816 white women after excluding women taking hormone replacement therapy or insulin for diabetes. White women had a low African ancestry (median = 0.4%, range=0.1 % to 17.1 %) and thus were considered as a single ancestry category. For African Americans, cutpoints of <85% (n=149), 85%-95% (n=230), and ≥95% (n=442) defined “low,” “medium,” and “high” African ancestry. Using multivariable linear regression, we estimated differences in IGF levels across ancestry categories while adjusting for age, body mass index (BMI), height, menopausal status, and BMI at age 21 years. Results: African American women having 85% African ancestry. For example, IGF-2 levels among white women and African American women with <85%, 85%-95%, and ≥95% African ancestry were 1771.9 ng/ml, 1713.5 ng/ml, 1620.3 ng/ml, and 1620.6 ng/ml, respectively. African American women with < 85% African ancestry had IGF-2 levels that were about 5.8% higher than African American women with 85%-95% (p=0.03) or ≥95% (p=0.01) ancestry. IGF-1 levels among white women and African American women with <85%, 85%-95%, and ≥95% African ancestry were 134.7 ng/ml, 143.8 ng/ml, 147.8 ng/ml, and 147.4 ng/ml, respectively, while IGFBP-3 levels were 3871.8 ng/ml, 3816.9 ng/ml, 3629.0 ng/ml, and 3693.9 ng/ml, respectively. African American women with 85% African ancestry, but these differences in IGF-1 and IGFBP-3 levels between African American ancestry groups were not statistically significant. We also calculated the molar ratio of IGF-1 to IGFBP-3 as an index of biologically available or free IGF-1. Differences in free IGF-1 among white women and African American women with <85%, 85%-95%, and ≥95% African ancestry were 0.126,0.137,0.148, and 0.145, respectively. Free IGF-1 levels were significantly lower among African American women with <85% compared to women with 85%-95% (p=0.02) or ≥95% (p=0.05) ancestry. Conclusion: Estimates of African ancestry are significantly associated with IGF-2 and free IGF-1, and suggest inherited genetic traits associated with African ancestry contribute to racial differences in IGF levels. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):PR-1.

Anthropometric Correlates of Insulin-Like Growth Factor 1 (IGF-1) and IGF Binding Protein-3 (IGFBP-3) Levels by Race/Ethnicity and Gender

The incidence of clinical prostate cancer in the Arab population is among the lowest in the world. High serum IGF-1 level has been implicated as a possible risk factor for the development of prostate cancer in Caucasians. The purpose of this study was to determine serum IGF-1 and IGFBP-3 levels in healthy Arab men and in Arab men with newly diagnosed benign prostatic hyperplasia (BPH) and prostate cancer, and to compare these values with values reported in Caucasians. Subjects were recruited in two groups: (a) indigenous, healthy Arab men aged 15-90 y (n = 383); (b) Arab men with newly diagnosed prostate cancer (n = 30) or BPH (n = 40). Blood was obtained from fasting patients and volunteers, between 8:00 a.m. and 12:00 noon. The serum concentrations of IGF-1 and IGFBP-3 were determined using Immunoradiometric assay (IRMA) kits. As in Caucasians, serum IGF-1 and IGFBP-3 levels declined with age in Arab men. The mean +/- s.d. of serum IGF-1 levels in healthy Arab men in the age group 15-20, 51-60, 61-70 y were lower (376.2 +/- 153.2, 134.9 +/- 105.7 and 89.6 +/- 48.4 ng/ml, respectively), compared to values reported for similarly aged Caucasians. Arab men with newly diagnosed prostate cancer had significantly higher serum IGF-1 level (P < 0.01) and lower IGFBP-3 levels (P < 0.01) compared to age-matched Arabs without the disease. Arab men have lower serum IGF-1 levels compared to Caucasians and this may be an important factor in the explanation of the low incidence of prostate cancer in the Arab population.

