Recreational Physical Activity and Breast Cancer Risk among Women under Age 45 Years

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1 American Journal of Epidemiology Copyright 1998 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 147, No. 3 Printed in U.S.A. Recreational Physical Activity and Breast Cancer Risk among Women under Age 45 Years Marilie D. Gammon, 1 Janet B. Schoenberg, 2 Julie A. Britton, 1 Jennifer L Kelsey, 3 Ralph J. Coates, 4 Donna Brogan, 5 Nancy Potischman, 6 Christine A. Swanson, 6 Janet R. Daling, 7 Janet L. Stanford, 8 and Louise A. Brinton 6 To evaluate whether recreational physical activity is associated with breast cancer among young women, the authors analyzed data from a population-based case-control study. Cases (n = 1,668) were women under age 45 years who had been newly diagnosed with breast cancer between 1990 and 1992 in Atlanta, Georgia, central New Jersey, or Seattle, Washington. Controls (n = 1,505) were frequency-matched to cases by 5-year age group and geographic area of residence. Breast cancer was not associated with recreational activity in any of the three time periods assessed (highest quartile of activity vs. lowest: age- and center-adjusted odds ratio (OR) = 0.94 (95% confidence interval (Cl) ) at ages years, OR = 1.08 (95% Cl ) at age 20 years, and OR = 1.18 (95% Cl -1.44) during the past year), with the average of the three time periods (OR =, 95% Cl ), or with daily climbing of at least two flights of stairs (without stopping) during the past year (daily climbing vs. never climbing: OR = 1.03, 95% Cl ). Estimates were not modified or confounded by body mass index, menopausal status, or caloric intake during the past year. These results do not support a protective role for physical activity in the risk of breast cancer among young women. Am J Epidemiol 1998; 147: breast neoplasms; exercise The evidence for an inverse relation between recreational physical activity and breast cancer risk is conflicting (1). Of the recently published studies (2-19), seven show a significant reduction in risk of approximately percent (2, 6, 8, 10, 11, 15, 18), four are supportive of an inverse relation (7, 9, 17, 19), and seven show no effect or even an increase in risk (3-5, 12-14, 16). Among those that show a protective effect, additional questions remain unanswered: first, whether the risk reduction applies to all women or is limited to Received for publication January 30,1997, and in final form June 25, Abbreviations: Cl, confidence interval; METs, metabolic equivalents; OR, odds ratio. 1 Division of Epidemiology, Columbia School of Public Health, New York, NY. 2 Applied Cancer Epidemiology Program, New Jersey Department of Health and Senior Services, Trenton, NJ. 3 Division of Epidemiology, Department of Health Research and Policy, Stanford University, Stanford, CA. 4 Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA. 5 Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, GA. 6 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD. 7 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. 8 Division of Public Health Sciences, University of Utah, Salt Lake City, UT. premenopausal women; second, whether there is an optimal time period in which the physical activity should occur, such as adolescence or early adulthood; and third, whether the intensity, frequency, or duration of the activity is important (1). Clarification of these issues is important. About half of all breast cancer cases can be explained by known risk factors for the disease (20), and most of the factors are not easily amenable to modification (1, 21, 22). Consequently, a possible protective role for physical activity holds promise in the development of an effective strategy for breast cancer risk reduction (23-25). To explore further the association between recreational physical activity and breast cancer among young women, we analyzed data from a recently conducted case-control study. MATERIALS AND METHODS The methods of this population-based case-control study (which was undertaken with the primary purpose of evaluating whether breast cancer risk in young women is positively associated with long-term oral contraceptive use, alcohol consumption, or adolescent diet) have been previously described (26). Briefly, cases were women under age 45 years with invasive or in-situ breast cancer newly diagnosed between May 1, 273

2 274 Gammon et al. 1990, and December 31, 1992, who were residents of one of three US geographic areas with a tumor registry: the metropolitan areas of Atlanta, Georgia, and Seattle, Washington, and five centrally located counties in New Jersey. Controls were women identified through Waksberg's method of random digit dialing (27), and they were frequency-matched to cases by 5-year age group and geographic center. Face-to-face interviews were completed with 1,668 cases (85.7 percent) and 1,505 controls (78.7 percent). Telephone numbers assessed as residential were called so that a brief telephone interview could be conducted to screen for eligibility. The screener response rate was 90.5 percent, yielding an overall response rate of 71.2 percent among control women. Primary reasons for nonparticipation in the study interview included subject refusal (6.6 percent and 12.9 percent of case and control women, respectively) and (among cases) physician refusal (5.8 percent). The median length of the structured questionnaire interview was 71 minutes. The interview included questions on contraceptive and reproductive histories, exogenous hormone use, medical history, family history of cancer, lifetime alcohol use, adolescent diet, smoking, and demographic characteristics. In addition, respondents completed a self-administered, 100-item