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1.  Similarity of Serum and Plasma Insulin-like Growth Factor Concentrations 
Biomarkers in Cancer  2015;7:13-17.
Insulin-like growth factors (IGFs) are implicated in many normal physiological processes and pathological states, including cancer. For large consortia projects, it may be necessary to make comparisons among studies with different specimens that were not collected specifically to optimize the measurement of IGFs.
This study aimed to compare IGFs in matched serum and plasma samples.
We measured IGF-I, IGF-II, insulin-like growth factor-binding protein (IGFBP)-3, C-peptide, and leptin in serum and ethylenediaminetetraacetic–containing-plasma samples obtained concurrently from 30 healthy women aged 64–80 years in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial using chemiluminescent or colorimetric enzyme-linked immune assays. Coefficients of variation (CVs) and correlations were determined.
Intraassay CVs ranged from 0.4% for IGFBP-3 to 10% for IGF-II. Mean concentrations of all analytes were higher in the serum, but the differences in mean concentrations of the analytes between serum and plasma were all <11%. Concordance correlation coefficients of matched serum/plasma specimens were 0.92, 0.91, 0.82, 0.96, and 0.99 for IGF-I, IGFBP-3, IGF-II, C-peptide, and leptin, respectively.
IGF concentrations measured in serum and plasma are highly correlated but are consistently slightly higher in serum, suggesting that IGF values should be corrected for systematic bias, particularly in consortial efforts when pooling data derived from different specimens.
PMCID: PMC4467203  PMID: 26106265
IGF; serum; plasma; leptin; C-peptide
2.  Competing risks of death in younger and older postmenopausal breast cancer patients 
World Journal of Clinical Oncology  2014;5(5):1088-1096.
AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.
METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.
RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality.
CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.
PMCID: PMC4259936  PMID: 25493245
Breast cancer; Postmenopausal; Hormone receptor positive; Competing risks; Tamoxifen; Octreotide LAR
3.  Genetic Variants, Prediagnostic Circulating Levels of Insulin-like Growth Factors, Insulin, and Glucose and the Risk of Colorectal Cancer: The Multiethnic Cohort Study 
Increased exposure of colonic and rectal epithelial cells to the promitotic and antiapoptotic effects of insulin and insulin-like growth factors (IGF) is hypothesized to increase colorectal cancer risk.
In a case–control study nested within the Multiethnic Cohort, we attempted to replicate associations for five genetic variants associated with IGF system biomarkers, insulin, or glucose and to examine their association with the risk of colorectal cancer. In a subset of participants, the association between circulating biomarkers and colorectal cancer risk was examined. Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CI) for genetic variants (1,954 cases/2,587 controls) and serum biomarkers (258 cases/1,701 controls).
Associations with circulating biomarkers were replicated in the Multiethnic Cohort for IGF1 rs35767 and for IGFBP3 rs2854744, rs2854746, and rs3110697 (P < 0.05). Homozygous carriers of the glucokinase regulator (GCKR) rs780094 variant T-allele were at a decreased risk of colorectal cancer (OR, 0.77; 95% CI, 0.64–0.92). In risk factor–adjusted models, participants with the highest prediagnostic IGF-II levels were at an increased risk [OR (T1 vs. T3), 1.58; 95% CI, 1.09–2.28; Ptrend = 0.011] and participants with the highest prediagnostic IGF-binding protein (IGFBP)-3 levels were at a decreased risk of colorectal cancer (OR, 0.53; 95% CI, 0.34–0.83; Ptrend = 0.003).
These data provide further support for a role of prediagnostic IGF and insulin levels in the etiology of colorectal cancer.
Future studies attempting to replicate the association between the GCKR rs780094 variant and the risk of colorectal cancer are warranted.
PMCID: PMC4494075  PMID: 22354904
4.  Association of C-peptide and leptin with prostate cancer incidence in the Health Professionals Follow-Up Study 
Cancer causes & control : CCC  2014;25(5):625-632.
