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Body mass index and breast cancer risk in African American women
Body Mass Index and Breast Cancer Risk in African American Women KANGMIN ZHU, MD, PHD, JOANNE CAULFIELD, MED, SANDRA HUNTER, BS, CHANEL L. ROLAND, BS, KATHLEEN PAYNE-WILKS, BA, AND LINDSAY TEXTER, BS
PURPOSE: Studies of the relationship between body mass index (BMI) and breast cancer in African American women have been few. We conducted a case–control study to examine whether BMI is associated with risk of breast cancer in this population. METHODS: Cases were 304 women diagnosed with breast cancer at the ages of 20 to 64 years. Controls were 305 women without a history of breast cancer. Telephone interviews were conducted to collect data on history of exposure to various factors at or before the date of diagnosis in cases or equivalent date in controls (reference date). Using logistic regression, we compared cases and controls in BMI at age 18, BMI at the reference date, and change in BMI between the two dates. RESULTS: Using BMI at reference date, we found an odds ratio (OR) of 1.75 (95% confidence interval [CI], 1.02–3.02) and 2.32 (95% CI, 1.33–4.03) for women with BMI of 25 to 29.9 and 30 or higher, respectively, compared with women having BMI lower than 25. The corresponding OR estimates for BMI at age 18 were not significantly different from the unity. The average annual change in BMI between age 18 and date of diagnosis or reference date was associated with breast cancer risk, as shown that more BMI change tended to increase breast cancer risk compared with the baseline quartile of change. When data were analyzed by menopausal status, the association was found for both post-menopausal and premenopausal tumors for BMI at reference date but not for BMI at age 18. There was a higher risk for more annual BMI change compared with the baseline for both pre-menopausal and post-menopausal women. CONCLUSION: Our results suggest that BMI at reference date and change in BMI were associated with increased risk of breast cancer in African American women, and the association might be found for both post-menopausal and pre-menopausal tumors. Ann Epidemiol 2005;15:123–128. Ó 2004 Elsevier Inc. All rights reserved. KEYWORDS:
African American, Breast Cancer, Case–Control Study, Epidemiology.
INTRODUCTION It has been postulated that obesity may increase the risk of breast cancer. This is based on the hypothesis that increased adipose tissue may be related to increased estrogen (1), which is a well-known breast cancer risk factor. This may be particularly true for post-menopausal tumor because plasma estrogens come primarily from adipose tissue after menopause (2). Obesity at puberty may be particularly important for research because it may stimulate estrogen secretion when progesterone levels are still low (3). Although not perfect, body mass index (BMI) has been commonly used as
From the United States Military Cancer Institute, Washington, DC (K.Z.); Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, PA (J.C., L.T.); and Department of Occupational and Preventive Medicine, Meharry Medical College, Nashville, TN (S.H., C.L.R., K.P.). Address correspondence to: Kangmin Zhu, M.D., Ph.D., United States Military Cancer Institute, Walter Reed Army Medical Center, Building 1, Suite A109, 6900 Georgia Avenue, NW, Washington, DC 20307-5001. Tel.: (202) 782-0544; Fax: (202) 782-5833. E-mail: kangmin.zhu@na. amedd.army.mil This study was supported by grants DAMD17-96-1-6270, DAMD1797-7287, and DAMD17-01-1-0595 from the Department of Defense, USA. Received January 14, 2004; accepted May 25, 2004. Ó 2004 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
a simple proxy measure for obesity in epidemiological studies. Many epidemiological studies have been conducted to assess the hypothesized association between BMI and breast cancer risk. These studies, conducted primarily in white women, generally showed an increased risk of postmenopausal breast cancer with increase in BMI (4–9) and an inverse association with risk of pre-menopausal breast cancer (4, 10–12). Studies of this relationship in African American women have been few, and the results have been inconsistent (13–16). In an early study (13), 529 African American cases with breast cancer were compared with 589 African American controls without the disease. It was found that obesity as measured by BMI increased the risk of breast cancer in post-menopausal African American women, but not in pre-menopausal African American women. Different results were shown in the study by Mayberry et al. (14), which included 490 cases and 485 controls. This study observed an increased risk associated with body mass index among women under the age of 40 at diagnosis, although the opposite tendency was shown when BMI at age 18 was used (14). In another study based on 193 cases and 164 controls, there were no significant associations between BMI and breast cancer for pre-menopausal women (15). However, 1047-2797/05/$–see front matter doi:10.1016/j.annepidem.2004.05.011
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BMI levels were lower in cases than in controls among postmenopausal women. In another study including only 30 cases and 30 controls (16), no significant association between BMI and breast cancer risk was found. There were potential drawbacks in these studies, such as hospital-based design (13) that may be prone to admission rate bias, lack of controlling for possible confounding factors (15), or small sample size (16). Moreover, only one study (14) examined BMI at age 18 and no studies investigated BMI change over time in relation to breast cancer in the population. More evidence on African American women’s risk of breast cancer in relation to BMI is important because African American women have a higher prevalence of both overweight and obesity than Caucasian women (17–20). Data from the National Health and Nutrition Examination Survey (18) showed that African American women had a higher prevalence of overweight (BMI 25–30) and obesity (BMI > 30) than Caucasian women and the increase in the prevalence of obesity over time was more striking in African American women. It has also been shown that the prevalence of obesity among African American women was approximately twice that of Caucasian women during the three decades from 1960 to 1990 and the greatest increase in obesity across all racial and ethnic groups of adolescents from 1970 to 2000 was among African American females (21, 22). Since obesity is modifiable, the elucidation of whether BMI is associated with breast cancer risk has important implications in public health. Because of the relative lack of published literature on studies in African American women and inconsistent results among limited publications, we conducted a case–control study to examine whether there is an association between BMI and breast cancer risk among African American women, providing more evidence on the topic. Specifically, we analyzed the data by BMI at age 18, at diagnosis, and change in BMI between the time points.