food frequency questionnaire (28). Anthropometric measurements were also taken. Subject responses for many of the established and suspected risk factors for breast cancer have been previously described (26). Briefly, increased risks were noted among women who reported black race, nulliparity or low parity, a late age at first birth, a previous breast biopsy, a first degree relative with breast cancer, long-term use of oral contraceptives, frequent alcohol intake, or low body mass (26). The frequencies of vigorous and moderate physical activity were assessed by questionnaire for three different time periods: ages years, age 20 years, and the year prior to the interview (referred to as the past year). For example, to assess vigorous activity levels during the past year, the respondent was asked, "Now think about your physical activity over the last 12 months, ignoring any recent changes. How often did you participate in vigorous activities such as lap swimming, dance, basketball, gymnastics, running, fast cycling, aerobics, or field hockey?". Respondents were also shown a card with frequency categories listed as daily, 4-6 times per week, 2-3 times per week, once per week, 1-3 times per month, or less than once per month or never. For each time period, similar questions were used to determine the frequency of moderate physical activities such as brisk walking, volleyball, recreational tennis, softball, leisurely cycling, or golfing. Because our assessment of recreational physical activity included measures of intensity (vigorous and moderate) and frequency (times per week or month) but not of duration (hours per episode of activity), estimates of kilocalories expended per day or per week could not be derived. Instead, vigorous and moderate physical activities for each of the three time periods were combined into a single activity score (29). First, vigorous and moderate activities were assigned a metabolic equivalent (MET) score, defined as the ratio of working metabolic rate to resting metabolic rate (29). The MET scores for vigorous (nine) and moderate (five) activities were then weighted by the midpoint of the reported frequency of the activity, converted to frequency of activity per week where appropriate, and summed to yield relative units of recreational physical activity per week for each time period. For example, a woman who reported her activity level during the past year as participation in vigorous activities 4-6 times per week (five times/week X 9 METs) and participation in moderate activities once per week (one time/ week X 5 METs) would be assigned 50 relative units of physical activity for the past year. The mean relative units of recreational physical activity were then calculated over the three time periods. During the interview, women were also asked whether they had participated in sports, such as gymnastics or ballet, that required them to keep their weight low when they were 12 or 13 years of age. Additionally, respondents were queried about how often they had climbed two or more flights of stairs (defined as >10 steps) without stopping during the year prior to the interview. Unconditional logistic regression (30) was used to determine odds ratios (estimates of relative risk) for breast cancer and their corresponding 95 percent confidence intervals. Relative units of recreational physical activity for each time period and for the average of the three time periods were evaluated 1) as quartiles (based on the distribution among the controls), using indicator variables, 2) as continuous variables, and 3) by partitioning activity to isolate the very highest levels. These methods yielded similar results; for simplicity, only the data based on quartiles are shown. All logistic regression analyses controlled for age and center. Multivariate models were also constructed to adjust for potential confounding and to statistically evaluate effect modification. Factors that were considered as potential confounders or effect modifiers included menopausal status, age at menarche, marital status, age at first birth, number of pregnancies, number of live births, number of miscarriages, number of

3 Physical Activity and Breast Cancer 275 induced abortions, ever lactating, level of education, family income, race, body mass index (weight (kg)/ height (m) 2 ) at age 20 years, adult body mass index (past year), months of oral contraceptive use, ever use of menopausal estrogens, usual alcohol use, smoking, caloric intake during the past year, history of breast biopsy, family history of breast cancer, frequency of breast self-examination and mammography, and interval of time between the interview and the reference date (date of diagnosis for cases and date of identification for controls). The distributions for many of these covariates by case-control status have been previously published (26). Polytomous logistic regression (30) was used to derive the odds ratios and corresponding confidence intervals with cases partitioned in two ways: by stage (in-situ (n = 227) or invasive (n = 1,389) cancer, with 31 cases having unknown stage of disease) or by treatment status (i.e., whether they received chemotherapy). For comparability, cases without a telephone at the time of diagnosis {n - 21) and controls with a history of breast cancer (n = 4) were excluded. Thus, 1,647 cases and 1,501 controls were available for these analyses. RESULTS When reported activities were converted to relative units of physical activity as described above, control women who reported that during the past year they had participated in vigorous activities more than four times per week or in moderate activities daily were, in general, classified in the highest quartile of physical activity. In