Hyperinsulinemia is hypothesized to influence prostate cancer risk. Thus, we evaluated the association of circulating C-peptide, which is a marker of insulin secretion, and leptin, which is secreted in response to insulin and influences insulin sensitivity, with prostate cancer risk.
We identified prostate cancer cases (n=1,314) diagnosed a mean of 5.4 years after blood draw and matched controls (n=1,314) in the Health Professionals Follow-Up Study. Plasma C-peptide and leptin concentrations were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated taking into account the matching factors age and history of a PSA test before blood draw and further adjusting for body mass index, diabetes, and other factors.
Neither C-peptide (quartile [Q]4 versus Q1: OR=1.05, 95% CI 0.82–1.34, p-trend=0.95) nor leptin (Q4 versus Q1: OR=0.85, 95% CI 0.65–1.12, p-trend=0.14) was associated with prostate cancer risk. Further, neither was associated with risk of advanced or lethal disease (N=156 cases; C-peptide: Q4 versus Q1, OR=1.18, 95% CI 0.69–2.03, p-trend=0.78; leptin: Q4 versus Q1, OR=0.74, 95% CI 0.41–1.36, p-trend=0.34).
In this large prospective study, circulating C-peptide and leptin concentrations were not clearly associated with risk of prostate cancer overall or aggressive disease. Well into the PSA era, our findings do not appear to be supportive of the hypothesis that hyperinsulinemia influences risk of total or aggressive prostate cancer.
PMCID: PMC4028628  PMID: 24664287
Prostate cancer; C-peptide; leptin; nested case-control study; risk
5.  Elevated circulating branched chain amino acids are an early event in pancreatic adenocarcinoma development 
Nature medicine  2014;20(10):1193-1198.
Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.
PMCID: PMC4191991  PMID: 25261994
6.  Protein expression of PTEN, insulin-like growth factor I receptor (IGF1R), and lethal prostate cancer: a prospective study 
Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality, and the potential effect modification by IGF1R, a direct activator of the PI3K pathway.
Protein expression in tumor were evaluated using tumor tissues obtained from 805 participants of the Physicians’ Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression, and its interaction with IGF1R, in relation to lethal prostate cancer (cancer-specific death or distant metastases).
Low PTEN expression was associated with an increase risk of lethal prostate cancer (HR = 1.7, 95% CI: 0.98-3.2, P for trend = 0.04). The association was attenuated after adjustment for Gleason grade, tumor stage, and PSA at diagnosis. A significant negative interaction between PTEN and IGF1R was found (P for interaction = 0.03). Either reduction in PTEN or increase in IGF1R expression was sufficient to worsen prognosis. Models including PTEN and IGF1R expression offer additional predicting power to prostate cancer survival, comparing to those only including demographic and clinical factors.
Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF1R expression remains at normal level.
PTEN and IGF1R expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer.
PMCID: PMC3818474  PMID: 23983239
Prostate cancer; PTEN; Tumor biomarker; Survival; Interaction
7.  Plasma c-peptide, mammographic breast density, and risk of invasive breast cancer 
Insulin may promote breast cancer directly by stimulating the insulin receptor or indirectly by increasing the plasma concentration of active sex hormones. The association between insulin and breast density, a strong breast cancer risk factor, has not been thoroughly studied. We measured associations between c-peptide (a molar marker of insulin secretion), breast cancer risk, and breast density measurements in case-control studies nested within the Nurses’ Health Study and Nurses’ Health Study II cohorts.
Breast cancer associations were estimated with multivariate logistic regression models and then pooled across cohorts (total n=1,084 cases and 1,785 controls). Mammographic density associations (percent dense area, dense area, and non-dense area) were estimated as the difference in least-square means of the density parameters between quartiles of c-peptide concentration in all breast cancer controls with available screening mammography films (n=1,469).
