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[Cancer Research 66, 2869-2875, March 1, 2006]
© 2006 American Association for Cancer Research

Epidemiology and Prevention

A Prospective Study of Hemoglobin A1c Concentrations and Risk of Breast Cancer in Women

Jennifer Lin1, Paul M. Ridker1,2,3, Nader Rifai2,5, I-Min Lee1,6, JoAnn E. Manson1,4,5,6, Julie E. Buring1,6,7 and Shumin M. Zhang1,6

1 Division of Preventive Medicine, 2 Center for Cardiovascular Disease Prevention, 3 The Donald W. Reynolds Center for Cardiovascular Research, Department of Medicine, and 4 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; 5 Department of Laboratory Medicine, Children's Hospital and Harvard Medical School; 6 Department of Epidemiology, Harvard School of Public Health; and 7 Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Jennifer Lin, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215. Phone: 617-278-0894; Fax: 617-232-3541; E-mail: jhlin{at}rics.bwh.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Impaired glucose metabolism and hyperinsulinemia have been hypothesized to increase breast cancer risk. However, findings from observational studies relating blood concentrations of hyperinsulinemia markers to breast cancer risk have been inconsistent. We prospectively evaluated whether hemoglobin A1c (HbA1c) concentrations predict breast cancer risk in a large female cohort. We included 27,110 female participants of the Women's Health Study who were, at baseline, free of cancer and had usable blood specimens as well as sufficient information on potential risk factors for breast cancer. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazards regression models. All Ps were two sided. During an average of 10 years of follow-up, 790 incident cases of invasive breast cancer were confirmed. Higher baseline HbA1c levels were not associated with an increased risk of breast cancer. The multivariate RR for the highest relative to the lowest quintile of HbA1c levels was 0.87 (95% CI, 0.69-1.10; Ptrend = 0.22). Higher HbA1c levels were also not associated with an increased risk of breast cancer according to alternative clinical cutoff points for HbA1c or in the analyses stratified by body mass index or according to certain tumor characteristics. However, a weakly inverse association was noted among postmenopausal women, especially among those who had never used hormone therapy. There was also a weakly inverse association between HbA1c levels and estrogen receptor–negative breast tumors. These data suggest that higher HbA1c concentrations do not seem to increase risk of breast cancer among apparently healthy women. (Cancer Res 2006; 66(5): 2869-75)


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Obesity has been suggested to increase risk of breast cancer among postmenopausal women (1, 2). Obesity has also been related to advanced disease at diagnosis and with a poor prognosis in both premenopausal and postmenopausal breast cancer (3–6). Insulin has been proposed as the potential mediating factor of these observations, because obesity is associated with hyperinsulinemia and insulin resistance (7). Insulin is a mitogenic agent that also has direct effects on the development of breast cancer pathogenesis (8–10).

Observational studies have provided inconsistent evidence for a positive association between hyperinsulinemia and risk of breast cancer. Some (11–13) but not all (14–17) studies reported an elevated risk of breast cancer among women with type 2 diabetes. Studies evaluating blood concentrations of hyperinsulinemia markers, such as circulating levels of glucose and insulin in relation to breast cancer risk, have also yielded inconclusive findings. Some studies have observed a positive association with breast cancer risk (18–24), whereas other studies have found no association (13, 25–29).

Because blood insulin and glucose levels are heavily influenced by recent meals, fasting blood samples are needed to obtain accurate measurement. However, not all findings on the association between hyperinsulinemia and breast cancer risk were based on fasting blood samples (20, 26), which may have contributed in part to the differences between studies. Hemoglobin A1c (HbA1c), another common measure for glucose metabolism, can be measured at any time of the day regardless of the length of fasting or the content of the previous meal (30). HbA1c reflects average glucose level over the past 6 to 8 weeks (31), which has been suggested to be a good marker for chronic hyperinsulinemia (32, 33). We therefore evaluated HbA1c concentrations in relation to risk of breast cancer. To our knowledge, the present study is the first large prospective cohort evaluating this association. Because of the complexity of breast cancer etiology, we further examined whether the association would be modified by several plausible biological factors, including sex hormone exposures and body mass index (BMI), and be varied by tumor characteristics.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study cohort. The Women's Health Study (WHS) is a completed randomized trial evaluating low-dose aspirin and vitamin E for the primary prevention of cancer and cardiovascular disease (34–36). Beginning in 1993, 39,876 female professionals in the United States ages ≥45 years and free of cancer and cardiovascular disease were enrolled into the trial. On enrollment in the trial, participants completed a baseline questionnaire about their medical history and potential risk factors for breast cancer. Participants were also asked to fill out a 131-item food frequency questionnaire, which asked the average use of food and beverages during the past year. Blood samples were collected in both EDTA and citrate tubes from 28,345 women (71% of the total WHS cohort) before randomization and were stored in liquid nitrogen freezers at –170°C. Women in both treatment assignment and placebo groups were included in the present study.