METHODS Study Subjects This study included 304 African American female cases diagnosed with breast cancer between 1995 and 1998, who were aged 20 to 64 years, lived in Davidson, Shelby, or Hamilton counties, Tennessee, and had a telephone service at the time of the study. The cases were identified from the Tennessee Cancer Reporting System (TCRS). TCRS is part of the North American Association of Central Cancer Registries. The percentage of complete ascertainment for the registry was approximately 80% during the study period. Six hundred seventy eligible women whose files indicated a physician’s name were identified from the TCRS, and each physician was approached for consent to contact the
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patient. Of the 670 eligible patients, 30 had died, and a physician’s consent for contact was obtained for 478. A mailing that described the study procedures and included a consent form for participation was sent to each patient. Non-respondents received a second packet and subsequent reminder calls. Of the 478 patients with a physician’s consent, 18 were deceased and 51 could not be located. Of the remaining 409 eligible patients, 304 (64% of those with a doctor’s consent or 74% of whom we contacted) agreed to participate in the study and were subsequently interviewed. We selected controls from African American women without a history of breast cancer. The controls were frequency matched to cases by 5-year age range and county. The selection was made through a one-step random-digit telephone dialing (RDD) (23) conducted immediately after the corresponding cases were interviewed. For the RDD procedures, we first grouped cases diagnosed in the same calendar year with telephone area codes from the same county, and then formed the sampling frame by age distribution of the cases in the area, using an eligibility table. We then randomly chose one of the telephone prefixes of the cases and appended four randomly-selected digits to form a telephone number. A call was made with this number to find an eligible woman according to ethnic background and age range. Up to nine calls over a 2-week period, including three day-time, three evening, and three weekend calls, were made for each telephone number that was not answered. In households with multiple eligible females, one eligible woman was randomly chosen. If an eligible woman was identified, we described the study purposes and procedures, and then asked whether she would give consent to be interviewed over the telephone. A total of 17,365 random numbers were called. Based on the outcome of the last call, out of these numbers, 4545 did not exist (including disconnected or changed numbers), 2332 were business numbers, 824 were a fax number, and 3874 had an unresolved result including an answering machine, a busy line, no one available when called, or other reasons. The random digit dialing calls resulted in 5970 households providing information on eligibility. Of these, 420 eligible women were identified, out of whom 305 (72.6%) were interviewed and used as controls. Participants were given $25 for a completed interview, and cases received an additional $10 for agreeing to release their tumor tissue specimens. These procedures were approved by the Institutional Review Board of Meharry Medical College. All participants gave their informed consent prior to participation. Data Collection Telephone interviews were conducted by trained interviewers to obtain information on the history of exposure to different factors. The interviews occurred generally 1 to 3 years after cancer diagnosis for cases. To reduce the
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potential effects of recall errors due to delayed interviews, we used a reference date. Information at or before the reference date was collected. The reference date for cases was defined as the date of diagnosis and for controls as the year corresponding to the diagnosis year of matched cases. Information collected included personal habits and lifestyle (smoking, alcohol use, exercise, dietary intake, use of electric bedding devices, and contraceptive use), menstrual, reproductive, and medical history (including benign breast disease, other cancers, and exogenous estrogen/progesterone use), family history of breast cancer in either a primary (mother, sister, daughter) or secondary (grandmother, aunt) relative, anthropometric variables (weight at reference date and at the age of 18, and maximum height), and demographic variables. Body mass index was calculated as weight in kilograms divided by height in meters squared (24).
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the BMI–breast cancer relationship. The variables adjusted in the models are indicated in the corresponding tables in the Results. RESULTS The demographic characteristics and anthropometric measures of the study subjects are shown in Table 1. Distributions in age, marital and employment status were similar between the two groups. However, cases tended to have a higher educational level and a higher family income than controls. Cases also tended to have higher levels of weight and BMI
TABLE 1. Demographic characteristics and anthropometric variables of African American women with and without diagnosis of breast cancer Cases
