1 Department of Internal Medicine and the Cancer Research and Treatment Center, Epidemiology and Cancer Prevention Program, University of New Mexico Health Sciences Center, Albuquerque, NM.
2 Department of Preventive Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
3 Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD.
4 Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
Received for publication September 22, 2003; accepted for publication June 10, 2004.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
anthropometry; biological markers; body composition; body constitution; breast neoplasms; Hispanic Americans; prognosis
Abbreviations: Abbreviations: CI, confidence interval; DXA, dual-energy, x-ray absorptiometry; HEAL, Health, Eating, Activity, and Lifestyle; OR, odds ratio; SD, standard deviation; SEER, Surveillance, Epidemiology, and End Results.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The associations of weight and weight gain with prognosis appear to be independent of menopausal status, and they persist after adjustment for stage and treatment, although results are inconsistent (1116). Centralized body fat distribution also appears to increase risk for recurrence and death (17). In some studies, the association of obesity with prognosis is strongest among women with positive estrogen and progesterone receptor status (18, 19), increased tumor size (13, 20), early stage of disease (16, 2123), and positive nodal status (13, 2325). However findings are inconsistent. Weight gain is reported in many women undergoing adjuvant therapy, although results vary by menopausal status (26). It is unclear whether these associations are modified by therapy or whether weight gain is due to the disease process.
In a cross-sectional analysis, we analyzed the associations of body composition and adult weight history with baseline prognostic markers in women diagnosed with incident, first primary breast cancer in the Health, Eating, Activity, and Lifestyle (HEAL) Study. The purpose of this cohort study is to evaluate the association between body composition, hormones, diet, physical activity, and prognosis over time for African-American, Hispanic, and non-Hispanic White women, ascertained through the Surveillance, Epidemiology, and End Results (SEER) Program cancer registries in New Mexico, western Washington, and Los Angeles, California (27, 28). In this analysis specific to Hispanic and non-Hispanic White women in New Mexico, we tested the hypothesis that obesity measures are associated with baseline prognostic markers and that these associations are modified by ethnicity. Among Hispanic women, breast cancer is the most commonly diagnosed cancer (30 percent) and the leading cause of death due to cancer (16 percent) (29). Although incidence rates are lower, survival rates for Hispanic women are worse compared with non-Hispanic White women. Overall, Hispanic women are more likely to be diagnosed with breast cancer at a younger age, with more advanced stage at diagnosis, with hormone receptor-negative tumors, and with worse prognosis (30, 31).
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Data collection and variable definition
Prognostic markers, stage, hormone receptor status, lymph node status, and tumor size were based on medical record abstraction. Stage of disease was based on American Joint Committee on Cancer (32) stage groupings: 0 (in situ), I, IIA, IIB, and IIIA, which in turn are based on the tumor-node-metastasis staging system. Hormone receptor assays were conducted in laboratories associated with the hospitals where cases were diagnosed. Lymph node status was based on whether nodes were examined and the number identified as positive or negative. Tumor size was based on the reported centimeters.
Data on height, weight history, demographics, and risk factors were collected via a standardized questionnaire administered by trained interviewers. Ethnicity was based on self-report at the time of interview. Self-reported weight at diagnosis, weight 1-year prior to diagnosis, and weight at ages 18, 35, and 50 years were collected to measure adult weight change. Blood samples were drawn at the time of interview.
Anthropometric measurements were taken with the subject wearing light indoor clothing or a hospital gown without shoes, using standardized methods (33). Height was measured to the nearest 0.02 cm using a wall-mounted stadiometer, and weight was measured to the nearest 0.01 kg with a calibrated-beam balance scale. Waist and hip circumferences were measured to the nearest 1.0 cm with the woman standing. Subscapular and triceps skinfold thicknesses were measured using calipers to the nearest 1.0 mm. Measuring equipment was calibrated regularly, and anthropometrists were trained and monitored by a qualified instructor. All measurements were taken twice at the time of interview, and the averages were used in analyses. Pearsons correlation coefficients for repeated measures were at least 0.99. Weight was also abstracted from medical records. Correlations among measured, abstracted, and recalled body weight were high: 0.97 between baseline weight and weight abstracted for date of surgery and 0.94 and 0.96 for measured weight at the time of interview with weight recalled by the subject for 1 year prior to diagnosis and at diagnosis, respectively.
Percent body fat was measured using dual-energy, x-ray absorptiometry (DXA) (Lunar model DPX; Lunar Radiation Corporation, Madison, Wisconsin). Eighteen percent of women did not have DXA scans. Percent body fat was predicted in these women using an equation based on bioelectric impedance and anthropometry that was calibrated against DXA and cross-validated in the women with DXA scans (34).