After adjustment for adiposity, c-peptide was not associated with any measure of breast density. However, c-peptide was associated with an approximately 50% increased risk of invasive breast cancer (top vs. bottom quartile, adjusted OR=1.5, 95% CI: 1.1, 2.0) that was robust to adjustment for plasma free estradiol and SHBG. The association was stronger for ER-negative disease (adjusted OR=2.0, 95% CI: 1.2, 3.6).
Our data suggest a positive association between hyperinsulinemia and breast cancer risk that occurs through non-estrogenic mechanisms, and that is not mediated by breast density.
Primary prevention of breast cancer in women with hyperinsulinemia may be possible by targeting insulin signaling pathways.
PMCID: PMC3809910  PMID: 24097198
8.  Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial 
Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-014-3141-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4196136  PMID: 25253174
Metformin; ki-67; Breast cancer; Clinical trial; Insulin resistance; HER2 breast cancer
9.  Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria 
Biochemical Journal  2014;462(Pt 3):475-487.
The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.
Metformin is a widely prescribed anti-diabetic, but its mode of action is disputed. It has been proposed to inhibit respiratory complex I. We show how metformin and related compounds affect both complex I and ATP synthase in mammalian mitochondria.
PMCID: PMC4148174  PMID: 25017630
ATP synthase; biguanide; complex I; metformin; NADH:quinone oxidoreductase; reactive oxygen species (ROS); AMPK, AMP-activated protein kinase; DMEM, Dulbecco’s modified Eagle’s medium; ECAR, extracellular acidification rate; FeCN, ferricyanide; HAR, hexaammineruthenium(III); OCR, oxygen consumption rate; OCT1, organic cation transporter 1; ROS, reactive oxygen species; SMP, submitochondrial particle
10.  Hyperglycemia, Insulin Resistance, Impaired Pancreatic β-Cell Function, and Risk of Pancreatic Cancer 
Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.
This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided.
The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001).
Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.
PMCID: PMC3714020  PMID: 23847240
11.  Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism 
Cancer research  2013;73(14):4429-4438.
Metformin inhibits cancer cell proliferation and epidemiology studies suggest an association with increased survival in cancer patients taking metformin, however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation while increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer.
PMCID: PMC3930683  PMID: 23687346
13.  Inflammatory Plasma Markers and Pancreatic Cancer Risk: a Prospective Study of 5 U.S. Cohorts 
Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α-receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1094 controls from Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL6, and TNF-αR2 and risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 (95% CI, 0.74-1.63; Ptrend= 0.81) for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, pre-diagnostic levels of circulating CRP, IL6, and TNF-αR2 were not associated with risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
PMCID: PMC3650127  PMID: 23462920
14.  Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial 
Osteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis.
We measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/− octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14).
Plasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels.
The hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study.
Trial registration
PMCID: PMC3978736  PMID: 24451146
15.  A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts 
The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.
To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case–control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P heterogeneity = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P trend = .04). Restricted cubic spline regression confirmed a nonlinear association (P nonlinearity < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P interaction > .10).
In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.
PMCID: PMC3545904  PMID: 23243202
16.  The Use of Metformin and the Incidence of Lung Cancer in Patients With Type 2 Diabetes 
Diabetes Care  2012;36(1):124-129.
Observational studies have associated metformin use with a decreased risk of lung cancer incidence in patients with type 2 diabetes, but the studies had important methodological shortcomings. The objective of this study was to determine whether metformin use is associated with a decreased risk of lung cancer in patients with type 2 diabetes, while avoiding previous biases.
Using the U.K. General Practice Research Database, we assembled a cohort of patients newly treated with oral hypoglycemic agents (OHAs) between 1988 and 2009. A nested case–control analysis was conducted, where case subjects with lung cancer occurring during follow-up were matched with up to 10 control subjects for age, sex, calendar time, and duration of follow-up. Conditional logistic regression was used to estimate adjusted rate ratios of lung cancer associated with ever use of metformin, along with measures of duration and cumulative dose. Models were adjusted for potential confounders, which included smoking.