Data Analysis We analyzed the relationship between breast cancer and BMI, the exposure variable for this study. BMI was defined according to different time points: at age 18 and at reference date. Self-reported maximum height was used to calculate BMI at both time points. We also computed BMI change per year between the two time points. For BMI at reference date, we used the World Health Organization cutoffs: 18.5 or lower (underweight), 18.5–24.9 (normal weight), 25–29.9 (overweight), and 30 or higher (obesity) (25). Since there were a small number of women with a BMI value of 18.5 or lower, the underweight and normal weight groups were combined in data analysis. The same cutoffs were used for BMI at age 18 because these values are very close to the 85th and 95th percentiles for age 18 (the criteria used to define overweight and obesity for the age) (26). For change of BMI from age 18 to reference year, we developed a quartile variable using 25th, 50th, and 75th percentiles from controls. In analysis, we first assessed the relation of breast cancer to BMI at reference date, BMI at age 18, and BMI change between the two time points for all women. We then repeated analysis for pre-menopausal and post-menopausal women, respectively. Pre-menopausal status was defined as a woman having menstrual periods during the 3-month period before the reference date, or not having periods during that time frame because of pregnancy. Post-menopausal status was defined as no periods during the time (except pregnancy). Logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for each exposure variable (27). In the analyses, we always adjusted for demographic variables that might have complex effects on study results. We also chose as potential confounders the variables that were significantly associated with the risk of breast cancer in our data or that could logically confound
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Characteristic Age (years) 20–39 40–49 50–59 60 and above Marital status Married Separated Divorced Widowed Never married Employment status Currently employed Not currently employed Education level High school or less Vocational/technical school Some college or junior college College, graduate school, professional school Religious affiliation Protestant Catholic Latter Day Saints None Income Less than $15,000 $15,000–$29,999 $30,000–$44,999 $45,000 or over Weight (lb) (mean and standard deviation) Weight at age 18 (lb) (mean and standard deviation) Maximum height (in) (mean and standard deviation) BMI (mean and standard deviation) BMI at age 18 (mean and standard deviation)
Controls
Number Percent Number Percent 33 105 106 60
11 35 35 20
33 105 109 58
11 34 36 19
129 31 75 25 44
42 10 25 8 14
132 35 61 34 41
44 12 20 11 14
213 91
70 30
208 95
69 31
113 34 79 77
37 11 26 25
140 29 77 55
46 10 26 18
263 9 17 14
87 3 6 5
275 7 11 11
90 2 4 4
85 67 65 76 168.5
28 22 21 25 37.4
107 88 56 42 163.9
35 29 18 14 40.0
125.8
22.4
127.4
24.3
64.7
2.8
64.5
3.0
28.4 21.2
6.2 3.6
27.8 21.6
7.0 4.3
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than controls while the level of weight at age 18 appeared to be slightly higher for controls. Compared with controls, cases were more likely to have a history of benign breast disease, a family history of breast cancer, use of electric bedding devices, a history of radiotherapy, and estrogen use, but less likely to consume alcohol (data not shown). For menstrual and reproductive factors, the most obvious differences between cases and controls were shorter menstrual cycle length and lower probability of having had an infertility test in cases, while other factors might also differ slightly between the two groups, such as older age at menopause and fewer parities in cases than in controls. Table 2 displays the relationship between breast cancer and BMI at reference date. When all subjects were analyzed without respect to menopausal status, women with a BMI value of 25 to 29.9 had nearly twice the risk of developing breast cancer compared with those who had a BMI value lower than 25 (OR, 1.76; 95% CI, 1.02–3.02). The corresponding OR for a BMI value of 30 or higher was 2.32 (95% CI, 1.33–4.03). The p-value for trend test was 0.003. When data were analyzed by menopausal status, similar results were obtained for post-menopausal women. For premenopausal women, the OR estimate seemed slightly higher and the p-value for trend was not significant. The OR estimates for BMI measures at age 18 are shown in Table 3. The OR estimates for different levels of BMI were close to one. Similar results were obtained when data were analyzed by menopausal status. Analysis of annual change in BMI showed that when the lowest quartile (0.104 or less) was used as the baseline, there
TABLE 2. Odds ratios and 95% confidence intervals of breast cancer for body mass index at reference date BMI level at age 18 All subjects ! 25 25 to ! 30 > 30 Pre-menopausal ! 25 25 to ! 30 > 30 Post-menopausal ! 25 25 to ! 30 > 30
Cases (nx) Controls (nx)
OR*
95% CIz p for trend
87 86 98
105 77 78
Reference 1.76 1.02–3.02 2.32 1.33–4.03
0.003
42 31 37
48 26 36
Reference 3.27 1.00–10.67 2.49 0.82–7.59
0.108
45 55 61
57 51 42
Reference 1.50 0.70–3.21 2.32 1.04–5.19
0.039
*Adjusted for family history of breast cancer, history of benign breast disease, alcohol use, smoking, menstrual status, age at menarche, menstrual cycle length, number of parities, age at first birth, miscarriages, history of radiotherapy, use of estrogen other than for birth control, history of losing weight, history of taking iron pills, age at first sexual intercourse, daily energy intake (kcal), physical activity, use of electric bedding devices, history of infertility, and demographic variables. Menopausal status was not in the model when data were analyzed by menopausal status. x Subjects with a missing value on any variables in the model were excluded. z CI, confidence interval.
TABLE 3. Odds ratios and 95% confidence intervals of breast cancer for body mass index at age 18 BMI level at age 18 All subjects ! 25 25 to ! 30 > 30 Pre-menopausal ! 25 25 to ! 30 > 30 Post-menopausal ! 25 25 to ! 30 > 30
Cases Controls (nx) (nx)
OR*
95% CIz
p for trend
231 28 8
212 34 11
Reference 0.87 0.45–1.65 1.06 0.35–3.22
0.847
95 10 4
88 14 7
Reference 0.93 0.26–3.41 1.84 0.27–12.45
0.668
136 18 4
124 20 4
Reference 0.99 0.40–2.48 1.35 0.20–9.15
0.856
*Adjusted for family history of breast cancer, history of benign breast disease, alcohol use, smoking, menstrual status, age at menarche, menstrual cycle length, number of parities, age at first birth, miscarriages, history of radiotherapy, use of estrogen other than for birth control, history of losing weight, history of taking iron pills, age at first sexual intercourse, daily energy intake (kcal), physical activity, use of electric bedding devices, history of infertility, and demographic variables. Menopausal status was not in the model when data were analyzed by menopausal status. x Subjects with a missing value on any variables in the model were excluded. z CI, confidence interval.