Statistical analyses
Analyses were based on a total of 150 Hispanic and 466 non-Hispanic White women. American Joint Committee on Cancer stage groupings were recoded as in situ (stage 0) versus invasive (stages IIIIA) for logistic regression analyses. Estrogen receptor status and lymph node status were coded as positive versus negative for invasive cases only. Tumor size was coded as less than 1.0 cm versus 1.0 cm or more. Several measures of obesity were analyzed because of its heterogeneous nature. Percent body fat and body mass index (weight (kg)/height (m)2) were included as overall measures of obesity. Waist circumference and the waist/hip ratio were used as indices of centralized body fat distribution, and the subscapular/triceps skinfold ratio was used as an index of centralized subcutaneous fat patterning (35). Young adult, midlife, late life, and lifetime weight change was calculated as differences between ages 18 and 35 years, 35 and 50 years, and 50 and 65 years and between age 18 years and age at diagnosis (excluding pregnancy), respectively. Differences between the two ethnic groups were evaluated using the appropriate statistic (Pearsons 2 or t test). All statistical tests were two sided.
Unconditional logistic regression models were used to evaluate the association of body composition and weight history measures with the prognostic markers for breast cancer (36). Separate logistic regression models were fit for each body composition or weight history measure because of the high level of association among these variables. Quartiles of the body composition and weight change distributions were derived from the combined cohort, and the second and third quartiles were combined, leaving three categories. Age, ethnicity, education, and menopausal status were included as covariates. Other covariates, including height, family history of breast cancer, age at menarche, parity, mammography screening interval, cigarette smoking for more than 6 months, and tamoxifen treatment, were evaluated but did not alter the findings and were not included in the final models. Interaction terms between ethnicity and all covariates were included in each model to provide ethnic-specific estimates of the body composition-weight history effects and to obtain significance tests. A single degree-of-freedom test of trend across the three categories of body composition-weight change was computed as a linear contrast using equally spaced weights. All p values reported for the logistic regression analyses are for the Wald chi-square statistic. Statistical analyses were performed using procedures of SAS version 8.02 (SAS Institute, Inc., Cary, North Carolina) software.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Hispanic women were somewhat more likely to have higher stage disease (stages IIAIIIA) and to have positive nodal involvement, but these differences were not statistically significant (table 2). They did, however, have larger tumors (p = 0.04) and a significantly greater percentage of estrogen receptor-negative (p = 0.003) and progesterone receptor-negative (p = 0.005) tumors (table 2). Hispanic women, compared with non-Hispanic White women, were characterized by significantly higher means on all body composition measures with the exception of body mass index at age 18 years (table 3). Additionally, they were characterized by a greater lifetime weight gain compared with non-Hispanic White women (17.4 vs. 14.3 kg; table 3).
|
|
|
Among Hispanic women, there was a nonsignificant trend of reduced risk of positive lymph node status with increased body size and adiposity that was strongest for women with a percent body fat of 43 or more (OR = 0.31, 95 percent CI: 0.07, 1.35). Results, although nonsignificant, showed an increased risk of positive lymph node status for non-Hispanic White women in the highest quartile for waist circumference, waist/hip ratio, body mass index, and subscapular/triceps ratio compared with women in the lowest quartile.
Association between weight gain and a tumor size of 1.0 cm or more showed a comparable, but nonsignificant, trend for reduced risk as seen for body composition measures among Hispanic women (table 4). Lifetime (OR = 0.22, 95 percent CI: 0.04, 1.31) and young adult (OR = 0.30, 95 percent CI: 0.08, 1.06) weight gains were associated with the greatest reductions (table 4). Weight history measures, with the exception of late life weight gain, were associated with an increased risk for tumor size of 1.0 cm or more among non-Hispanic White women. Compared with that for the lowest quartile, the odds ratio for larger tumors increased from 1.64 for young adult weight gain (95 percent CI: 0.89, 3.04) to about a twofold risk for both midlife (OR = 2.05, 95 percent CI: 1.07, 3.93) and lifetime (OR = 2.27, 95 percent CI: 1.23, 4.19) weight gains (table 4).
There were no significant associations between body composition or weight change measures and either estrogen receptor-negative status or invasive stage. Additionally, the trend seen for obesity and weight gain with tumor size and lymph node status was not apparent for these prognostic markers. Inclusion of height, parity, age at menarche, family history, tamoxifen, mammography screening interval, and smoking into the models did not alter the divergent pattern or appreciably change the effect estimates (data not shown).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Centralized obesity and the timing of its development are associated with an altered metabolic pattern (38) and may influence both breast cancer risk and prognosis. Hispanic women in the Southwest are characterized by a greater degree and an earlier age at onset of centralized obesity compared with other women (39). It is therefore interesting that in the present study Hispanic women reporting a greater young adult weight gain had a reduced risk for tumor size of 1.0 cm or more, whereas non-Hispanic White women in the highest quartile for midlife weight gain had a significant risk for increased tumor size of 1.0 cm or more. This suggests that Hispanic ethnicity interacts with the timing of weight gain to alter the associations of weight and body composition with tumor characteristics.
Previous reports on the association of obesity with increased tumor size and lymph node involvement have been inconsistent (13, 14, 40, 41). Our finding of an inverse relation of obesity and weight gain with tumor size in Hispanic women versus increased risk among non-Hispanic White women is consistent across all measures of body composition and obesity. Increased waist circumference showed the strongest association with tumor size and the most marked divergence between Hispanic and non-Hispanic White women. Waist circumference may be a more sensitive measure of centralized body fat and the associated metabolic and hormonal abnormalities than other body composition measures (42, 43). Hispanic women in general are characterized by a higher prevalence of overweight, obesity, and centralized obesity (44) compared with non-Hispanic White women, although it is unclear as to a mechanism responsible for the association seen in this study.