HbA1c concentrations were measured by turbidometric immunoassay in RBC using the Hitachi 911 Analyzer (Roche Diagnostics, Indianapolis, IN), and the coefficient of variation for quality control samples was 7.2%. The current analysis was limited to 27,110 women who had usable HbA1c data as well as sufficient information on potential risk factors for breast cancer. In a sample of 394 women in our cohort, HbA1c levels were moderately related to circulating insulin levels (Spearman correlation = 0.22; ref. 37).

Ascertainment of invasive breast cancer cases. Every 6 months during the first year of follow-up and then annually thereafter, we asked participants whether they had been newly diagnosed with end points of interest, including breast cancer. For those who reported a diagnosis of breast cancer and for those who were deceased, we sought permission to obtain medical records and pathology reports. The Endpoint Committee of Physicians then reviewed the records to confirm the diagnosis. During an average of 10 years of follow-up between 1993 and 2004, we documented 790 incident cases of invasive breast cancer.

Statistical analysis. We first categorized women according to quintiles of HbA1c levels among all women and compared mean values or proportions of baseline risk factors for breast cancer according to these quintiles. For the analysis of invasive breast cancer, we also grouped women into five categories of HbA1c levels with increments of 0.5%: <5.0%, 5.0% to <5.5%, 5.5% to <6.0%, 6.0% to <6.5%, and ≥6.5%, which are more clinically relevant cutoff points.

We used Cox proportional hazards regression to estimate relative risks (RR) and 95% confidence intervals (95% CI) for invasive breast cancer, comparing the incidence rate for a given quintile or category of HbA1c with the rate for the lowest quintile or the referent category. Analyzed models were first adjusted for age (in years) and randomized treatment assignment (aspirin versus placebo, vitamin E versus placebo). The multivariate models were additionally adjusted for risk factors for breast cancer assessed at baseline, including BMI [weight (kg) / height (m)2; <25, 25 to <30, ≥30 kg/m2], physical activity (total expenditure in kcal/wk, in quartiles), family history of breast cancer in a first-degree relative (yes, no), history of benign breast disease (yes, no), age at menarche (≤11, 12, 13, ≥14 years), parity (0, 1-2, 3-4, ≥5 children), age at first birth (≤19, 20-24, 25-29, ≥30 years), menopausal status (premenopausal, postmenopausal), postmenopausal hormone therapy (never, past, current), multivitamin use (never, past, current), smoking status (never, past, current), alcohol consumption (never, 0.1 to <5, 5 to <15, ≥15 g/d), and total energy intake (kcal/d, in quintiles). We further examined whether the association between HbA1c levels and breast cancer risk differed according to the strata of menopausal status (premenopausal, postmenopausal), postmenopausal hormone therapy use (never, past, current), BMI (<25, 25 to <30, ≥30 kg/m2), aspirin treatment assignment (yes, no), and vitamin E treatment assignments (yes, no). We also examined the association according to hormone receptor status [estrogen receptor (ER)–positive, ER-negative, progesterone receptor (PR)–positive, PR-negative, positive for both ER and PR], tumor size (≤2, >2 cm), lymph node metastasis (yes, no), and tumor grade (well, moderately, and poorly differentiated).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In this prospective cohort of women, mean ± SD values of baseline HbA1c concentrations were 5.1 ± 0.6% among all women, 5.0 ± 0.5% among 7,442 premenopausal women, and 5.1 ± 0.7% among 14,786 postmenopausal women. Only 3.1% of all women in this cohort had HbA1c levels of ≥6.0%.

Table 1 presents the baseline characteristics of all women according to quintiles of HbA1c concentrations. Women who had higher HbA1c levels tended to be older, heavier, and physically inactive and were more likely to be current smokers but less likely to receive mammogram screening and be current users of postmenopausal hormone therapy and multivitamins. They also were less likely to report a previous history of benign breast disease but more likely to report having had a history of diabetes at baseline (Table 1). Women with higher HbA1c levels also consumed less alcohol but had higher intake of total calories. Family history of breast cancer, parity, age at first birth, and age at menarche did not seem to differ substantially across the quintiles of HbA1c levels.