contrast, those who reported participating in both vigorous and moderate activities three times or less per month during the past year were generally classified in the lowest quartile of relative units. The distributions of the relative units of physical activity for each of the three time periods and for the average of the three time periods ranged from a low of 1.62 to a high of Among control women, the median relative units of physical activity were 48 for ages years, 14 for age 20 years and the year prior to interview, and 30 for the average of the three time periods. Pearson correlation coefficients between relative units-for each of- the three time- periods and the average of the three periods were 0.77 for ages 12-13, 0.72 for age 20, and 0.56 for the past year. Correlations among the three time periods were not high: 0.32 for the correlation between ages and age 20; 0.11 for that between ages and the past year; and 0.22 for age 20 and the past year. We examined the distributions of the average physical activity scores of the three time periods among control women according to selected established and suspected risk factors for breast cancer. Among controls, New Jersey women were significantly more likely to be below the median of average physical activity, and those in the highest quartile of past-year caloric intake were more likely to be above the median of average physical activity {p < 0.05). In addition, control women were more likely to be above the median of the average physical activity score of the three time periods if they were younger than 42 years of age, had had a first birth before age 22 years, had a family income of $34,000 or less, identified themselves as African-American, consumed seven or more alcoholic drinks per week, or were in the highest quartile of past-year caloric intake (> 1,831 kcal/day) (p < 0.10); also, controls were more likely to exercise at or below the median levels if they had a family history of breast cancer {p < 0.10). Table 1 gives the odds ratios for breast cancer by physical activity level in the three time periods assessed, and for the estimated average of the three time periods. Breast cancer risk among women under age 45 years was not associated with recreational physical activity. Among young women who reported weekly activity levels at ages years that were in the highest quartile, the age- and center-adjusted odds ratio was 0.94 (95 percent confidence interval (CI) ) compared with women in the lowest quartile. With further adjustments for age at first birth, race, usual alcohol use, caloric intake in the past year, family income, and family history of breast cancer, the comparable estimate of effect was only slightly altered (multivariate adjusted odds ratio (OR) = 0.98, 95 percent CI ). As table 1 shows, none of the estimates observed for weekly physical activity at age 20 years, the year prior to the interview, or the average of the three time periods were substantially different from a null effect. Table 2 shows breast cancer risk in relation to the average of recreational physical activity levels over the three time periods, stratified by age at diagnosis, age at menarche, menopausal status, body mass index at age 20 and in adulthood, and caloric intake during the year prior to interview. Although there was a consistent reduction in risk across levels of physical activity among-women in the highest quartile~of-pastyear caloric intake, the formal evaluation of interaction between physical activity and caloric intake using logistic regression was not statistically significant (p > 0.05). Breast cancer risk in relation to recreational physical activity was also not found to vary substantially with any of the other factors shown in table 2, or with any of the covariates listed in "Materials and Methods." In addition, there was little heterogeneity in the relation with physical activity assessed in any of the three time periods (data not shown).

4 276 Gammon et al. TABLE 1. Odds ratios for breast cancer in relation to recreational physical activity, by time period, among 3,148 women under age 45 years in Atlanta, central New Jersey, and Seattle, Time period and physical activity (relative units*) Ages years 1 ( ) 2 ( ) 3 ( ) 4 ( ) p for linear trend No. of controls (n = 1,501)t No. of cases 1,647)t Ageand centeradjusted OR* % CIJ OR adjusted for multiple variables % Cl OR adjusted for multiple variables^ % Cl Age 20 years 1 ( ) 2 ( ) 3( ) 4 ( ) p for linear trend Past year (year before interview) 1 ( ) 2 ( ) 3( ) 4 ( ) p for linear trend Average of the three time periods 1 ( ) 2( ) 3 (30.01^*2.95) 4 ( ) p for linear trend * For calculation of relative units, see "Materials and Methods." t Numbers of cases and controls given are those for the model that adjusted for age and center. Information on past-year and average recreational physical activity was missing for one case. t OR, odds ratio; Cl, confidence interval. Adjusted for age, center, age at first birth, race, alcohol, caloric intake in the past year, family income, and family history of breast cancer. For this model, 95 cases and 87 controls had missing information on at least one of the covariates. U Adjusted for age, center, age at first birth, age at menarche, parity, lactation, number of abortions, number of miscarriages, menopausal status, marital status, education, family income, race, body mass index at age 20 years, body mass index in adulthood, months of oral contraceptive use, use of menopausal estrogens, alcohol use, smoking, caloric intake in the past year, history of breast biopsy, and family history of breast cancer. For this model, 150 cases and 190 controls had missing information on at least one of the covariates. Results were not