was a higher risk of breast cancer for all three higher quartiles of BMI change (Table 4). These tendencies were observed for both pre- and post-menopausal tumors (except the highest change level for post-menopausal women). TABLE 4. Odds ratios and 95% confidence intervals of breast cancer for change per year in body mass index Annual BMI change All subjects Quartile < 0.104 Quartile 0.104 to ! 0.202 Quartile 0.202 to ! 0.364 Quartile > 0.364 Pre-menopausal Quartile < 0.104 Quartile 0.104 to ! 0.202 Quartile 0.202 to ! 0.364 Quartile > 0.364 Post-menopausal Quartile < 0.104 Quartile 0.104 to ! 0.202 Quartile 0.202 to ! 0.364 Quartile > 0.364
Cases Controls (nx) (nx)
OR*
p for 95% CIz trend
47 88 82 50
81 60 57 58
Reference 2.70 1.50–4.87 2.92 1.57–5.42 1.57 0.82–3.02 0.095
20 35 24 30
38 19 21 30
Reference 8.10 1.96–33.44 2.89 0.67–12.50 3.05 0.84–11.12 0.314
27 53 58 20
43 41 36 28
Reference 2.50 1.08–5.82 3.25 1.32–8.02 0.97 0.34–2.78 0.498
*Adjusted for BMI at age 18, family history of breast cancer, history of benign breast disease, alcohol use, smoking, menstrual status, age at menarche, menstrual cycle length, number of parities, age at first birth, miscarriages, history of radiotherapy, use of estrogen other than for birth control, history of losing weight, history of taking iron pills, age at first sexual intercourse, daily energy intake (kcal), physical activity, use of electric bedding devices, history of infertility, and demographic variables. Menopausal status was not in the model when data were analyzed by menopausal status. x Subjects with a missing value on any variables in the model were excluded. z CI, confidence interval.
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However, the dose–response effect was not obvious for all these analyses. DISCUSSION Our results suggest that increased BMI at reference date was associated with increased risk of breast cancer in African American women for both post-menopausal and pre-menopausal tumors. BMI at age 18 was not related to increased breast cancer risk. When average BMI change per year was analyzed, it was found that more BMI change increased the risk of breast cancer compared with the lowest quartile of change. However, the increase in the risk did not manifest a dose–effect trend by increasing quartiles, suggesting that even a slight increase in the annual BMI change might be a risk factor for the disease but the increase in risk might not be a linear function of the BMI change. This pattern held true for both pre-menopausal and post-menopausal tumors (except the highest change level for post-menopausal cancer). Previous studies have suggested that BMI increases postmenopausal breast cancer risk, but decreases the risk of premenopausal cancer. This has been generally observed for BMI at reference date, but is less consistent for BMI at a young age (4, 28–30). Change in BMI or weight has been generally associated with increased risk of post-menopausal breast cancer (4, 6, 8, 29, 30) while results on pre-menopausal tumors were less coherent (4, 30, 31). Our findings in African American women seem somewhat different from the general notion. Since studies in African American women have been few, particularly on BMI at age 18 and BMI change, our results need to be confirmed. Some limitations of our study should be kept in mind when evaluating our results. Non-participation of study subjects might be a problem. A substantial proportion of eligible cases did not participate because no doctor’s consent was available, or no consent was obtained from the women. If the non-participating patients differed systematically from the participating cases in BMI, the results might be biased. We were unable to assess the possible effects of selection bias by direct examination of differences in BMI between the participants and non-participants. However, the participating and non-participating patients could be compared in tumor characteristics using data from the TCRS. The comparisons showed that non-participants were more likely to have a distant metastasis of the tumor (data not shown). Some studies have found that obesity is related to a more severe form of tumor at diagnosis (32, 33). Thus, the non-participating patients might be more likely to be obese and BMI might be underestimated in the cases. Whether and how an odds ratio estimate is influenced also depends on the difference in BMI between participating and non-participating controls. Some studies found that
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people with low socioeconomic status are less likely to participate in a study (34) and are more likely to have higher levels of BMI (35, 36). Although the participation of women eligible as controls was relatively high in our study, we do not exclude the possibility that non-participating controls had higher BMI values and thus BMI levels among the participating controls were underestimated. The effects of non-participation are difficult to evaluate due to lack of sound data from non-participants and because mechanisms of non-participation are complex and may differ between cases and controls. Inaccuracy in estimating BMI was another potential problem. Information on weight and height, which were used to calculate BMI, was based on self-reports and might not reflect the true values. Although most studies comparing self-reported weight and height with measured ones or pictorials, including those in African American women (37), showed a high correlation between them (37–41), the differences between the self-reported and measured weight and height may exist (42), especially in people aged 60 years or older (43). Although most of our study subjects were younger than 60 years of age, the study might not be free of noticeable reporting errors since other variables such as race, education, and income may also be related to the reporting inaccuracy (44). Moreover, we do not exclude the possibility that the cases were more likely to be aware of the hypothesized association between overweight and breast cancer and therefore over-reported weight, and as a result the calculated BMI was higher. The other problem related to the assessment of BMI was that maximum height was used for the calculation of BMI both at reference date and at age 18. While it might have limited effects on younger women, it might lead to an underestimated BMI at reference date for older study subjects because of possibly reduced height for the elderly. However, such effects were not differential between cases and controls and therefore might not substantially have changed the results. Obesity is a public health problem in African American women. It is imperative to have more evidence on whether obesity is associated with increased risk of breast cancer. Since obesity may be modifiable, the elucidation of the association is important for the prevention of breast cancer in the population. The authors thank Ms. Rebecca Jones and Mr. Patrick Turri for identifying patients, Drs Robert Levine and Louis Bernard for their support, and Ms. Tina Cantrell for secretarial assistance during the original study.