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  		Table 1. Age-adjusted baseline characteristics according to quintiles of HbA1c levels among 27,110 women in the WHS, 1993-2004

 
Higher HbA1c levels were not associated with an elevated risk of breast cancer based on the quintile distribution among all women in the crude model adjusted for age and random treatment assignment (Table 2). Additional adjustment for risk factors for breast cancer did not materially change the results; the multivariate RR comparing the highest with the lowest quintile of HbA1c levels was 0.87 (95% CI, 0.69-1.10; Ptrend = 0.22). The results were not appreciably altered in analyses based on alternative categorization of HbA1c levels using clinical cutoff points (Table 2).


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  		Table 2. RR and 95% CI of invasive breast cancer according to categories (in quintiles and using clinical cutoff points) of HbA1c concentrations in the WHS

 
To determine whether diabetes diagnosis at baseline may bias the observed association, we repeated the analysis of invasive breast cancer by excluding 659 women (15 cases of invasive breast cancer) who reported having had a diagnosis of diabetes at baseline. The new results remained unchanged; the multivariate RRs (95% CI) for the higher quintiles were 0.94 (0.76-1.17), 0.86 (0.69-1.08), 0.88 (0.71-1.11), and 0.88 (0.70-1.12; Ptrend = 0.28).

There was no association between HbA1c levels and breast cancer risk among premenopausal women (Table 3). However, a weakly inverse association was seen among postmenopausal women (Table 3). When we further evaluated the association between HbA1c and breast cancer by hormone therapy use among postmenopausal women, the inverse association was mostly seen among never hormone therapy users (Table 3). In addition, we found no significant interactions of HbA1c levels with BMI in relation to breast cancer risk (Table 4). The association between HbA1c levels and breast cancer also did not differ according to aspirin and vitamin E treatment assignments (P for interactions > 0.9).


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  		Table 3. RR and 95% CI of invasive breast cancer according to quintiles of HbA1c concentrations by hormone levels (menopausal status and postmenopausal hormone therapy) in the WHS

 

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  		Table 4. RR and 95% CI of invasive breast cancer according to quintiles of HbA1c concentrations by BMI in the WHS

 
Separate analyses according to various hormone receptor status also did not reveal positive associations with HbA1c levels (Table 5). A weakly inverse association with HbA1c levels was observed for ER-negative breast cancer (P for interaction with ER status = 0.14). No significant associations were found by tumor size and lymph node metastasis (Table 5). Finally, a slightly inverse association was observed with well-differentiated breast tumors.


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  		Table 5. RR and 95% CI of invasive breast cancer according to quintiles of HbA1c concentrations by tumor characteristics in the WHS

 
To address the potential bias of HbA1c measurement due to some clinical symptoms before breast cancer was diagnosed, we did additional analysis by excluding 64 incident cases of breast cancer diagnosed during the first year of follow-up. The new results were not changed (data not shown). In view of the potential effect of screening test, we did the analysis stratified by use of mammogram screening examination; the multivariate RRs (95% CI) for the higher four quintiles were 1.01 (0.77-1.34), 0.86 (0.64-1.15), 1.00 (0.75-1.33), and 0.83 (0.61-1.14; Ptrend = 0.27) among women undergoing the mammogram screening and 0.89 (0.60-1.33), 0.88 (0.60-1.31), 0.71 (0.47-1.08), and 0.87 (0.58-1.30; Ptrend = 0.39) among women not undergoing the mammogram screening.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this prospective study of women, higher HbA1c levels were not associated with an elevated risk of breast cancer. No significant association with HbA1c levels was also observed according to tumor characteristics, such as tumor size and lymph node metastasis. However, a weakly inverse association was noted among postmenopausal women, especially among those who had never used hormone therapy. There was also a weakly inverse association between HbA1c levels and ER-negative breast tumors.

Hyperinsulinemia and impaired glucose metabolism have been linked to an increased risk of breast cancer (38, 39). Possible mechanisms for this association include the direct action of insulin, which promotes the proliferation of breast cancer cells (8–10). Insulin also suppresses hepatic secretion of insulin-like growth factor (IGF)–binding protein-1, thereby increasing the bioavailability of IGF-I (40, 41). IGF-I also has a direct effect on tumor progression by stimulating cell proliferation and by inhibiting apoptosis (42, 43).

