Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials.

BACKGROUND: We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. METHODS: Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. RESULTS: In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. CONCLUSIONS: Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. CLINICAL TRIALS NUMBERS: CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.

Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab.

BACKGROUND: Phase III trials of the anti-insulin-like growth factor type 1 receptor (IGF-IR) antibody figitumumab (F) in unselected non-small-cell lung cancer (NSCLC) patients were recently discontinued owing to futility. Here, we investigated a role of free IGF-1 (fIGF-1) as a potential predictive biomarker of clinical benefit from F treatment. MATERIALS AND METHOD: Pre-treatment circulating levels of fIGF-1 were tested in 110 advanced NSCLC patients enrolled in a phase II study of paclitaxel and carboplatin given alone (PC) or in combination with F at doses of 10 or 20 mg kg(-1) (PCF10, PCF20). RESULTS: Cox proportional hazards model interactions were between 2.5 and 3.5 for fIGF-1 criteria in the 0.5-0.9 ng ml(-1) range. Patients above each criterion had a substantial improvement in progression-free survival on PCF20 related to PC alone. Free IGF-1 correlated inversely with IGF binding protein 1 (IGFBP-1, ρ=-0.295, P=0.005), and the pre-treatment ratio of insulin to IGFBP-1 was also predictive of F clinical benefit. In addition, fIGF-1 levels correlated with tumour vimentin expression (ρ=0.594, P=0.021) and inversely with E-cadherin (ρ=-0.389, P=0.152), suggesting a role for fIGF-1 in tumour de-differentiation. CONCLUSION: Free IGF-1 may contribute to the identification of a subset of NSCLC patients who benefit from F therapy.

Insulin-like growth factors and risk of kidney cancer in men.

BACKGROUND: Insulin-like growth factor-I (IGF-I) has been shown to increase kidney growth, glomerular filtration rate, and renal function. METHODS: In the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study of 29 133 Finnish male smokers aged 50-69 years, serum concentrations of IGF were measured in samples collected in 1985-1988. A total of 100 men with kidney cancer diagnosed > or =5 years after blood collection through 1997 were compared with a subcohort of 400 men; logistic regression models were used to estimate the risk of developing kidney cancer. RESULTS: Men with IGF-I levels >113 ng ml(-1) were 59% less likely to develop kidney cancer than men with levels < or =113 ng ml(-1) (odds ratio=0.41; 95% confidence interval=0.23-0.75). The IGF binding protein-3 (IGFBP-3) levels did not alter the association. No association was observed between IGFBP-3, or molar ratio of IGF-I/IGFBP-3, and kidney cancer. CONCLUSIONS: Low serum IGF-I levels in this cohort of older middle-aged male smokers are associated with increased kidney cancer risk, independent of IGFBP-3.

Insulin-like growth factors and liver cancer risk in male smokers.

BACKGROUND: The liver is the primary source of circulating insulin-like growth factor (IGF)-I, yet the relation between IGFs and liver cancer is uncertain. METHODS: In a case-cohort study within a cohort of 29,133 male smokers we examined associations of serum IGF-I and IGF binding protein (IGFBP)-3 with liver cancer (50 cases). RESULTS: Nonlinear associations between liver cancer and IGF-I and IGFBP-3 were observed (P=0.04 and P<0.01, respectively), strongest association at lowest levels (odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1-0.7 for 80 vs 30 ng ml(-1) of IGF-I; OR=0.2, 95% CI=0.1-0.6 for 1400 vs 700 ng ml(-1) of IGFBP-3). CONCLUSIONS: Low IGF-I and IGFBP-3 levels in male smokers are associated with increased risk of liver cancer.

Epidermal growth factor receptor gene-amplified MDA-468 breast cancer cell line and its nonamplified variants.

We have recently reported (J. Filmus, M. N. Pollak, R. Cailleau, and R. N. Buick, Biochem. Biophys. Res. Commun. 128:898-905, 1985) that MDA-468, a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited in vitro pharmacological doses of EGF. We have derived several MDA-468 clonal variants which are resistant to EGF-induced growth inhibition. These clones had a number of EGF receptors, similar to normal human fibroblasts, and had lost the EGF receptor gene amplification. Karyotype analysis showed that MDA-468 cells had an abnormally banded region (ABR) in chromosome 7p which was not present in the variants. It was shown by in situ hybridization that the amplified EGF receptor sequences were located in that chromosome, 7pABR. Five of the six variants studied were able to generate tumors in nude mice, but their growth rate was significantly lower than that of tumors derived from the parental cell line. The variant that was unable to produce tumors was found to be uniquely dependent on EGF for growth in soft agar.

Insulinlike growth factor I: a potent mitogen for human osteogenic sarcoma.