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40. Klipstein-Grobusch K, Kroke A, Boeing H. Reproducibility of self-reported past body weight. Eur J Clin Nutr. 1998;52:525–528. 41. Spencer EA, Appleby PN, Davey GK, Key TJ. Validity of self-reported height and weight in 4808 EPIC-Oxford participants. Public Health Nutr. 2002;5:561–565. 42. Nawaz H, Chan W, Abdulrahman M, Larson D, Katz DL. Self-reported weight and height: Implications for obesity research. Am J Prev Med. 2001;20:294–298. 43. Kuczmarski MF, Kuczmarski RJ, Najjar M. Effects of age on validity of selfreported height, weight, and body mass index: Findings from the Third National Health and Nutrition Examination Survey. J Am Diet Assoc. 2001;101:28–34. 44. Villanueva. EV. The validity of self-reported weight in US adults: A population based cross-sectional study. BMC Public Health. 2001;1:11.
PURPOSE: Studies of the relationship between body mass index (BMI) and breast cancer in African American women have been few. We conducted a case–control study to examine whether BMI is associated with risk of breast cancer in this population. METHODS: Cases were 304 women diagnosed with breast cancer at the ages of 20 to 64 years. Controls were 305 women without a history of breast cancer. Telephone interviews were conducted to collect data on history of exposure to various factors at or before the date of diagnosis in cases or equivalent date in controls (reference date). Using logistic regression, we compared cases and controls in BMI at age 18, BMI at the reference date, and change in BMI between the two dates. RESULTS: Using BMI at reference date, we found an odds ratio (OR) of 1.75 (95% confidence interval [CI], 1.02–3.02) and 2.32 (95% CI, 1.33–4.03) for women with BMI of 25 to 29.9 and 30 or higher, respectively, compared with women having BMI lower than 25. The corresponding OR estimates for BMI at age 18 were not significantly different from the unity. The average annual change in BMI between age 18 and date of diagnosis or reference date was associated with breast cancer risk, as shown that more BMI change tended to increase breast cancer risk compared with the baseline quartile of change. When data were analyzed by menopausal status, the association was found for both post-menopausal and premenopausal tumors for BMI at reference date but not for BMI at age 18. There was a higher risk for more annual BMI change compared with the baseline for both pre-menopausal and post-menopausal women. CONCLUSION: Our results suggest that BMI at reference date and change in BMI were associated with increased risk of breast cancer in African American women, and the association might be found for both post-menopausal and pre-menopausal tumors. Ann Epidemiol 2005;15:123–128. Ó 2004 Elsevier Inc. All rights reserved. KEYWORDS:
African American, Breast Cancer, Case–Control Study, Epidemiology.
INTRODUCTION It has been postulated that obesity may increase the risk of breast cancer. This is based on the hypothesis that increased adipose tissue may be related to increased estrogen (1), which is a well-known breast cancer risk factor. This may be particularly true for post-menopausal tumor because plasma estrogens come primarily from adipose tissue after menopause (2). Obesity at puberty may be particularly important for research because it may stimulate estrogen secretion when progesterone levels are still low (3). Although not perfect, body mass index (BMI) has been commonly used as
From the United States Military Cancer Institute, Washington, DC (K.Z.); Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, PA (J.C., L.T.); and Department of Occupational and Preventive Medicine, Meharry Medical College, Nashville, TN (S.H., C.L.R., K.P.). Address correspondence to: Kangmin Zhu, M.D., Ph.D., United States Military Cancer Institute, Walter Reed Army Medical Center, Building 1, Suite A109, 6900 Georgia Avenue, NW, Washington, DC 20307-5001. Tel.: (202) 782-0544; Fax: (202) 782-5833. E-mail: kangmin.zhu@na. amedd.army.mil This study was supported by grants DAMD17-96-1-6270, DAMD1797-7287, and DAMD17-01-1-0595 from the Department of Defense, USA. Received January 14, 2004; accepted May 25, 2004. Ó 2004 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
a simple proxy measure for obesity in epidemiological studies. Many epidemiological studies have been conducted to assess the hypothesized association between BMI and breast cancer risk. These studies, conducted primarily in white women, generally showed an increased risk of postmenopausal breast cancer with increase in BMI (4–9) and an inverse association with risk of pre-menopausal breast cancer (4, 10–12). Studies of this relationship in African American women have been few, and the results have been inconsistent (13–16). In an early study (13), 529 African American cases with breast cancer were compared with 589 African American controls without the disease. It was found that obesity as measured by BMI increased the risk of breast cancer in post-menopausal African American women, but not in pre-menopausal African American women. Different results were shown in the study by Mayberry et al. (14), which included 490 cases and 485 controls. This study observed an increased risk associated with body mass index among women under the age of 40 at diagnosis, although the opposite tendency was shown when BMI at age 18 was used (14). In another study based on 193 cases and 164 controls, there were no significant associations between BMI and breast cancer for pre-menopausal women (15). However, 1047-2797/05/$–see front matter doi:10.1016/j.annepidem.2004.05.011
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BMI levels were lower in cases than in controls among postmenopausal women. In another study including only 30 cases and 30 controls (16), no significant association between BMI and breast cancer risk was found. There were potential drawbacks in these studies, such as hospital-based design (13) that may be prone to admission rate bias, lack of controlling for possible confounding factors (15), or small sample size (16). Moreover, only one study (14) examined BMI at age 18 and no studies investigated BMI change over time in relation to breast cancer in the population. More evidence on African American women’s risk of breast cancer in relation to BMI is important because African American women have a higher prevalence of both overweight and obesity than Caucasian women (17–20). Data from the National Health and Nutrition Examination Survey (18) showed that African American women had a higher prevalence of overweight (BMI 25–30) and obesity (BMI > 30) than Caucasian women and the increase in the prevalence of obesity over time was more striking in African American women. It has also been shown that the prevalence of obesity among African American women was approximately twice that of Caucasian women during the three decades from 1960 to 1990 and the greatest increase in obesity across all racial and ethnic groups of adolescents from 1970 to 2000 was among African American females (21, 22). Since obesity is modifiable, the elucidation of whether BMI is associated with breast cancer risk has important implications in public health. Because of the relative lack of published literature on studies in African American women and inconsistent results among limited publications, we conducted a case–control study to examine whether there is an association between BMI and breast cancer risk among African American women, providing more evidence on the topic. Specifically, we analyzed the data by BMI at age 18, at diagnosis, and change in BMI between the time points.