To our knowledge, this is the first prospective evaluation of HbA1c concentrations, a marker for impaired glucose metabolism and hyperinsulinemia, in relation to risk of breast cancer among middle-aged and older women. Our finding that HbA1c levels were not significantly associated with breast cancer risk is in accordance with the observation of two previous prospective studies evaluating fasting glucose levels (13, 25). In contrast, a case-control study nested in a large female cohort observed an increased risk of breast cancer with higher fasting glucose levels (24). Studies evaluating serum insulin levels have also yielded mixed results. Two studies observed a positive association between serum insulin levels and breast cancer risk (22, 23), whereas two other studies found no association (26, 27). Blood concentrations of C-peptide, a marker of pancreatic insulin secretion, are positively associated with an increased risk of breast cancer in some (18–21) but not all (27, 28) studies. Inconsistent findings between studies could have resulted from different study design, because most case-control studies (18–21, 23), but not cohort studies (13, 25, 28), reported a positive association between insulin resistance markers and breast cancer risk. A lack of adjustment for several risk factors in most case-control studies may have confounded the observed association. As shown in a cohort study, the association between incidence of diabetes (fasting glucose ≥126 mg/dL or nonfasting glucose level ≥200 mg/dL) and risk of breast cancer was substantially attenuated after adjustment for obesity and several risk factors for breast cancer (29).

Both estrogen and insulin-elevated IGF-I have been shown to synergistically stimulate proliferation of breast cancer cells by inducing changes in the expression of cell cycle components (44, 45). When either action is blocked, inhibition of tumor growth has been observed (46). Accordingly, in the absence of estrogens or when estrogen levels are low, the role of insulin in breast cancer development may be less effective. Indeed, we found that HbA1c levels were not positively associated with breast cancer risk among postmenopausal women, especially among those who had not received postmenopausal hormone therapy. Our findings contrast with four other studies that observed either no difference in the association by menopausal status (18, 19) or a positive association only among postmenopausal women (12, 22). The interaction between estrogens and HbA1c in relation to breast cancer development warrants more investigation.

Because of the combined mutual reinforcing effects of estrogens and IGF-I on breast cancer proliferation (44, 45), the growth effect of IGF-I was found in ER-positive cell lines but was inhibited in ER-negative breast cancer cell lines (47). The Nurses' Health study found that the association with incidence of type 2 diabetes was predominantly with ER-positive breast tumors (12). In addition, a weakly inverse association was noted in our cohort between HbA1c levels and ER-negative breast tumors. The role of PR expression in the association between hyperinsulinemia and breast cancer risk remains unknown. In our cohort, we found that the association was not altered according to PR expression.

Disturbed glucose metabolism and hyperinsulinemia have also been related to a poor prognosis of breast cancer (48). In a prospective study of 512 nondiabetic early-stage breast cancer patients, elevated insulin levels were associated with increased tumor recurrence at distant metastatic sites and shortened overall survival (48). In our cohort, the association between HbA1c levels and breast cancer risk was not changed by tumor size and lymph node metastasis. However, a weakly inverse association between HbA1c and well-differentiated breast tumor grade was observed. It is likely that women with higher HbA1c levels are less likely to be screened for breast cancer. When we examined the potential bias by conducting the analysis stratified by the use of mammogram screening, we found the estimates remained similar, suggesting that our results are unlikely to be explained by screening.

Several limitations present in the study merit further consideration. Although we have adjusted for several potential risk factors for breast cancer in the analytic models, we still cannot exclude the possibility of residual confounding by these factors. In addition, there was possibility that women might have had clinical symptoms before being diagnosed with breast cancer. This concern was minimized by additional analysis with the exclusion of cases diagnosed during the first year of follow-up after blood collection. Moreover, we only used one single baseline measurement for HbA1c. However, HbA1c levels are reportedly stable over time (49), and single baseline HbA1 levels have strongly predicted the risk for cardiovascular disease in adults (37).

In conclusion, our data do not support the evidence that higher HbA1c concentrations increase risk of breast cancer among apparently healthy women. However, our findings that estrogens may interact with HbA1c in relation to breast cancer risk warrant more detailed investigation to elucidate the true associations between insulin and estrogens and risk of breast cancer.


   Acknowledgments
 
Grant support: National Cancer Institute grant CA47988 and National Heart, Lung, and Blood Institute grant HL43851 and National Cancer Institute career development award KCA112529 (J. Lin).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank the entire staff of the WHS under the leadership of David Gordon as well as Mary Breen, Susan Burt, Marilyn Chown, Georgina Friedenberg, Inge Judge, Jean Mac-Fadyean, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson and the Endpoints Committee of the WHS (Dr. Wendy Y. Chen) and Rimma Dushkes for technical assistance with the article.

Received 10/31/05. Revised 12/20/05. Accepted 12/30/05.


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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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