Type of breast cancer

OBJECTIVE -- Hyperinsulinemia may promote mammary carcinogenesis. Insulin resistance has been linked to an increased risk of breast cancer and is also characteristic of type 2 diabetes. We prospectively evaluated the association between type 2 diabetes and invasive breast cancer incidence in the Nurses' Health Study.

RESEARCH DESIGN AND METHODS -- A total of 116,488 female nurses who were 30-55 years old and free of cancer in 1976 were followed through 1996 for the occurrence of type 2 diabetes and through 1998 for incident invasive breast cancer, verified by medical records and pathology reports.

RESULTS -- During 2.3 million person-years of follow-up, we identified 6,220 women with type 2 diabetes and 5,189 incident cases of invasive breast cancer. Women with type 2 diabetes had a modestly elevated incidence of breast cancer (hazard ratio [HR] = 1.17; 95% CI 1.01- 1.35) compared with women without diabetes, independent of age, obesity, family history of breast cancer, history of benign breast disease, reproductive factors, physical activity, and alcohol consumption. This association was apparent among postmenopausal women (1.16; 0.98- 1.62) but not premenopausal women (0.83; 0.48-1.42). The association was predominant among women with estrogen receptor--positive breast cancer (1.22; 1.01-1.47).

CONCLUSIONS -- Women with type 2 diabetes may have a slightly increased risk of breast cancer.

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Breast cancer incidence is higher in more affluent countries and among women with high socioeconomic status (1,2). Although lower parity, delayed childbearing, and higher alcohol consumption in high socioeconomic status populations may explain part of this observation (2), a lifestyle characterized by sedentary routines (3) and possibly a diet high in refined carbohydrates, sugars, and animal fats may also play an important role. This Western lifestyle often results in insulin resistance, a condition characterized by a decreased sensitivity of target tissues to circulating insulin and compensatory hyperinsulinemia (4). Insulin inhibits the production of sex hormone-binding globulin (SHBG) (5,6), which results in an increase in free steroid hormones, free estrogens in particular, because testosterone successfully competes with estrogen for SHBG (7).

Insulin is also a growth-promoting hormone with mitogenic effects in both normal and malignant breast tissue (8,9). Insulin suppresses IGF binding protein-1 and thus increases bioavailable IGF-1 (10). The effect of estradiol on hormone-dependent breast cancer cell proliferation may depend on the presence of insulin or IGE (9,11).

Insulin resistance coupled with an insulin secretory defect causes type 2 diabetes. Hyperinsulinemia with insulin resistance also has been postulated to increase the risk of breast cancer (12-14). Obesity is associated with type 2 diabetes and leads to a rise in endogenous estrogen levels.

With the worldwide increase in obesity and type 2 diabetes, an association between type 2 diabetes and breast cancer might have public health implications. We used data from the large ongoing Nurses' Health Study cohort to investigate whether type 2 diabetes is associated with subsequent incidence of breast cancer independent of adiposity.

RESEARCH DESIGN AND METHODS

Population

The Nurses' Health Study was established in 1976 when 121,700 female registered nurses 30-55 years of age completed a mailed questionnaire on their health status and on various potential risk factors for cancer, cardiovascular disease, and other major illnesses. Participants receive follow-up questionnaires biennially to update information on demographic, anthropometric, and lifestyle factors and on newly diagnosed diseases including diabetes and breast cancer. The response rate still exceeds 90%. The Nurses' Health Study was approved by the institutional review board of the Brigham and Women's Hospital (Boston, MA).

Diabetes confirmation and validation

All women who report a physician diagnosis of diabetes on the biennial questionnaire are mailed a supplemental questionnaire requesting detailed information on diagnosis, laboratory results, and treatment. Participants who confirmed a diagnosis of diabetes on this supplementary questionnaire were considered to have "definite" type 2 (non-insulin-dependent) diabetes if they met the National Diabetes Data Group criteria for diabetes (15), did not meet criteria for type 1 (insulin-dependent and ketosisprone) diabetes, and were diagnosed at age [greater then or equal to]30 years. No weight criteria were used in the type 2 classification. Only women with definite type 2 diabetes were classified as diabetic in this analysis; women who reported a diagnosis of diabetes on the main questionnaire but were classified as probable or unlikely on the basis of supplementary questionnaire information and women who were classified as having type 1 diabetes were excluded from this analysis.

The validity of supplementary questionnaires to confirm and characterize diabetes type was evaluated in a random subsample of Nurses' Health Study participants with self-reported type 2 diabetes (16). Of 84 women contacted, 71 gave permission for medical record review; records were obtained for 62 women. Self-reports of type 2 diabetes were confirmed by medical record review by an endocrinologist for 61(98%) of the cases.

The diagnostic criteria for diabetes were changed by the American Diabetes Association in 1997 (17). Because we assessed diabetes only up to 1996 for this analysis, the change in criteria did not affect our diabetes definition.

Information on diabetes medication (insulin and sulfonylureas) was obtained from the main and supplementary questionnaires.

Identification of breast cancer

On each biennial questionnaire, participants were asked whether they had been newly diagnosed with breast cancer during the previous 2 years, and if so, what was the date of diagnosis. The National Death Index is also routinely searched for deaths among women who do not respond to the questionnaires. All women who reported breast cancer (or the next of kin for those who had died) were asked for permission to review the relevant medical records to confirm the diagnosis. Pathology reports, obtained for 93% of the cases, confirmed breast cancer in >99% of women whose reports were reviewed. Although medical records could not be obtained for 7% of the cases, analyses were based on all reports of newly diagnosed breast cancer, because the degree of accuracy of the participants' reports was extremely high among those for whom records were obtained. Cases of breast carcinoma in situ (n = 612) were censored from this analysis because we do not follow them further for the occurrence of invasive breast cancer in our coh ort. Only a fraction of in situ breast cancers progresses to become invasive. We excluded ductal carcinoma in situ as end point because differential use of preventive services could lead to higher detection of carcinoma in situ and lead to spurious associations. Diabetic women see providers more often than healthy women and therefore might have greater access to screening.

Population for analysis

Women who reported cancer (except for nonmelanoma skin cancer) at baseline in 1976 were excluded from the analyses (n = 3,302), as were those who reported type 1 diabetes (n = 497) or type 2 diabetes that was not confirmed by the supplementary questionnaire (n = 1,091) or if their date of diagnosis of diabetes was missing (n = 4). Women who reported onset of diabetes before age 30 years were excluded from the study population, as they were more likely to have type 1 diabetes (n = 112). Participants also were excluded if their date of birth was missing (n = 27), if they died shortly after agreeing to participate in the study (n = 2), if they did not report their height (n = 149), or if they developed breast cancer during follow-up but their date of diagnosis was not available (n = 29). This left a study population of 116,488 women. During follow-up, women were censored from the analysis if they developed breast cancer or any other cancer, if they died, or if they were lost to follow-up.

Statistical analysis