Insulinlike growth factor I (IGF-I) is among the peptide mitogens that play key roles in the regulation of normal skeletal growth. To investigate the possibility that certain skeletal neoplasms retain a sensitivity to mitogenic stimulation by IGF-I, we studied the effects of this growth factor on human osteosarcoma. Competitive-binding assays and affinity-labeling experiments on membranes prepared from MG-63 immortalized human osteosarcoma cells and primary human osteogenic sarcoma cells demonstrate the presence of specific IGF-I receptors. Furthermore, we show that IGF-I is a potent stimulator of proliferation of MG-63 cells in vitro and is active at concentrations as low as 10(-10) M. A blocking antibody against the IGF-I receptor (alpha-IR3) significantly reduces IGF-I-stimulated proliferation in a dose-dependent manner. These results are consistent with the hypothesis that at least a subset of human osteogenic sarcomas are responsive to IGF-I and indicate that it may be possible to exploit this responsiveness therapeutically.

Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.

BACKGROUND: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. METHODS: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. RESULTS: IGFBP-3 levels correlated with IGF-I levels (r=.64) and with IGF-II levels (r=.90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m]2), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR]=2.51; 95% confidence interval [CI]=1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR=0.28; 95% CI=0.12-0.66; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. CONCLUSIONS: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.

Estrogen and antiestrogen modulation of MCF7 human breast cancer cell proliferation is associated with specific alterations in accumulation of insulin-like growth factor-binding proteins in conditioned media.

Many neoplastic cell lines secrete insulin-like growth factor binding proteins (IGFBPs). The physiological role of these proteins is incompletely characterized; under various conditions IGFBPs have been observed to either enhance or inhibit the biological activity of insulin-like growth factors. MCF7 human breast cancer cells are known to be mitogenically responsive to insulin-like growth factors and estrogens, to secrete several IGFBPs, including BP-2, BP-4 and BP-5, and to be growth inhibited by antiestrogens. We report here that the pure antiestrogen ICI 182,780 and, to a lesser extent, the commonly used drug tamoxifen significantly increase levels of a M(r) 43,000-46,000 IGFBP (BP-3) and significantly reduce levels of a M(r) 24,000 IGFBP (BP-4) in the conditioned medium of MCF7 cells. Effects of estradiol and antiestrogens on M(r) 30,000 and M(r) 36,000 IGFBPs are also described. The effects of ICI 182,780 on IGFBPs in the conditioned medium of MCF7 cells may contribute to the remarkable ability of this compound to attenuate insulin-like growth factor I stimulated MCF7 cell proliferation.

Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer.

Germ-line mutations in BRCA1 confer an increased risk of developing breast and ovarian cancer, but little is known about the clinical course of breast cancer in BRCA1 mutation carriers compared with noncarriers. Two recurrent BRCA1 mutations (185delAG and 5382insC) are common ( approximately 1.3%) in Ashkenazi Jews and account for about 20% of breast cancers diagnosed before age 40 in this group. We assayed paraffin-embedded tumor blocks from 117 unselected Ashkenazi Jewish women with primary breast cancer, diagnosed before age 65 at a single institution, for the presence of either of the two BRCA1 mutations. We reviewed the medical records and constructed survival curves for BRCA1-positive and -negative subgroups. Twelve of the women (10.3%) were found to carry BRCA1 mutations (eight mutations were 185delAG, and four were 5382insC). The probability of death from breast cancer in the first 5 years was 35.7% in the BRCA1 mutation-positive group and 4.3% in the 100 women without a mutation (P = 0.0023). The 5-year distant disease-free survival was 68.2% in BRCA1 mutation carriers and 88.7% in noncarriers (P = 0.019). These data suggest that breast cancer occurring in an Ashkenazi Jewish woman carrying a germ-line BRCA1 mutation has an adverse prognosis. This information is available before the diagnosis of breast cancer, and therefore, this finding may have important implications for prevention of breast cancer in BRCA1 mutation carriers.

A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women.