materially changed when analyses were conducted that included imputed values for variables with missing information for a number of women, such as body mass index. There was limited variation in risk among case women by stage (in-situ vs. invasive disease) and by treatment status (whether they received chemotherapy) (data not shown). The risk of breast cancer among women under age 45 was not associated with self-reported moderate or vigorous activities (e.g., prior to conversion to a single score). Age- and center-adjusted odds ratios for engaging in physical activity daily, versus less than once per month, were as follows: 0.88 (95 percent Cl ) and 0.93 (95 percent Cl ) for moderate and vigorous activity, respectively, at ages years; 1.01 (95 percent Cl ) and 1.20 (95 percent Cl ) at age 20 years; and 1.10 (95 percent Cl ) and 1.32 (95 percent Cl ) during the year prior to interview. There was also no indication that risk was associated with participation in sports that required keeping weight low at ages years (ever vs. never participating: ageand center-adjusted OR = 1.06, 95 percent Cl ) or with daily climbing of two or more flights of stairs without stopping during the year prior to interview (ever vs. never climbing: age- and centeradjusted OR = 1.03, 95 percent Cl ). These

5 Physical Activity and Breast Cancer 277 TABLE 2. Odds ratios for breast cancer risk according to quartile of the average of recreational physical activity levels over three time periods (ages years, age 20 years, and the past year), by selected covanates, among 3,148 women under age 45 years in Atlanta, central New Jersey, and Seattle, Covariate Age (years) at diagnosis < >42 Age (years) at menarchs < Menopausai status Premenopausal PostmenopausalU Postmenopausal* Body mass index** at age 20 years < Body mass index in adulthood (past year) < Caloric intake during the past year (kcal/day) <1,129 1,129-1,455 1,456-1,830 1,831 No. of controls (n- 1,501) , No. of cases (n = 1,647) , ( ) ORt4 Quartile of the average of activity over the three time periods (relative units*) 2 ( ) OR % Clt ( ) OR % Cl ( ) OR % Cl * For calculation of relative units, see "Materials and Methods." t OR, odds ratio; Cl, confidence interval. t Reference category. Adjusted for age and center. Information was missing on average recreational physical activity for one case subject; on age at menarche for two cases and two controls; on menopausai status for two cases and five controls; on body mass index at age 20 years for 33 cases and 32 controls; on body mass index in adulthood for 53 cases and 105 controls; and on caloric intake during the past year for 59 cases and 50 controls. 11 Includes women who were naturally postmenopausal and those who were surgically postmenopausal with no ovaries remaining. # Includes women who were surgically postmenopausal with ovaries remaining and those who were postmenopausal for medical and unknown reasons. ** Weight (kg)/height (m)*. estimates were not confounded or modified by the other factors listed in "Materials and Methods." DISCUSSION Our study has many methodological strengths, including a population-based sample of women from three geographically diverse locations, relatively high response rates among cases and controls, and a highly structured questionnaire that assessed a comprehensive list of potential confounders and effect modifiers. In addition, the study assessed the frequency of vigorous and moderate physical activities at three different points in time (menarche, early adulthood, and later adulthood) that are relevant to two possible biologic mechanisms by which exercise may affect breast cancer (a change in menstrual characteristics or a change in body size). Nevertheless, limitations of these data should be considered, including possible problems with recall. Case and control women were asked to report participation in recreational physical activities for three time periods, including years of age, which for

6 278 Gammon et al. respondents in their fifties was about 30 years earlier. Remembering one's frequency of participation in physical activities at specific ages may be difficult. If there was poor recall of exercise based on women's being asked to remember events in the distant past, we would expect to see variation in reported activity levels by the ages of the subjects at identification; this relation was not observed in our data. If recall of physical activity were affected by the cases' breast cancer diagnoses, risk might be expected to vary with the length of time between diagnosis and interview, or according to tumor stage (i.e., in-situ vs. invasive cancer) or treatment status. However, we observed no substantial variations in risk by these factors. Although the study hypothesis was not widely known at the time the subjects were interviewed, physical, activity has been well publicized as socially and medically desirable. Thus, it is possible that both cases and controls may have overreported their exercise levels, especially their levels at a young age. Exposure misclassification may also have resulted from our lack of information on number of hours spent in each activity (e.g., duration), although we did collect information on the frequency and intensity of recreational exercise. If such nondifferential errors did occur in these data, any true protective effect of physical activity may have been masked; alternatively, spurious effects are possible, though unlikely, given the fact that our exposure assessment was not simply dichotomous (31). The assessment instrument we used is very similar to that in an Australian study which reported a reduction in breast cancer risk (7). Our study and the Australian study slightly modified the original instrument, which