METHODS Study Subjects This study included 304 African American female cases diagnosed with breast cancer between 1995 and 1998, who were aged 20 to 64 years, lived in Davidson, Shelby, or Hamilton counties, Tennessee, and had a telephone service at the time of the study. The cases were identified from the Tennessee Cancer Reporting System (TCRS). TCRS is part of the North American Association of Central Cancer Registries. The percentage of complete ascertainment for the registry was approximately 80% during the study period. Six hundred seventy eligible women whose files indicated a physician’s name were identified from the TCRS, and each physician was approached for consent to contact the
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patient. Of the 670 eligible patients, 30 had died, and a physician’s consent for contact was obtained for 478. A mailing that described the study procedures and included a consent form for participation was sent to each patient. Non-respondents received a second packet and subsequent reminder calls. Of the 478 patients with a physician’s consent, 18 were deceased and 51 could not be located. Of the remaining 409 eligible patients, 304 (64% of those with a doctor’s consent or 74% of whom we contacted) agreed to participate in the study and were subsequently interviewed. We selected controls from African American women without a history of breast cancer. The controls were frequency matched to cases by 5-year age range and county. The selection was made through a one-step random-digit telephone dialing (RDD) (23) conducted immediately after the corresponding cases were interviewed. For the RDD procedures, we first grouped cases diagnosed in the same calendar year with telephone area codes from the same county, and then formed the sampling frame by age distribution of the cases in the area, using an eligibility table. We then randomly chose one of the telephone prefixes of the cases and appended four randomly-selected digits to form a telephone number. A call was made with this number to find an eligible woman according to ethnic background and age range. Up to nine calls over a 2-week period, including three day-time, three evening, and three weekend calls, were made for each telephone number that was not answered. In households with multiple eligible females, one eligible woman was randomly chosen. If an eligible woman was identified, we described the study purposes and procedures, and then asked whether she would give consent to be interviewed over the telephone. A total of 17,365 random numbers were called. Based on the outcome of the last call, out of these numbers, 4545 did not exist (including disconnected or changed numbers), 2332 were business numbers, 824 were a fax number, and 3874 had an unresolved result including an answering machine, a busy line, no one available when called, or other reasons. The random digit dialing calls resulted in 5970 households providing information on eligibility. Of these, 420 eligible women were identified, out of whom 305 (72.6%) were interviewed and used as controls. Participants were given $25 for a completed interview, and cases received an additional $10 for agreeing to release their tumor tissue specimens. These procedures were approved by the Institutional Review Board of Meharry Medical College. All participants gave their informed consent prior to participation. Data Collection Telephone interviews were conducted by trained interviewers to obtain information on the history of exposure to different factors. The interviews occurred generally 1 to 3 years after cancer diagnosis for cases. To reduce the
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potential effects of recall errors due to delayed interviews, we used a reference date. Information at or before the reference date was collected. The reference date for cases was defined as the date of diagnosis and for controls as the year corresponding to the diagnosis year of matched cases. Information collected included personal habits and lifestyle (smoking, alcohol use, exercise, dietary intake, use of electric bedding devices, and contraceptive use), menstrual, reproductive, and medical history (including benign breast disease, other cancers, and exogenous estrogen/progesterone use), family history of breast cancer in either a primary (mother, sister, daughter) or secondary (grandmother, aunt) relative, anthropometric variables (weight at reference date and at the age of 18, and maximum height), and demographic variables. Body mass index was calculated as weight in kilograms divided by height in meters squared (24).