The cohort included 115,923 new users of OHAs, with 1,061 patients diagnosed with lung cancer during follow-up (rate 2.0/1,000 person-years). Metformin use was not associated with a decreased rate of lung cancer (rate ratio 0.94 [95% CI 0.76–1.17]). No dose-response was observed by number of prescriptions received, cumulative duration of use, and dose.
Metformin use is not associated with a decreased risk of lung cancer in patients with type 2 diabetes. The decreased risk reported in other observational studies is likely due to bias from methodological shortcomings. Nonetheless, greater consideration should be given to clarify inconsistencies between experimental models and population studies.
PMCID: PMC3526233  PMID: 22923670
17.  Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, growth hormone, and mammographic density in the Nurses' Health Studies 
Higher circulating insulin-like growth factor I (IGF-1) levels have been associated with higher mammographic density among women in some, but not all studies. Also, few studies have examined the association between mammographic density and circulating growth hormone (GH) in premenopausal women. We conducted a cross-sectional study among 783 premenopausal women and 436 postmenopausal women who were controls in breast cancer case–control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989–1990 (NHS) or in 1996–1999 (NHSII), and mammograms were obtained near the time of blood draw. Generalized linear models were used to assess the associations of IGF-1, IGF-binding protein-3 (IGFBP-3), IGF-1:IGFBP-3 ratio, and GH with percent mammographic density, total dense area, and total non-dense area. Models were adjusted for potential confounders including age and body mass index (BMI), among others. We also assessed whether the associations varied by age or BMI. In both pre- and postmenopausal women, percent mammographic density was not associated with plasma levels of IGF-1, IG-FBP-3, or the IGF-1:IGFBP-3 ratio. In addition, GH was not associated with percent density among premenopausal women in the NHSII. Similarly, total dense area and non-dense area were not significantly associated with any of these analytes. In postmenopausal women, IGF-1 was associated with higher percent mammographic density among women with BMI <25 kg/m2, but not among overweight/obese women. Overall, plasma IGF-1, IGFBP-3, and GH levels were not associated with mammographic density in a sample of premenopausal and postmenopausal women.
PMCID: PMC3696995  PMID: 23085768
Insulin-like growth factor 1; Insulin-like growth factor-binding protein-3; Mammographic density; Breast cancer
18.  Glycemic load effect on fasting and post-prandial serum glucose, insulin, IGF-1 and IGFBP-3 in a randomized, controlled feeding study 
European journal of clinical nutrition  2012;66(10):1146-1152.
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 IGFBP-3.
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. 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.
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 to 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/240min) (p<0.01) and 2253±539 (μU/mL/240min) (p<0.01) lower following the low- compared to the high-GL test meal. There was no effect of GL on mean HOMA-IR 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.
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.
PMCID: PMC3463643  PMID: 22892437
Adiposity; Glycemic Index; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Binding Protein 3; Randomized Controlled Trial [Publication Type]
19.  Racial variation in vitamin D cord blood concentration in White and Black male neonates 
Cancer causes & control : CCC  2012;24(1):91-98.
To evaluate racial variation in umbilical cord blood concentration of vitamin D and to explore its correlation with markers of the insulin-like growth factor axis (IGFs) and sex steroid hormones in white and black male neonates.
In 2004/2005 venous umbilical cord blood samples were collected from 75 black and 38 white male neonates, along with maternal and birth characteristics from two hospitals in Maryland, US. 25-hydroxyvitamin D [25(OH)D], and 1,25-dihydroxyvitamin D [1,25(OH)2D] were measured by radioimmunoassay (RIA), testosterone, estradiol and sex hormone binding globulin (SHBG) by immunoassay and IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed.
Mean 25(OH)D levels were lower in black than in white neonates (11.44; 95% CI 10.10–12.95 ng/mL vs. 18.24; 95% CI 15.32–21.72 ng/mL; p<0.0001). Black neonates were at higher risk of suboptimal vitamin D levels [25(OH)D < 20 ng/mL] than whites (84% vs. 63%). 25(OH)D concentrations varied by season in whites but not in blacks and were significantly inversely correlated with mother’s parity (number of live births) in blacks but not in whites. Mean concentration of 1,25(OH)2D did not differ by race. 25(OH)D and 1,25(OH)2D did not correlate with IGFs, sex steroid hormones and SHBG.
