AS129 - Association of diabetes and insulin-like growth factor-I (IGF-I) with risks of colorectal, breast, and endometrial cancer
Investigator Names and Contact Information
Howard Strickler (howard.strickler@einsteinmed.org)
Introduction/Intent
Increasing evidence indicates that high serum insulin-like growth factor-I (IGF-I) is associated with elevated risk of colorectal, breast, and endometrial cancer. Three Insulin Resistance Syndrome-related conditions, type 2 diabetes, obesity, and sedentary lifestyle, are also associated with greater risk of these cancers, and hyperinsulinemia is hypothesized to drive these relationships, at least in part. Insulin shares 40% sequence homology with IGF-I, and biological studies indicate that they are both mitogens. However, few epidemiologic studies have evaluated cancer risk based on insulin levels, and none have been prospective with sufficient sample size or adequate control for confounders. Similarly, there are sparse epidemiologic data regarding free IGF-I and cancer, even though the unbound form is the main bioactive component.
An initial cross-sectional pilot study by our group found that free IGF-I was more strongly associated with breast cancer than total IGF-I (see Reprint #5). To provide definitive evidence of their associations with cancer, a prospective epidemiologic investigation of insulin and free IGF-I is needed. Studies must also consider histologic type, grade of neoplasia, stage at diagnosis and, in breast cancer, estrogen receptor status, since insulin and IGF-I both have effects on the estrogen receptor. The potential impact of race on these associations is another gap in our knowledge. Few minority women were included in previous investigations, even though rates of diabetes, the relation of obesity and mortality, serum IGF-I levels, and risks of cancer, all vary by race. Moreover, little is known regarding the factors that influence IGF-I levels in elderly women.
The purpose of this application is to prospectively study the effects of high serum levels of insulin and free IGF-I on risk of colorectal, breast and endometrial cancer in postmenopausal women. Specimens and data will be obtained from the Observational Study (OS) of the Women’s Health Initiative (WHI), a large (n=93,725), ethnically and geographically diverse cohort of postmenopausal women aged 50-79. We propose conducting a case-cohort investigation, testing baseline serum samples for fasting levels of glucose, insulin, total and free IGF-I, IGF binding protein-3 (IGFBP-3), and total estradiol. WHI-OS subjects selected for this study will have been in the cohort an average of 7 years, with cases excluded if diagnosed during the first 18 months. We will study all colorectal (n=500), endometrial (n=300), and half of the 1900 breast cancer (n=900) cases that are expected, as well as a random subset of the whole cohort (subcohort n=900), to address the following specific aims:
- To prospectively study the independent effects of high serum insulin and free IGF-I on risk of colorectal, breast and endometrial cancer in postmenopausal women, by using a case-cohort investigation to assess:
- The relation of fasting levels of glucose and insulin, insulin resistance (i.e., HOMA index - a measure of the glucose/insulin steady state calculated from fasting levels), total estradiol, total and free IGF-I, as well as IGFBP-3, with incident cancers.
- The strengths of these associations according to histologic type, tumor grade, stage at diagnosis and, in the case of breast cancer, sex hormone receptor status.
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To determine within the subcohort the factors related to levels of total IGF-I, free IGF-I and IGFBP-3, including age, race, obesity, hormone replacement therapy, use of insulin, prescription medicines, nutrition (e.g., food frequency questionnaire data), and lifestyle factors (e.g., exercise). These results will be essential in assessing confounders in Specific Aim #1 and, moreover, it will be of scientific, perhaps clinical, relevance to identify the modifiable and unmodifiable factors correlated with IGF-I levels.
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To assess whether type 2 diabetes is an independent risk factor for colorectal, breast and endometrial cancer, after controlling for insulin resistance (HOMA index), total IGF-I, free IGF-I and IGFBP-3, by:
- Using fasting glucose levels to find subjects with undiagnosed diabetes (fasting glucose >125 mg/dl) and impaired fasting glucose (IFG; fasting glucose 110-125 mg/dl), a source of misclassification in most earlier studies, and which together involve >15% of women over age 50.
- Studying the risk of incident cancers in diabetics relative to those without either diabetes or IFG.
Materials/Methods
This study proposes an investigation to prospectively study the effects of high insulin and insulin-like growth factor-I (IGF-I) levels on risk of colorectal, breast, and endometrial cancers in postmenopausal women. Baseline serum specimens will be obtained from the Women’s Health Initiative (WHI) Observational Study (OS), a large (n=93,725), ethnically and geographically diverse cohort of postmenopausal women aged 50-79 at baseline, enrolled between 1993-1998, and followed annually.
A case-cohort design will be used because it is more efficient than nested case-control for evaluation of multiple outcomes.
Results/Findings
Some of the publications related to this ancillary study are: 459, 460, 461, 1173.
Ms459 - Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Manson JE, Li J, Harris TG, Rohan TE, Xue X, Ho GY, Einstein MH, Kaplan RC, Burk RD, Wylie-Rosett J, Pollak MN, Anderson G, Howard BV, Strickler HD. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):921-9.
Ms460 - Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Howard BV, Wylie-Rosett J, Anderson GL, Ho GY, Kaplan RC, Li J, Xue X, Harris TG, Burk RD, Strickler HD. Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res. 2008 Jan 1;68(1):329-37.
Ms461 - Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009 Jan 7;101(1):48-60. Epub 2008 Dec 30.
Ms1173 - Hvidtfeldt UA, Gunter MJ, Lange T, Chlebowski RT, Lane DS, Farhat GN, Freiberg MS, Keiding N, Lee JS, Prentice R, Tjonneland A, Vitolins MZ, Wassertheil-Smoller S, Strickler HD, Rod NH. Quantifying mediating effects of endogenous estrogen and insulin in the relation between obesity, alcohol consumption and breast cancer. Cancer Epidemiol Biomarkers Prev. 2012 May 7. [Epub ahead of print]
For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.
Data Dictionaries and Study Documentation
This section displays all study-related data dictionaries and study-related files. The investigators for this study will upload the datasets, data dictionaries, and other study-related files. Study-related files will be made available to the public one year after the completion of the ancillary study, with the exception of the datasets, which will only be available to those with a Data Distribution Agreement. Those will be available to those with permission to download and will appear as a download link next to the data dictionary
Data Dictionaries
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Study Documents
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| NameAS129 subject selection 1-30-02 summary.pdf | Description |
