Is Body Fat Topography a Risk Factor for Breast Cancer?

Various chronic illnesses are related to the pattern of body fat distribution. At equal degrees of relative or absolute body fat, a predominant upper (central) body fat distribution, as defined by an increased waist-to-hip ratio (WHR), correlates positively with glucose intolerance, diabetes mellitus, hyperlipidemia, coronary artery disease, hypertension, stroke, and premature (as well as overall) death [1-5]. Conversely, generally healthier populations have been shown to exhibit a decreased WHR (lower body fat distribution) [6]. Interrelations among these diverse metabolic disorders and their convincing association with the distinct WHR phenotype of upper body fat predominance suggest that the regional distribution of adipose tissue, with its site-specific hormonal activity and metabolic responsiveness [7, 8], may have relevance in other diseases associated with characteristic metabolic profiles. Indeed, endometrial cancer, a malignancy long known to be associated with obesity, diabetes, and hypertension [9-11], has recently been shown to have a significant association with upper or central body fat distribution [12, 13]. This body fat pattern is a stronger predictor than body mass of endometrial, and possibly ovarian, carcinomas [6]. Breast cancer, the most prevalent malignancy occurring in white women, has generally not been associated with the other clinical entities that have been linked to an increased WHR [14, 15]. A recent evaluation of mammographic breast morphologic analysis and body fat distribution found that women who had a high WHR were significantly less likely to have a putative high-risk mammographic pattern compared with women who had a low WHR, independent of age and the degree of obesity [16]. More importantly, data from a population-based, prospective study have shown no association between breast cancer development and body fat topography [12]. Surprisingly, however, three other clinical studies have noted a positive relation between upper or central body fat distribution and breast cancer risk [17-19]. We present the results of prospective body fat topography assessment in a large cohort of demographically homogeneous women, analyzed with particular attention to the menopausal status of the participants. Women subsequently diagnosed with breast cancer were compared with women evaluated by rigorous pathologic and clinical criteria and considered to be at low risk for breast cancer. Methods Participants Consecutive white American women of any age were recruited the day before the excision of an undiagnosed breast mass between 1 August 1988 and 1 December 1989 at Memorial Sloan-Kettering Cancer Center, according to the guidelines of the Institutional Review Board. To avoid confounding variables, women were excluded if they had any major systemic illnesses because of the association between body fat topography and various metabolic disorders. Obesity alone (without diabetes or hypertension) was not considered an exclusion criterion, unless morbid obesity (> 100% above ideal body weight) was present. Women were excluded if they experienced a weight gain or loss of 10% or more of their current weight in the previous 3 years. Because hormonal status independently affects WHR [1, 6, 20] as well as breast cancer risk [14, 15], the hormonal status of potential participants was carefully defined: Women either had to be premenopausal or to have had a known menopause with no postmenopausal hormone replacement. Premenopausal women with intact ovaries after hysterectomy were disqualified because the date of ovarian cessation could not be ascertained. Patients taking any hormonal preparation (for example, birth control pills, fertility drugs, or estrogen replacement) and pregnant patients (determined by history) were excluded. The research nurse reviewed the admission history and physical examination of 400 white American women before their diagnostic breast surgery. Three refused participation (all three were later noted to have benign biopsy results). Ten patients were eliminated for hormone use or uncertain date of menopause (six were benign; four had cancer on biopsy). One patient with cancer was eliminated for weight change. Seventy-two patients were eliminated for illnesses: 40 had cancer and 33 had benign findings on biopsy. In order of frequency, the most common illnesses were hypertension, diabetes, and asthma. These conditions were responsible for more than 80% of the illness exclusions. The total number of patients excluded was 87 (45 with cancer and 42 with benign findings on subsequent biopsy). The remaining 313 women, found to be eligible and having consented to participation, formed the study group. Study Protocol The study parameters (clinical variables and the anthropometric measurements) were obtained from all participants before the diagnostic breast operation. Clinical information about the major breast cancer risk factors (age, heredity, and hormonal