Suboptimal vitamin D levels were prevalent especially in blacks and influenced by mother’s parity and by season. The observed vitamin D differences between black and white neonates warrant further evaluation of the etiology of the disparity in chronic diseases in adulthood.
PMCID: PMC3529856  PMID: 23139102
Vitamin D; umbilical cord blood; black and white Americans
20.  Alterations in Cellular Energy Metabolism Associated with the Antiproliferative Effects of the ATM Inhibitor KU-55933 and with Metformin 
PLoS ONE  2012;7(11):e49513.
KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT), we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation.
PMCID: PMC3504012  PMID: 23185347
21.  Serum C-Reactive Protein and Risk of Pancreatic Cancer in Two Nested, Case-Control Studies 
Many epidemiologic studies have examined the association between CRP and risk of cancer with inconsistent results.
We conducted two nested, case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial to test whether pre-diagnostic circulating CRP concentrations were associated with pancreatic adenocarcinoma. Between 1985 and 2004, 311 cases occurred in ATBC and between 1994 and 2006, 182 cases occurred in PLCO. Controls (n=510 in ATBC, n=374 in PLCO) were alive at the time the case was diagnosed and were matched by age, date of blood draw, sex, and race. We used conditional logistic regression adjusted for smoking to calculate odds ratios (OR) and 95% confidence intervals (CI) for pancreatic cancer.
CRP concentrations (ng/ml) tended to be inversely or not associated with pancreatic cancer risk in ATBC, PLCO, and combined analyses (per standardized quintile increase in CRP, continuous OR= 0.94, 95% CI 0.89, 0.99; OR=0.99, 95% CI 0.95, 1.04; OR=0.98, 95% CI 0.95, 1.01, respectively). In combined analyses, we observed a significant interaction (p-interaction=0.02) such that inverse associations were suggestive in younger (OR=0.95; 95% CI, 0.90–1.01), but not older participants.
Our results do not support the hypothesis that higher CRP concentrations are associated with incident pancreatic cancer.
Our results highlight the importance of investigating more specific biomarkers for inflammation that may reflect the biological mechanisms underlying pancreatic cancer in prospective cohort studies.
PMCID: PMC3495286  PMID: 21173171
CRP; ATBC; PLCO; Pancreatic; Case-Control
22.  Body Size in Early Life and Adult Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 
American Journal of Epidemiology  2011;174(6):642-651.
Body size in early life has been associated with breast cancer risk. This may be partly mediated through the insulin-like growth factor (IGF) pathway. The authors assessed whether birth weight, body fatness at ages 5 and 10 years, and body mass index (BMI; weight (kg)/height (m)2) at age 18 years were associated with plasma concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 in 6,520 women aged 32–70 years at blood draw from the Nurses’ Health Study (1990–2006) and Nurses’ Health Study II (1997–2005). Birth weight, body fatness in childhood, and BMI at age 18 years were inversely associated with adult IGF-1 levels. For example, IGF-1 levels were 11.9% lower in women who reported being heaviest at age 10 years than in those who were leanest at age 10 (P-trend < 0.0001). Further, women who reported their birth weight as ≥10 pounds (≥4.5 kg) (vs. <5.5 pounds (<2.5 kg)) had 7.9% lower IGF-1 levels (P-trend = 0.002). Women whose BMI at age 18 years was ≥30 (vs. <20) had 14.1% lower IGF-1 levels (P-trend < 0.0001). Similar inverse associations were observed for insulin-like growth factor binding protein 3. These observations did not vary by adult BMI or menopausal status at blood draw. These findings suggest that altered IGF-1 levels in adulthood may be a mechanism through which early-life body size influences subsequent breast cancer risk.
