1 Division of Cancer Prevention and Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
2 Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN.
3 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
4 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
Received for publication October 9, 2001; accepted for publication May 7, 2002.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
breast neoplasms; glucose; insulin
Abbreviations: Abbreviation: ARIC, Atherosclerosis Risk in Communities.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Type 2 diabetes has been hypothesized to be associated with breast cancer risk, because of its association with obesity and insulin. However, results from epidemiologic studies have been inconsistent (713).
The main purpose of this prospective study was to examine the association of breast cancer with fasting insulin level, fasting glucose level, and diabetes and to evaluate the role that these factors might play in breast cancer etiology.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Baseline measurements
Data on a wide range of physiologic and lifestyle factors, including anthropometric measures, were collected by trained staff. Interviewers collected information on age at menarche, menopausal status, age at menopause, number of pregnancies, number of livebirths, history (and age) of hysterectomy and/or oophorectomy, use of oral contraceptives, hormone replacement therapy, smoking, physical activity, usual alcohol intake, and previous cancer diagnoses. Participants were also asked whether they had ever been diagnosed with diabetes and whether they were taking medication to control diabetes.
A fasting blood sample was taken from each participant. Serum glucose level was assayed by a hexokinase/glucose-6-phosphate dehydrogenase method. Serum insulin level was assessed by nonspecific radioimmunoassay (123Insulin Kit; Cambridge Medical Diagnostics, Inc., Billerica, Massachusetts). Reliability coefficients for insulin and glucose, obtained in subjects who were examined several times, were 0.81 and 0.84, respectively (16).
ARIC cancer questionnaire
In 1994, ARIC staff administered a supplemental questionnaire by telephone to collect data on additional cancer risk factors not measured as part of the ARIC Study. Of the 8,710 female ARIC participants, 8,140 (93 percent) responded to this questionnaire. Information requested included age at first birth and history of any cancer (including site and age of onset) in first-degree relatives.
Ascertainment of incident breast cancer cases
Incident cancers diagnosed among ARIC cohort members between January 1, 1987, and December 31, 1995, were ascertained by two methods: linkage to a cancer registry and/or medical record review of potential cases identified through the annual follow-up of the ARIC cohort via telephone. Three of the four ARIC communities are covered by state and/or county cancer registries, including the Minnesota Cancer Surveillance System, the North Carolina Central Cancer Registry, the Washington County (Maryland) Cancer Registry, and the (statewide) Maryland Cancer Registry. To identify cases in Jackson, Mississippi, which has no cancer registry, and to identify additional missed cancer cases in the other three ARIC communities, staff retrieved medical records for participants who reported having a cancer-related hospitalization during annual follow-up telephone calls. Information related to the cancer diagnosis, including primary site, date of diagnosis, and source of diagnostic information (e.g., a pathology report), was abstracted from the medical records by study staff.
Data analysis
The cohort for this analysis included 7,894 Black and White female ARIC cohort participants who had fasted for at least 8 hours prior to the baseline clinic visit and did not report a history of cancer at baseline. An additional 817 women with prevalent diabetes or unknown diabetes status at baseline were excluded from analyses of insulin levels. Women were considered to have prevalent diabetes if they reported a history of diabetes or pharmacologic treatment for diabetes or if they had a fasting glucose level of at least 126 mg/dl or a nonfasting glucose level of at least 200 mg/dl (17).
Person-years at risk were calculated for each participant as time between the baseline examination date and December 31, 1995, or the date of breast cancer diagnosis, death, or loss to follow-up, whichever occurred first. We created quintiles for fasting insulin level. We created a three-level categorical variable for fasting glucose level, with the upper level comprising women who met our definition of prevalent diabetes. The SAS procedure PHREG (SAS Institute, Inc., Cary, North Carolina) was used to fit Cox proportional hazards regression models. The final multivariable model included factors that were associated with breast cancer incidence or that acted as confounders by influencing the parameter estimate for the independent variable of interest.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Breast cancer incidence in the ARIC cohort was associated with most accepted risk factors for breast cancer, including younger age at menarche, later age at first birth, family history of breast cancer, and alcohol intake (data not shown). There was no apparent association of body mass index with breast cancer among women aged 4550 years at baseline; however, there were only 51 cases in this age group, and the 95 percent confidence intervals were wide. Multivariate-adjusted relative risks for increasing quintiles of body mass index among older women were 1.00 (referent), 1.82, 1.32, 1.59, and 1.79 (p trend = 0.28). There was no association of breast cancer incidence with waist:hip ratio.
Table 1 shows the prevalence of breast cancer risk factors across quintiles of fasting serum insulin level. Insulin levels were higher in women who were older, those who were younger at menarche, and those who were physically inactive; insulin levels were lower in women who were Caucasian, those who were more educated, and those who currently used hormone replacement therapy, drank alcohol, or smoked. Fasting insulin level increased across quintiles of body mass index and waist:hip ratio and was relatively constant across quintiles of height (data not shown). There was no association of fasting insulin with breast cancer incidence (table 2). However, the age-, race-, and center-adjusted relative risks of breast cancer were 1.32 (95 percent confidence interval: 0.96, 1.81) for fasting glucose levels of 100125 mg/dl and 1.60 (95 percent confidence interval: 1.02, 2.50) for diabetic women in comparison with the referent level (<100 mg/dl). These associations, not unexpectedly, were attenuated after body mass index was added to the regression model, and they were attenuated further with the addition of other breast cancer risk factors. After multivariable adjustment, including adjustment for body mass index, the relative risk for diabetic women versus the referent women was 1.39 (95 percent confidence interval: 0.86, 2.23). There was no evidence of effect modification by age group (50 years vs. >50 years) for either insulin or glucose.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Laakso (18) has reported that fasting insulin level is a moderately good measure of insulin resistance among subjects with normal glucose tolerance (r = 0.66). Because insulin resistance is a characteristic of type 2 diabetes and has been implicated in the promotion of breast cancer cell proliferation in vitro and in increased insulin-like growth factor activity in breast tissue, diabetes may be associated with increased breast cancer risk (9, 10, 12). Results from epidemiologic studies of breast cancer and diabetes have not provided strong support for this hypothesis (9), although in two recent studies investigators reported modest positive associations of breast cancer with type 2 diabetes (11, 12). However, in one of those studies, researchers could not adequately take into account the contribution of obesity (12). In the ARIC Study, we found that the age-, race-, and center-adjusted relative risk for the association between diabetes and breast cancer decreased from 1.60 to 1.48 after additional adjustment for body mass index, and the risk was further attenuated to 1.39 by further multivariate adjustment (table 2).
Strengths of the ARIC Study include the ability to identify women with undiagnosed (or unreported) diabetes, to fully adjust for body mass index, and to examine dose-response for fasting glucose and breast cancer incidence. However, data from this study did not support our main hypothesis that serum insulin level is associated positively with breast cancer incidence. Although there was no association of fasting insulin level with breast cancer incidence, a modest positive, independent association of diabetes with the disease cannot be ruled out entirely.
![]() |
ACKNOWLEDGMENTS |
---|
The authors thank the staff of the Atherosclerosis Risk in Communities Study for their important contributions.
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|