There are several possible limitations to this study. Participation rates were modest, more so among Hispanic women, introducing possible selection bias if nonparticipants were characterized by a differential association between body composition measures and prognostic markers. In a previous paper, we compared HEAL Study participants with all breast cancer patients in the respective SEER Program registries who met the same eligibility criteria for age, ethnicity, stage, lymph node, and estrogen receptor status (27). Age and ethnicity were similar to overall SEER Program data, but there were small differences for stage, lymph node, and estrogen receptor status. For stage, the primary difference was due to a higher number of cases in the SEER Program database with an unknown stage; however, an overall comparison of in situ with invasive disease was not significantly different (p = 0.828). A greater proportion of SEER Program cases had lymph node-positive disease (24 percent) and a negative (21 percent) or unknown (35 percent) estrogen receptor status compared with HEAL Study cases (20, 14, and 29 percent, respectively). The lower percentage of unknowns in the HEAL Study data is probably due to additional abstraction conducted after a 1-year period. A second limitation is reduced statistical power due to the small sample size, especially for Hispanic women. However, our study included a larger number of Hispanic women than most other published studies on breast cancer. Sample size was also insufficient to determine if ethnic differences in the body composition-weight change associations were confounded by menopausal status.
Recall bias related to self-reported body weight across a womans lifetime is another potential limitation. In general, accuracy is considered good (3, 45), with correlations reported to be greater than 0.80 (46, 47) and as high as 0.92 for adults (4060 years) recalling weight at age 18 years at two time points across a 12-year period (48). We were unable to assess the reliability of recalled body weight at ages 18, 35, or 50 years. However, we compared weights from a variety of sources, including measurement at interview, self-report for 1 year prediagnosis and at diagnosis, and medical record report at the time of surgery. Correlations across these direct and indirect measures were greater than or equal to 0.94 with no significant differences by ethnicity. Effect estimates based on body mass index measured during the interview were comparable in direction and magnitude with those based on recalled weight.
Despite these potential limitations, our data suggest a divergent pattern between Hispanic and non-Hispanic White women for the association of body composition and weight history with tumor characteristics and prognostic markers. The consistent finding of an inverse association between both obesity measurements and self-reported adult weight and height with increased tumor size and positive nodal status among Hispanic women, in contrast to an increased risk among non-Hispanic White women, argues for the presence of an important modifying effect by ethnicity, rather than a chance finding. However, this possibility cannot be ruled out. This consistency is suggestive of a trend that is unlikely to be due to any single factor such as recall bias or measurement bias.
We hypothesize that Hispanic ethnicity modifies the hormone-mediated effects of obesity on breast cancer. Hispanic women may be less susceptible to the obesity-associated proliferative effects of estrogen on breast epithelium. The mechanisms underlying this hypothetical reduced susceptibility are unknown but may involve factors regulating the expression of hormone receptors as well as circulating concentrations of hormones other than estrogen. It is possible that Hispanic women have a different distribution of genetic polymorphisms than do non-Hispanic White women, which modify obesity-related hormonal risk factors for tumor phenotype. At present, these genes are unknown and this hypothesis is speculative.
Estrogen receptor-positive status increases with age and predicts a better response to estrogen-blocking treatments such as tamoxifen, whereas estrogen receptor-negative status is characterized by a poorer response to treatments targeted at the estrogen axis and more aggressive metastatic potential and is correlated with other negative prognostic factors including poorly differentiated tumors, a high Ki-67 proliferative index, increased cathepsin D, and genetic abnormalities including p53 mutations (4951). Previous studies have documented that estrogen receptor-negative tumors are more frequent among Hispanic (30 percent) women compared with non-Hispanic White (22 percent) women and are associated with early age at disease onset (52, 53). In this study, prevalence estimates for estrogen receptor-negative tumors were 26 percent for Hispanic versus 15 percent for non-Hispanic White women, comparable to estimates (27 vs. 20 percent) previously reported for New Mexico women (54). The reason for a higher frequency of estrogen receptor-negative status in Hispanic women is unknown but may be genetically based.
In conclusion, we hypothesize that the obesity-estrogen model of breast cancer developed mainly from studies of non-Hispanic White women may not necessarily apply to Hispanic women. Obesity-related changes in estrogen and metabolism may not have the same relation to breast cancer risk or prognosis in Hispanic women as in non-Hispanic White women. Further examination of the HEAL Study data, which include hormonal and metabolic markers, histopathologic markers, dietary intake, and physical activity level, may help to illuminate the apparent ethnic difference in the relation of obesity to prognostic markers and may clarify whether the relations suggested in this report are pertinent for recurrence and survival. These findings suggest that Hispanic women may have a different breast cancer phenotype than non-Hispanic White women have, which associates differently with body composition and weight history. Prognosis studies with an emphasis on a larger sample of Hispanic women are warranted.
![]() |
ACKNOWLEGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|