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the BMI–breast cancer relationship. The variables adjusted in the models are indicated in the corresponding tables in the Results. RESULTS The demographic characteristics and anthropometric measures of the study subjects are shown in Table 1. Distributions in age, marital and employment status were similar between the two groups. However, cases tended to have a higher educational level and a higher family income than controls. Cases also tended to have higher levels of weight and BMI
TABLE 1. Demographic characteristics and anthropometric variables of African American women with and without diagnosis of breast cancer Cases
Data Analysis We analyzed the relationship between breast cancer and BMI, the exposure variable for this study. BMI was defined according to different time points: at age 18 and at reference date. Self-reported maximum height was used to calculate BMI at both time points. We also computed BMI change per year between the two time points. For BMI at reference date, we used the World Health Organization cutoffs: 18.5 or lower (underweight), 18.5–24.9 (normal weight), 25–29.9 (overweight), and 30 or higher (obesity) (25). Since there were a small number of women with a BMI value of 18.5 or lower, the underweight and normal weight groups were combined in data analysis. The same cutoffs were used for BMI at age 18 because these values are very close to the 85th and 95th percentiles for age 18 (the criteria used to define overweight and obesity for the age) (26). For change of BMI from age 18 to reference year, we developed a quartile variable using 25th, 50th, and 75th percentiles from controls. In analysis, we first assessed the relation of breast cancer to BMI at reference date, BMI at age 18, and BMI change between the two time points for all women. We then repeated analysis for pre-menopausal and post-menopausal women, respectively. Pre-menopausal status was defined as a woman having menstrual periods during the 3-month period before the reference date, or not having periods during that time frame because of pregnancy. Post-menopausal status was defined as no periods during the time (except pregnancy). Logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for each exposure variable (27). In the analyses, we always adjusted for demographic variables that might have complex effects on study results. We also chose as potential confounders the variables that were significantly associated with the risk of breast cancer in our data or that could logically confound
125
Characteristic Age (years) 20–39 40–49 50–59 60 and above Marital status Married Separated Divorced Widowed Never married Employment status Currently employed Not currently employed Education level High school or less Vocational/technical school Some college or junior college College, graduate school, professional school Religious affiliation Protestant Catholic Latter Day Saints None Income Less than $15,000 $15,000–$29,999 $30,000–$44,999 $45,000 or over Weight (lb) (mean and standard deviation) Weight at age 18 (lb) (mean and standard deviation) Maximum height (in) (mean and standard deviation) BMI (mean and standard deviation) BMI at age 18 (mean and standard deviation)
Controls
Number Percent Number Percent 33 105 106 60
11 35 35 20
33 105 109 58
11 34 36 19
129 31 75 25 44
42 10 25 8 14
132 35 61 34 41
44 12 20 11 14
213 91
70 30
208 95
69 31
113 34 79 77
37 11 26 25
140 29 77 55
46 10 26 18
263 9 17 14
87 3 6 5
275 7 11 11
90 2 4 4
85 67 65 76 168.5
28 22 21 25 37.4
107 88 56 42 163.9
35 29 18 14 40.0
125.8
22.4
127.4
24.3
64.7
2.8
64.5
3.0
28.4 21.2
6.2 3.6
27.8 21.6
7.0 4.3
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than controls while the level of weight at age 18 appeared to be slightly higher for controls. Compared with controls, cases were more likely to have a history of benign breast disease, a family history of breast cancer, use of electric bedding devices, a history of radiotherapy, and estrogen use, but less likely to consume alcohol (data not shown). For menstrual and reproductive factors, the most obvious differences between cases and controls were shorter menstrual cycle length and lower probability of having had an infertility test in cases, while other factors might also differ slightly between the two groups, such as older age at menopause and fewer parities in cases than in controls. Table 2 displays the relationship between breast cancer and BMI at reference date. When all subjects were analyzed without respect to menopausal status, women with a BMI value of 25 to 29.9 had nearly twice the risk of developing breast cancer compared with those who had a BMI value lower than 25 (OR, 1.76; 95% CI, 1.02–3.02). The corresponding OR for a BMI value of 30 or higher was 2.32 (95% CI, 1.33–4.03). The p-value for trend test was 0.003. When data were analyzed by menopausal status, similar results were obtained for post-menopausal women. For premenopausal women, the OR estimate seemed slightly higher and the p-value for trend was not significant. The OR estimates for BMI measures at age 18 are shown in Table 3. The OR estimates for different levels of BMI were close to one. Similar results were obtained when data were analyzed by menopausal status. Analysis of annual change in BMI showed that when the lowest quartile (0.104 or less) was used as the baseline, there
TABLE 2. Odds ratios and 95% confidence intervals of breast cancer for body mass index at reference date BMI level at age 18 All subjects ! 25 25 to ! 30 > 30 Pre-menopausal ! 25 25 to ! 30 > 30 Post-menopausal ! 25 25 to ! 30 > 30
Cases (nx) Controls (nx)
OR*
95% CIz p for trend
87 86 98
105 77 78
Reference 1.76 1.02–3.02 2.32 1.33–4.03
0.003
42 31 37
48 26 36
Reference 3.27 1.00–10.67 2.49 0.82–7.59
0.108
45 55 61
57 51 42
Reference 1.50 0.70–3.21 2.32 1.04–5.19
0.039
*Adjusted for family history of breast cancer, history of benign breast disease, alcohol use, smoking, menstrual status, age at menarche, menstrual cycle length, number of parities, age at first birth, miscarriages, history of radiotherapy, use of estrogen other than for birth control, history of losing weight, history of taking iron pills, age at first sexual intercourse, daily energy intake (kcal), physical activity, use of electric bedding devices, history of infertility, and demographic variables. Menopausal status was not in the model when data were analyzed by menopausal status. x Subjects with a missing value on any variables in the model were excluded. z CI, confidence interval.
TABLE 3. Odds ratios and 95% confidence intervals of breast cancer for body mass index at age 18 BMI level at age 18 All subjects ! 25 25 to ! 30 > 30 Pre-menopausal ! 25 25 to ! 30 > 30 Post-menopausal ! 25 25 to ! 30 > 30
Cases Controls (nx) (nx)
OR*
95% CIz
p for trend
231 28 8
212 34 11
Reference 0.87 0.45–1.65 1.06 0.35–3.22
0.847
95 10 4
88 14 7
Reference 0.93 0.26–3.41 1.84 0.27–12.45
0.668
136 18 4
124 20 4
Reference 0.99 0.40–2.48 1.35 0.20–9.15
0.856
*Adjusted for family history of breast cancer, history of benign breast disease, alcohol use, smoking, menstrual status, age at menarche, menstrual cycle length, number of parities, age at first birth, miscarriages, history of radiotherapy, use of estrogen other than for birth control, history of losing weight, history of taking iron pills, age at first sexual intercourse, daily energy intake (kcal), physical activity, use of electric bedding devices, history of infertility, and demographic variables. Menopausal status was not in the model when data were analyzed by menopausal status. x Subjects with a missing value on any variables in the model were excluded. z CI, confidence interval.