and reproductive factors) was obtained by interview. More minor or controversial risk factors, such as alcohol consumption, smoking history, or mammographic parenchymal patterns, were not considered. Data were collected on the number of pregnancies and deliveries as well as on the age of first full-term delivery. An extensive family history confirmed the status of all first-degree relatives: their current age or age at death, the presence or absence of unilateral or bilateral breast cancer, and the age at breast cancer diagnosis. After the interview, anthropometric measurements were done according to the method of Ashwell and colleagues [21] by a single examiner to reduce intertester errors. Waist circumference was measured with the participant standing with abdomen relaxed, arms at sides, and feet together without footwear. The research nurse faced the participant and measured with a tape to the nearest 0.5 cm in the horizontal plane on the bare skin at the level of the natural waist, the narrowest part of the torso at the end of a normal expiration. Hip circumference was measured with the participant standing in the same position. The research nurse measured with a tape to within 0.5 cm around the buttocks in the horizontal plane at the largest circumference between the waist and thigh. The measurement was usually over the greater trochanters. Participants were weighed without footwear or underwear and wore the standard lightweight cotton hospital gown. Using the Detecto Floor Scales Model II (Detecto, Inc., Brooklyn, New York), each participant's weight was measured to the nearest 0.5 kg. Height was measured to the nearest 0.5 cm using the standard vertical attached rod on the Detecto Floor Scales Model II. Participants did not wear shoes during height measurements. Case-Control Assignment The results of the paraffin histologic sections obtained from the diagnostic breast surgery of study participants were made available by the Department of Pathology in several days. Of the 313 women studied, 156 had invasive breast carcinoma (stage I or II). These women constituted the cases. Because the remaining women with benign breast biopsies evaluated at a comprehensive cancer center may not be typical of women nationwide, we conducted a rigorous assessment to separate those at high risk from those at average risk. Of the 157 women who did not have invasive breast cancer, 126 were considered to be without high risk (controls), and 31 were considered to be at high risk for invasive breast cancer. Histologic and Clinical Risk Assessment The breast tissue of 157 women without invasive breast cancer was studied for histologic changes associated with an increased risk for breast cancer, that yielding a breast cancer incidence of at least 1% per year [22]. A histologic diagnosis of ductal or lobular carcinoma in situ or a benign biopsy sample showing atypical proliferative disease as defined by the classification of Page and coworkers, adopted in 1986 by the consensus meeting of the American College of Pathologists [23] and modified in 1991 [22], conferred a high-risk status. Of the 157 patients without invasive breast cancer, 22 had ductal or lobular carcinoma in situ (15 had ductal carcinoma in situ, 3 had lobular carcinoma in situ, and 4 had both ductal and lobular carcinoma in situ). Four patients had atypical hyperplasia. Therefore, 26 patients (22 with in situ carcinoma and 4 with atypical hyperplasia) were considered to be at high risk for developing breast cancer of 1% per year based on histologic criteria. Of the remaining 131 patients with benign biopsy results, 110 had Page and Dupont classification (1991) [22], diagnoses that conferred no increased risk (fibroadenoma, cyst, fibrosis, or adenosis), and 21 had sclerosing adenosis, papilloma with fibrovascular core, or moderate or florid hyperplasia, diagnoses that conferred a detectable but clinically irrelevant risk. A family history of breast cancer diagnoses in first-degree relatives, depending on their age at diagnosis and whether the disease is bilateral, can place a woman at a risk for breast cancer development of 1% per year [24]. Five patients had such a family history and were added to the high-risk category due to clinical criteria. No other patients were at this level of risk when evaluated by a combination criteria of specific clinical and histologic risk factors [25]. Thirty-one patients (26 for histologic criteria and 5 for clinical criteria) therefore were removed from the group of 157 patients without invasive breast cancer and were analyzed separately as a group at high risk for invasive breast cancer. The other 126 women without breast cancer were estimated to have a risk similar to that of the average white American woman and thus served as controls. Statistical Analysis A series of anthropometric measurements (height, weight, waist circumference, hip circumference, WHR, body mass index [BMI]) and clinical parameters (age at diagnosis, menopausal status, any family his