has been assessed for validity (29), prohibiting direct comparison of the reported recreational activity levels. In our assessment of physical activity, we did not consider other sources of activity such as occupational activity or activities of daily living. This may have resulted in some misclassification of exposure, primarily between moderate and vigorous levels of activities (32), among cases and controls. However, it is unclear whether there is an association between breast cancer risk and occupationally derived exercise or with a combined measure of activity from recreational and occupational sources (1). In addition, other case-control studies that have considered only recreational levels of activity, rather than both recreational and occupational levels, have been able to detect a decrease in breast cancer risk (6-10, 14). Other US investigations have also found no decrease in risk in relation to recreational activity, including three cohort studies from University of Pennsylvania alumni (3), the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (4), the Framingham Heart Study (5), and four case-control studies (12-14, 16). This is in contrast to two other cohort studies (one carried out among US college alumni (2) and one among Danish screenees (11)) and eight casecontrol studies (four among Americans (6, 8,10,18), two among Japanese (15,17), one among Australians (7), and the other among Italians (9)) that have observed a decrease in risk that is often modest in magnitude. Reasons for the discrepant results across studies are not entirely clear, but they could be due to variations in the assessment of recreational physical activity (1). Valid and reliable measurement of current or historical physical activity levels by questionnaire is difficult (33-35). If there is a true relation between exercise and breast cancer, it may be difficult to detect and estimate with any accuracy, given the high level of measurement error in the instruments used (30). In addition, the critical time period in which the activity occurs could also affect study results (1). For example, if physical activity reduces breast cancer risk by affecting menstrual characteristics in the period just prior to or following menarche (36), then measurement of activity levels during adolescence and the teenage years should be of high priority. However, if physical activity affects breast cancer risk among postmenopausal women by reducing body size (1), then measurement of adult physical activity levels may be more important. Studies which show that ballet dancers and others who engage in strenuous activities have activity-related changes in menstruation onset or other menstrual characteristics (37, 38) suggest that the intensity, frequency, or duration of the activity may be important (1). The five previously published cohort studies, three of which showed no association between breast cancer and recreational activity, generally relied on physical activity levels recorded at baseline in adulthood (4, 5, 11) or in college records (2, 3). In contrast, the 12 case-control studies, seven of which have observed a decrease in risk with increasing activity, have been able to more completely assess lifetime physical activity levels (6) or levels at several different points in a woman's life (9, 12, 14, 16-18). To date, the most complete method used to assess recreational activity was that used by Bernstein et al. (6) and Carpenter et al. (10), who reported a 40 percent reduction in risk among women under age 40 years (6) and a 50 percent reduction among women over age 55 (10). Although our method of assessing recreational physical activity was not as comprehensive as that of Bernstein and colleagues (6, 10), women in our study were asked to report on the intensity and frequency of the exercise in which they engaged at three different points in time

7 Physical Activity and Breast Cancer 279 that are relevant to two possible biologic mechanisms. Our assessment method improves upon many previously used instruments which have relied on college records (2, 3) or on a simple self-assessment score (4, 11, 12), or which were restricted to assessment of activity in a single period of time (2-5, 7, 8, 11, 13). Another possible reason for the discrepant results across studies is the variation in age or menopausal status among the study subjects (1). However, even when studies are partitioned according to menopausal status, results remain conflicting. Of the 11 studies (4, 5, 7, 8, 10-15, 17) that reported on postmenopausal women only, six case-control studies (7, 8, 10, 14, 15, 17) and two cohort studies (4, 11) reported a decrease in risk; three were statistically significant (10, 14, 15). The other four investigations with information on risk among postmenopausal women a cohort study (5) and three case-control studies (12, 13, 17) showed either an increase in risk or no association with physical exercise. Of the seven previous studies (4, 6,7, 11, 13, 15, 17) that reported on premenopausal women only, two case-control studies (6, 7) and one cohort study (11) observed a decreasing trend in risk with increasing levels of activity, and three case-control studies (13, 15, 17) found a nonsignificant decrease in risk but no apparent trend. In contrast, the one remaining study on premenopausal women, a cohort study (4), observed a nonsignificant increase in risk. In conclusion, our data do not support the hypothesis of a reduced risk of breast cancer among young women with increased recreational physical activity in adolescence, in young adulthood, or during the year prior to interview, or with the average of activity over the three time periods. 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