Insulin-like growth factor-1 (IGF-1) is an important mitogen, and IGF binding protein-3 (IGFBP-3) has opposing effects. Acromegalics, who have abnormally elevated levels of IGF-1, are at increased risk of colorectal tumors. Recent studies have found that IGF-1 levels correlate with risk of prostate cancer and colorectal cancer in men, premenopausal breast cancer in women, and lung cancer in men and women. We examined whether prediagnostic plasma levels of IGF-1 and IGFBP-3 influence risk of colorectal cancer and adenoma in women. From 1989 to 1990, a total of 32,826 women from the Nurses' Health Study provided blood specimens that were archived in liquid nitrogen. During 6 years of follow-up from 1989 to 1994, we documented 79 new cases of colorectal cancer, 90 cases of intermediate/late-stage adenoma (> or =1 cm or tubulovillous/villous histology), and 107 cases of early-stage adenoma (<1 cm and tubular histology). After matching controls (2:1 for cancers and 1:1 for adenomas) to cases by age, month of blood draw, fasting status, and indication for endoscopy (for adenoma controls), plasma IGF-1 and IGFBP-3 levels were measured. Controlling for IGFBP-3 level, relative to women in the low tertile of IGF-1, those in the high tertile were at elevated risk of intermediate/late-stage colorectal neoplasia adenoma [multivariate relative risk (RR), 2.78; 95% confidence interval (CI), 0.76-9.76] and cancer (RR, 2.18; 95% CI, 0.94-5.08). Controlling for IGF-1 level, relative to women in the low tertile of IGFBP-3, women in the high tertile of IGFBP-3 were at lower risk of intermediate/late-stage colorectal adenoma (RR, 0.28; 95% CI, 0.09-0.85) and cancer (RR, 0.28; 95% CI, 0.10-0.83). Neither IGF-1 nor IGFBP-3 had any appreciable relation with early-stage adenoma. These analyses indicate that high levels of circulating IGF-1 and particularly low levels of IGFBP-3 are associated independently with an elevated risk of large or tubulovillous/villous colorectal adenoma and cancer.

Racial variation in insulin-like growth factor-1 and binding protein-3 concentrations in middle-aged men.

African-American men have the highest and Asian-American men have the lowest prostate cancer incidence rates in the United States; internationally, rates for the Asian continent are among the lowest. Higher insulin-like growth factor (IGF)-1, which participates in the control of cellular growth and differentiation and is modulated by IGF-binding protein-3 (IGFBP-3), was associated with an increased prostate cancer risk in three recent studies. We, therefore, investigated whether plasma levels of IGF-1 and IGFBP-3 vary by race in United States men selected from among members of the Health Professionals Follow-up Study who were 47-78 years old in 1993-1995 when they provided blood (n = 18,000). All of the men who described their major ancestry as African American (n = 63) and a random sample of 75 Asians and 75 Caucasians were invited to provide a second blood sample in 1997, of whom 42, 52, and 55, respectively, did so. IGF-1 and IGFBP-3 concentrations were determined by ELISA. We used nonparametric methods to assess racial variation in age-adjusted levels. Caucasians had the highest median IGF-1 level (224 ng/ml), followed by Asians (208 ng/ml) and African Americans (205 ng/ml). Median IGFBP-3 concentration was similar between Caucasians and Asians but was more than 13% lower in African Americans. Median molar IGF-1:IGFBP-3 ratio was greatest in Caucasians and lowest in Asians. The lower IGF-1 blood levels relative to IGFBP-3 levels among Asian men are consistent with their lower prostate cancer incidence. Although differences in circulating IGF-1 do not seem to account for the greater prostate cancer risk among African-American men, their absolute lower levels of IGFBP-3 may be contributory.

Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = 0.22). Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = 0.05). Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = 0.25). Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = 0.13). Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = 0.0002 and P = 0.0003, respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size.

Direct effects of tamoxifen on growth hormone secretion by pituitary cells in vitro.

There is now strong evidence to suggest that insulin-like growth factor I (IGF-I) plays an important role in breast cancer proliferation. Recently we observed that tamoxifen-treated stage I breast cancer patients have serum IGF-I levels significantly lower than placebo-treated patients. Since IGF-I is growth hormone (GH) dependent, we have tested the hypothesis that tamoxifen alters serum IGF-I levels through direct inhibition of GH secretion. Immature lamb pituitary cultures were examined for acute (3 h) or chronic (1-6 day) effects of the drug, using doses (0.1-10 mumol/l) based on known steady state levels in patients on tamoxifen therapy (0.31-3.1 mumol/l). Tamoxifen had a direct, dose-related, inhibitory effect on GH release from pituitary somatotropes, during acute as well as chronic treatment. The 10 mumol/l dose consistently decreased both basal and growth hormone releasing factor stimulated GH release. These in vitro data are consistent with our hypothesis that tamoxifen suppresses serum IGF-I levels by acting at the pituitary to inhibit GH release.

Presence of somatomedin receptors on primary human breast and colon carcinomas.

Competitive binding techniques were used to study the interaction of insulin-like growth factor I (IGF-I) with a plasma membrane-enriched subcellular fraction purified from primary breast and colon carcinoma specimens obtained at surgery. The presence of specific binding sites for IGF-I was detected in all tumour specimens studied. Scatchard analysis and competition studies with insulin and insulin-like growth factor-II (IGF-II) revealed the presence of specific IGF-I receptors, showing a Kd-value of approximately 2 nM. These results are consistent with the hypothesis that somatomedins play a role in determining the proliferative behaviour of human breast and colon tumors, and suggest that recent laboratory studies showing dependence of neoplastic cells on somatomedins for optimum proliferation may have clinical relevance.