PMCID: PMC3166705  PMID: 21828371
birth weight; body mass index; breast neoplasms; child; growth; insulin-like growth factor 1; insulin-like growth factor binding protein 3; obesity
23.  Racial variation in umbilical cord blood sex steroid hormones and the insulin-like growth factor axis in African-American and white female neonates 
Cancer causes & control : CCC  2012;23(3):445-454.
To evaluate whether there is racial variation in venous umbilical cord blood concentrations of sex steroid hormones and the insulin-like growth factor (IGF)-axis between female African-American and white neonates.
Maternal and birth characteristics and venous umbilical cord blood samples were collected from 77 African-American and 41 white full-term uncomplicated births at two urban hospitals in 2004 and 2005. Cord blood was measured for testosterone, dehydroespiandrosterone-sulfate (DHEAS), estradiol, sex-steroid hormone binding globulin (SHBG) by immunoassay. IGF-1, IGF-2, and IGF binding protein-3 (IGFBP-3) were measured by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed for the hormones.
African-American neonates weighed less at birth (3,228 vs. 3,424 grams, p<0.004) than whites. Birth weight was positively correlated with IGF-1, IGFBP-3 and the molar ratio of IGF1 to IGFBP-3, but inversely correlated with the molar ratio of IGF-2 to IGFBP-3. Adjusted models showed higher testosterone (1.82 vs. 1.47 ng/mL, p=0.006) and the molar ratio of testosterone to SHBG (0.42 vs. 0.30, p=0.03) in African-American compared to white female neonates. IGF-1, IGF-2, and IGFBP-3 were lower in African-American compared to white female neonates, but only the difference for IGF-2 remained significant (496.5 vs. 539.2 ng/mL, p=0.04).
We provide evidence of racial variation in cord blood testosterone and testosterone to SHBG in African-American compared to white female neonates, and higher IGF-2 in white compared to African-American female neonates. Findings suggest plausible explanations for a prenatal influence on subsequent breast cancer risk and mortality. Further work is needed to confirm these observations.
PMCID: PMC3333795  PMID: 22252677
umbilical cord blood; IGF axis; sex steroid hormones; African American
24.  Vitamin D Status in Patients With Stage IV Colorectal Cancer: Findings From Intergroup Trial N9741 
Journal of Clinical Oncology  2011;29(12):1599-1606.
Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival, but the prevalence of vitamin D deficiency in advanced colorectal cancer and its influence on outcomes are unknown.
Patients and Methods
We prospectively measured plasma 25(OH)D levels in 515 patients with stage IV colorectal cancer participating in a randomized trial of chemotherapy. Vitamin D deficiency was defined as 25(OH)D lower than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as ≥ 30 ng/mL. We examined the association between baseline 25(OH)D level and selected patient characteristics. Cox proportional hazards models were used to calculate hazard ratios (HR) for death, disease progression, and tumor response, adjusted for prognostic factors.
Among 515 eligible patients, 50% of the study population was vitamin D deficient, and 82% were vitamin D insufficient. Plasma 25(OH)D levels were lower in black patients compared to white patients and patients of other race (median, 10.7 v 21.1 v 19.3 ng/mL, respectively; P < .001), and females compared to males (median, 18.3 v 21.7 ng/mL, respectively; P = .0005). Baseline plasma 25(OH)D levels were not associated with patient outcome, although given the distribution of plasma levels in this cohort, statistical power for survival analyses were limited.
Vitamin D deficiency is highly prevalent among patients with stage IV colorectal cancer receiving first-line chemotherapy, particularly in black and female patients.
PMCID: PMC3082978  PMID: 21422438
25.  A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3 
Human Molecular Genetics  2011;20(6):1241-1251.
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10−8 (P = 3.3 × 10−101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10−26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10−21) and higher IGF-I (P = 4.9 × 10−9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10−11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10−10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10−7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
PMCID: PMC3043664  PMID: 21216879

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