Expression of estrogen receptors in non-malignant mammary tissue modifies the association between insulin-like growth factor 1 and breast cancer risk

Introduction: Previous research in the Nurses' Health Study (NHS) and NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans. Methods: We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (i.e., type 1, 2, or 3) and whether any type 1 or any type 3 lobules were present. Lobule type then was classified as: 1) predominant type 1/no type 3 lobules, which is suggestive of complete involution or 2) other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, IGF binding protein-3 (IGFBP-3), and the ratio of IGF-1-to-IGFBP-3 levels with lobule type. Results: In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type1/no type 3 lobules (p&amp;lt;0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (OR quartile 4 vs. quartile 1=0.37, 95%CI: 0.15–0.89). Greater ratios of IGF-1-to-IGFBP-3 levels also were associated with decreased odds of predominant type1/no type 3 lobules (OR quartile 4 vs. quartile 1=0.26, 95%CI: 0.11–0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type. Conclusion: Higher IGF-1 levels and a greater IGF-1-to-IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of growth factors in the structure of breast lobules and lobular involution. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A68.

There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury. We have measured the circulating level of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures. The serum level of IGF-1 was significantly lower in patients with both head injury and fracture and fracture only compared with that in healthy volunteers (p < 0.01 and p < 0.02, respectively). The level of IGFBP-3 was also significantly lower in patients with both head injury and fracture (p < 0.01). Our findings showed, however, that the level of IGF-1 and IGFBP-3 varied from week to week in both the patients and healthy control subjects. These results indicate that the levels of circulating IGF-1 and IGFBP-3 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury.

Low serum insulin-like growth factor 1 (IGF-1) level is associated with shorter overall survival (OS) in patients with advanced unresectable hepatocellular carcinoma (HCC). This study aimed to evaluate whether preoperative IGF-1 levels are associated with OS and recurrence-free survival (RFS) in patients with HCC who underwent hepatectomy. Patients who underwent hepatectomy for HCC between 2001 and 2023 were identified from a prospectively maintained database at the MD Anderson Cancer Center. Patients with IGF-1 measured within 8 weeks after hepatectomy were included. The median IGF-1 level was used as a cutoff value to categorize high and low IGF-1 levels. The primary endpoint was OS, and the secondary endpoint was RFS. A total of 51 patients were included in this study. The median age was 66 years, and 65% of patients were males. The median IGF-1 level was 87ng/mL. Patients with low IGF-1 levels were more likely to be ≥65 years old, with history of diabetes mellitus, hypertension, and tobacco use, and to have multinodular tumors and higher alpha-fetoprotein levels. After a median follow-up of 61 months, no difference in RFS between the high and low IGF-1 groups was found. OS was significantly longer in patients with high IGF-1 levels than in those with low IGF-1 levels (5-year OS: 80% vs 45%, respectively; P =.027). On multivariate analysis, a high IGF-1 level was significantly associated with better OS (hazard ratio, 0.33 [95% CI, 0.12-0.93]). Low preoperative IGF-1 levels were a predictor of poor survival after liver resection for HCC but did not correlate with recurrence rates. This may be related to poor hepatic reserve in patients with low IGF-1 levels.

Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins. We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium. After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10(-4)); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R(2) = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers. Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women. Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.