Serum insulin-like growth factor-I (IGF-I) does not correlate positively with isometric strength, fatigue, and quality of life in post-polio syndrome.

OBJECTIVES AND BACKGROUND: To determine if serum insulin-like growth factor-I (IGF-I) levels are associated with strength, body mass index (BMI), fatigue, or quality of life in post-poliomyelitis syndrome (PPS). PPS is likely due to a distal disintegration of enlarged post-polio motor units as a result of terminal axonal sprouting. Age-related decline in growth hormone and IGF-I (which support terminal axonal sprouts) is proposed as a contributing factor. METHODS: As part of the North American Post-Poliomyelitis Pyridostigmine Study (NAPPS), baseline data on maximum voluntary isometric contraction (MVIC), BMI, subjective fatigue (fatigue severity scale, Hare fatigue symptom scale), health-related quality of life (short form health survey-36; SF-36), and serum IGF-I levels were gathered on 112 PPS patients. Pearson correlation coefficients were calculated to evaluate the association between serum IGF-I and MVIC in 12 muscles, BMI, two fatigue scales, and SF-36 scale scores. RESULTS: There is a significant inverse correlation of IGF-I levels with MVIC in left ankle dorsiflexors (r=-0.30, P<0.01), and left and right knee extensors (r=-0.22, -0.25, P=<0.01, 0.01), but no significant correlations in other muscles. When men and women were evaluated separately, inverse correlations of IGF-I levels with MVIC were found only in men. IGF-I correlated inversely with BMI (r=-0.32, P=0006) and age (r=-0.32, P=0.0005). IGF-I did not correlate with the fatigue or SF-36 scales. CONCLUSIONS: In this exploratory study, we found that contrary to our expectations, IGF-I did not correlate positively with strength. IGF-I correlated negatively with strength in several lower extremity muscles, BMI, and age. IGF-I is likely not an important factor in the pathogenesis of fatigue and in determining quality of life in PPS, but its role on strength should be studied further.

Somatostatin analogue SMS 201-995 reduces serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I.

Tumors of several organs have been shown to bear cell surface receptors for insulin-like growth factor I (IGF-I), and to exhibit dependence on this mitogen for optimum proliferation both in vivo and in vitro. To investigate the feasibility of a novel form of endocrine therapy that would exploit such dependence, we treated 8 patients with non-endocrine solid tumours with the somatostatin analogue SMS 201-995, in an effort to reduce growth hormone-stimulated IGF-I production. Significant decreases in basal and arginine-stimulated serum growth hormone and serum IGF-I were noted. This approach deserves evaluation as a potentially useful form of palliative endocrine therapy for certain cancers.

Glycemic load effect on fasting and post-prandial serum glucose, insulin, IGF-1 and IGFBP-3 in a randomized, controlled feeding study.

BACKGROUND/OBJECTIVES: The effect of a low glycemic load (GL) diet on insulin-like growth factor-1 (IGF-1) concentration is still unknown but may contribute to lower chronic disease risk. We aimed to assess the impact of GL on concentrations of IGF-1 and IGF-binding protein-3 (IGFBP-3). SUBJECTS/METHODS: We conducted a randomized, controlled crossover feeding trial in 84 overweight obese and normal weight healthy individuals using two 28-day weight-maintaining high- and low-GL diets. Measures were fasting and post-prandial concentrations of insulin, glucose, IGF-1 and IGFBP-3. In all 80 participants completed the study and 20 participants completed post-prandial testing by consuming a test breakfast at the end of each feeding period. We used paired t-tests for diet component and linear mixed models for biomarker analyses. RESULTS: The 28-day low-GL diet led to 4% lower fasting concentrations of IGF-1 (10.6 ng/ml, P=0.04) and a 4% lower ratio of IGF-1/IGFBP-3 (0.24, P=0.01) compared with the high-GL diet. The low-GL test breakfast led to 43% and 27% lower mean post-prandial glucose and insulin responses, respectively; mean incremental areas under the curve for glucose and insulin, respectively, were 64.3±21.8 (mmol/l/240 min; P<0.01) and 2253±539 (µU/ml/240 min; P<0.01) lower following the low- compared with the high-GL test meal. There was no effect of GL on mean homeostasis model assessment for insulin resistance or on mean integrated post-prandial concentrations of glucose-adjusted insulin, IGF-1 or IGFBP-3. We did not observe modification of the dietary effect by adiposity. CONCLUSIONS: Low-GL diets resulted in 43% and 27% lower post-prandial responses of glucose and insulin, respectively, and modestly lower fasting IGF-1 concentrations. Further intervention studies are needed to weigh the impact of dietary GL on risk for chronic disease.

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts.

Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case-control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60-1.48), 0.96 (95% CI, 0.61-1.52), and 1.21 (95% CI, 0.75-1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54-1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.