was a higher risk of breast cancer for all three higher quartiles of BMI change (Table 4). These tendencies were observed for both pre- and post-menopausal tumors (except the highest change level for post-menopausal women). TABLE 4. Odds ratios and 95% confidence intervals of breast cancer for change per year in body mass index Annual BMI change All subjects Quartile < 0.104 Quartile 0.104 to ! 0.202 Quartile 0.202 to ! 0.364 Quartile > 0.364 Pre-menopausal Quartile < 0.104 Quartile 0.104 to ! 0.202 Quartile 0.202 to ! 0.364 Quartile > 0.364 Post-menopausal Quartile < 0.104 Quartile 0.104 to ! 0.202 Quartile 0.202 to ! 0.364 Quartile > 0.364
Cases Controls (nx) (nx)
OR*
p for 95% CIz trend
47 88 82 50
81 60 57 58
Reference 2.70 1.50–4.87 2.92 1.57–5.42 1.57 0.82–3.02 0.095
20 35 24 30
38 19 21 30
Reference 8.10 1.96–33.44 2.89 0.67–12.50 3.05 0.84–11.12 0.314
27 53 58 20
43 41 36 28
Reference 2.50 1.08–5.82 3.25 1.32–8.02 0.97 0.34–2.78 0.498
*Adjusted for BMI at age 18, family history of breast cancer, history of benign breast disease, alcohol use, smoking, menstrual status, age at menarche, menstrual cycle length, number of parities, age at first birth, miscarriages, history of radiotherapy, use of estrogen other than for birth control, history of losing weight, history of taking iron pills, age at first sexual intercourse, daily energy intake (kcal), physical activity, use of electric bedding devices, history of infertility, and demographic variables. Menopausal status was not in the model when data were analyzed by menopausal status. x Subjects with a missing value on any variables in the model were excluded. z CI, confidence interval.
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However, the dose–response effect was not obvious for all these analyses. DISCUSSION Our results suggest that increased BMI at reference date was associated with increased risk of breast cancer in African American women for both post-menopausal and pre-menopausal tumors. BMI at age 18 was not related to increased breast cancer risk. When average BMI change per year was analyzed, it was found that more BMI change increased the risk of breast cancer compared with the lowest quartile of change. However, the increase in the risk did not manifest a dose–effect trend by increasing quartiles, suggesting that even a slight increase in the annual BMI change might be a risk factor for the disease but the increase in risk might not be a linear function of the BMI change. This pattern held true for both pre-menopausal and post-menopausal tumors (except the highest change level for post-menopausal cancer). Previous studies have suggested that BMI increases postmenopausal breast cancer risk, but decreases the risk of premenopausal cancer. This has been generally observed for BMI at reference date, but is less consistent for BMI at a young age (4, 28–30). Change in BMI or weight has been generally associated with increased risk of post-menopausal breast cancer (4, 6, 8, 29, 30) while results on pre-menopausal tumors were less coherent (4, 30, 31). Our findings in African American women seem somewhat different from the general notion. Since studies in African American women have been few, particularly on BMI at age 18 and BMI change, our results need to be confirmed. Some limitations of our study should be kept in mind when evaluating our results. Non-participation of study subjects might be a problem. A substantial proportion of eligible cases did not participate because no doctor’s consent was available, or no consent was obtained from the women. If the non-participating patients differed systematically from the participating cases in BMI, the results might be biased. We were unable to assess the possible effects of selection bias by direct examination of differences in BMI between the participants and non-participants. However, the participating and non-participating patients could be compared in tumor characteristics using data from the TCRS. The comparisons showed that non-participants were more likely to have a distant metastasis of the tumor (data not shown). Some studies have found that obesity is related to a more severe form of tumor at diagnosis (32, 33). Thus, the non-participating patients might be more likely to be obese and BMI might be underestimated in the cases. Whether and how an odds ratio estimate is influenced also depends on the difference in BMI between participating and non-participating controls. Some studies found that
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people with low socioeconomic status are less likely to participate in a study (34) and are more likely to have higher levels of BMI (35, 36). Although the participation of women eligible as controls was relatively high in our study, we do not exclude the possibility that non-participating controls had higher BMI values and thus BMI levels among the participating controls were underestimated. The effects of non-participation are difficult to evaluate due to lack of sound data from non-participants and because mechanisms of non-participation are complex and may differ between cases and controls. Inaccuracy in estimating BMI was another potential problem. Information on weight and height, which were used to calculate BMI, was based on self-reports and might not reflect the true values. Although most studies comparing self-reported weight and height with measured ones or pictorials, including those in African American women (37), showed a high correlation between them (37–41), the differences between the self-reported and measured weight and height may exist (42), especially in people aged 60 years or older (43). Although most of our study subjects were younger than 60 years of age, the study might not be free of noticeable reporting errors since other variables such as race, education, and income may also be related to the reporting inaccuracy (44). Moreover, we do not exclude the possibility that the cases were more likely to be aware of the hypothesized association between overweight and breast cancer and therefore over-reported weight, and as a result the calculated BMI was higher. The other problem related to the assessment of BMI was that maximum height was used for the calculation of BMI both at reference date and at age 18. While it might have limited effects on younger women, it might lead to an underestimated BMI at reference date for older study subjects because of possibly reduced height for the elderly. However, such effects were not differential between cases and controls and therefore might not substantially have changed the results. Obesity is a public health problem in African American women. It is imperative to have more evidence on whether obesity is associated with increased risk of breast cancer. Since obesity may be modifiable, the elucidation of the association is important for the prevention of breast cancer in the population. The authors thank Ms. Rebecca Jones and Mr. Patrick Turri for identifying patients, Drs Robert Levine and Louis Bernard for their support, and Ms. Tina Cantrell for secretarial assistance during the original study.
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