The insulin-like growth factor (IGF) pathway is believed to play a role in carcinogenesis of the mammary gland. Single nucleotide polymorphisms (SNPs) of IGF-I, IGF-binding protein-3 (IGFBP-3), IGF receptor 1, insulin receptor substrate 1, and phosphoinositide-3-kinase, catalytic, beta polypeptide genes, which are members of the IGF pathway, have been associated with risk of common cancers, breast density, and/or IGF levels but results remain inconclusive. Thus, we evaluated the association of 11 targeted IGF pathway SNPs with circulating IGF levels and mammographic breast density. Among 741 white premenopausal women, blood samples were collected at time of screening mammography, and plasma IGF-I and IGFBP-3 levels were measured by ELISA. Percent and absolute breast density were estimated using a computer-assisted method. Multivariate linear models were used to examine the associations. Women carrying increasing number of copies of the rare allele of IGF-I rs1520220 and rs6220 SNPs had increased percent breast density (P(trend) = 0.04 and 0.06, respectively). Carriers of increasing number of copies of the rare allele of phosphoinositide-3-kinase, catalytic, beta polypeptide rs361072 SNP had decreased percent (P(trend) = 0.04) and absolute (P(trend) = 0.02) breast density. An association of insulin receptor substrate 1 rs1801278 SNP with absolute density (P(trend) = 0.03) was also observed. All four IGFBP-3 SNPs (including rs2854744) were associated with IGF-I and IGFBP-3 levels. This study shows that several components of the IGF pathway are associated with breast density or IGF levels. Our findings provide additional support for the idea that several components of the IGF pathway may affect breast cancer risk and that this effect on breast cancer development may be mediated, at least in part, through its influence on the morphogenesis of breast tissue.

To identify endocrinologic problems, particularly those concerning growth, in collodion babies (CBs). Clinically identified newborn CBs were included in the study group (group 1). Because CBs are generally born premature, small for gestational age (SGA), or both, a control group matched to the study group in terms of gestational age and birthweight (group 2) was also established. Blood specimens were collected from both groups for thyroid function tests and to measure serum growth hormone (GH), insulinlike growth factor 1 (IGF-1) and IGF binding protein-3(IGFBP-3) levels. Group 1 consisted of 42 CBs (25 male, 17 female) with gestational ages of 32 to 42weeks and birthweights of 1,400 to 4,000g. Twelve were assessed as premature and 17 as SGA. Serum IGF-1 and IGFBP-3 levels were lower and serum GH levels higher than in controls. Primary hypothyroidism was diagnosed in 10 patients in the study group, subclinical hypothyroidism in 2, and central hypothyroidism in 1. A statistically significant difference was determined between the groups in terms of primary hypothyroidism (p=0.01). Serum GH levels were weakly negatively correlated with birthweight (correlation coefficient [r]=-0.32, p=0.04) and serum IGF-1 (r=-0.38, p=0.001) and IGFBP-3 (r=-0.36, p=0.002) levels. Premature birth and SGA are common in CBs. GH levels are high and IGF-1 and IGFBP-3 levels low at birth as a sign of GH resistance in these patients. The greater prevalence of hypothyroidism in these children is also significant.

Objectives. The aim of this study was to determine the normal values of serum IGF-1 and IGFBP-3 in Turkish children and adults (1–79 years). Material and methods. The study included 571 healthy children and 625 healthy adults from the West Black Sea region of Turkey. Serum IGF-1 and IGFBP-3 concentrations were determined using a chemiluminescent immunometric assay on an Immulite 1000 analyzer. Results. IGF-1 and IGFBP-3 levels tended to be higher in girls compared to boys among the children. The differences were statistically significant in puberty from age 12–14 years for IGF-1 and prepubertally from age 9–10 years for IGFBP-3. Peaks of serum IGF-1 levels were observed 2 years earlier in girls (14 years) than boys (16 years). The general pattern of IGFBP-3 was similar to IGF-1 during puberty. In adults, IGF-1 and IGFBP-3 levels decreased by age. There was no significant difference in IGF-1 and IGFBP3 values between men and women in any age group. Conclusions. This study established age- and sex-specific reference values for serum IGF-1 and IGFBP-3 in healthy Turkish children and adults.

8100 Background: To determine whether concentrations of transforming growth factor α (TGFa), amphiregulin (ARG), both ligands of the epidermal growth factor receptor (EGFR), insulin-like growth factor 1(IGF1) or IGF-binding protein 3 (IGFBP3) measured in serum of advanced non-small cell lung cancer (NSCLC) patients are predictive of EGFR-inhibitors (EGFRi) response. Methods: We assessed serum levels of marker candidates using ELISA (TGA and ARG) and chemiluminescent (IGF1 and IGFBP3) assays. Sixty-one advanced NSCLC patients treated with EGFRi (gefitinib or erlotinib, &gt;14 days) were matched for gender, age and histology to a control group of 63 EGFRi-untreated advanced NSCLC patients. We dichotomized marker levels at the 20th, 50th or 80th percentile and evaluated whether the effect of EGFRi treatment on overall survival (OS) differed by marker level based on multivariate proportional hazards regression with an interaction term. We adjusted for gender, smoking, stage, histology and prior chemotherapy. Results: While 6-months OS did not appreciably differ between 50 EGFRi treated and 50 control patients whose TGFa levels were below the 80th percentile (39% vs. 54%, multivariate HR 0.78, 95% CI 0.45–1.34, p=0.359), it was substantially worse for 11 EGFRi treated patients compared with 13 control patients whose TGFa levels were high (9% vs. 42%, multivariate HR 2.38, 95% CI 0.87–6.52, p=0.092). The difference of EGFRi effects by TGFa level was statistically significant (interaction p=0.033). There was no evidence that EGFRi treatment effects differed by levels of ARG, IGF1 and IGFBP3. Patients with high concentrations of IGFBP3 (above the median) had significantly longer OS than patients with low IGFBP3 concentrations, independent of treatment (HR 0.46, 95% CI 0.29–0.73, p=0.001). Conclusions: This is the first study in NSCLC patients of Caucasian origin in which serum concentrations of TGFa are predictive for EGFR-inhibitor response, suggesting this is a potential predictive marker for EGFRi treatment. Furthermore, we coincidentally found that levels of IGFBP3 are predictive for overall survival, indicating this might be a prognostic factor in advanced NSCLC patients. [Table: see text]

Serum insulin-like growth factor (IGF) and IGF binding protein (BP) levels were studied in 89 constitutionally tall children and adolescents (height greater than mean for age + 3 SD in 90% of the subjects). After separation by acidic gel filtration, the samples were assayed for IGF using a protein-binding assay (which measures mainly IGF I-related peptides) and for IGF BP by titration, in both cases using IGF I as tracer. The reference standard was a pool of normal adult serum with an assigned potency of 1 U IGF and 1 U IGF BP/ml. IGF levels increased with age in a manner similar to that in normal subjects, but at higher concentrations (P less than 0.02). The values were 0.77 +/- 0.05 (SE) U/ml in 1- to 5-yr-old children, 0.96 +/- 0.08 U/ml in 5- to 11-yr-old prepubescent children and 1.51 +/- 0.07 U/ml during puberty. BP levels developed in a different way from the above in that the increase with age was slight (0.70 +/- 0.07, 0.67 +/- 0.09, and 0.97 +/- 0.07 U/ml, respectively, for the three periods considered) and the levels were lower than those of normal subjects (P less than 0.005). After fusion of the epiphyses both IGF and BP levels were within the range of normal values. Thirteen girls underwent prolonged treatment (mean, 26 months) with ethinyl estradiol (250-300 micrograms/day). Deceleration in growth was accompanied by a progressive decrease in IGF levels throughout the period of therapy and a rise in BP levels during the first 6 months, after which they stabilized within the range of normal values. Although it is possible that excessive secretion of GH (which was not demonstrated by the usual tests) may be the cause of the elevated IGF levels during growth in these constitutionally tall subjects, it seems likely that the high IGF levels combined with the abnormally low levels of BP were responsible for their excessive growth.

BackgroundActivation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy.Patients and methodsSerum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O’Quigley procedure. Survival analyses were performed using Cox regression analysis.ResultsHigh baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009–0.602 and HR 0.090, 95% CI 0.011–0.712, respectively) in univariate and multivariate analyses (HR 0.063, 95% CI 0.007–0.590 and HR 0.057, 95% CI 0.005–0.585, respectively). OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively).ConclusionHigh circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated with improved EFS and a trend for improved OS in Ewing sarcoma patients treated with VIDE chemotherapy. These findings suggest the need for further investigation of the IGF-1 pathway as a biomarker of disease progression in patients with Ewing sarcoma.