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Physical activity reduces breast cancer risk: A case–control study in Tunisia
Cancer Epidemiology 35 (2011) 540–544
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Physical activity reduces breast cancer risk: A case–control study in Tunisia Msolly Awatef a,*, Gharbi Olfa a, Chafai Rim a, Kassab Asma b, Mahmoudi Kacem a, Hochlef Makram a, Ben Fatma Leila a, Landolsi Amel a, Ben Ahmed Slim a a b
Department of Medical Oncology, CHU Farhat Hached, Sousse 4000, Tunisia Biochemistry Laboratory, CHU Farhat Hached, Sousse 4000, Tunisia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 November 2010 Received in revised form 13 February 2011 Accepted 16 February 2011 Available online 5 April 2011
Purpose: This study examined the relationship between lifetime history of physical activity and breast cancer risk. Methods: The case–control study was conducted on 400 women with histological confirmed breast cancer operated during the 2006–2009 period at Farhat Hached University Hospital, Sousse, Tunisia, and 400 cancer-free controls, aged 25–75 years. The physical activity was assessed using a structured questionnaire on each activity: type, duration, frequency, and intensity. Odds ratios (ORs), 95% confidence intervals (CI) and a full confounding assessment, included in this analysis, were derived using logistic regression. Results: These cases had lower lifetime averages for total physical activity for both forms of activity measurements (hours/week/year and MET-hours/week/year) and (Ptrend < 0.001 and Ptrend = 0.002, respectively). Significant risk reductions were found in total physical activity for both forms of activity measurements (OR = 0.27, 95% CI: 0.18–0.52, OR = 0.42, 95% CI: 0.26–0.73, respectively) for the highest versus the lowest level of activity (Ptrend = 0.001 and 0.004, respectively). The stratification by menopausal status showed a significant 56% reduction in breast cancer risk for postmenopausal women (Ptrend = 0.001, adjusted for age). The risk was further reduced to 68% (Ptrend = 0.002, multivariate adjusted). Among pre-menopausal women, the total physical activity was not significantly associated with reduced risk, ORs were 0.88 (95% CI: 0.40–1.99, age adjusted) and 0.43 (95% CI: 0.12– 1.38, multivariate adjusted). Conclusion: These data are in concordance with the majority of previous reports which involved physical inactivity as an important risk factor for breast cancer. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Physical activity Case–control study
1. Introduction Breast carcinoma is the most common malignancy diagnosed among women in Tunisia. It accounts for 20–25% of malignant tumours in Tunisian women with an annual incidence of about 2.15 cases per 10,000 women [1]. Extensive research has been conducted on the etiology of this disease. The majority of them have been carried more of interest on hormonal, family history, reproductive and dietary factors showing that the risk is increased by obesity in postmenopausal women, early menarche, late menopause and excessive alcohol consumption [2]. However, most of risk factors are not easily modifiable. Physical activity is one of
Abbreviations: MET, metabolic equivalent; OR, odds ratios; CI, confidence interval; BMI, body mass index; HRT, hormonal releasing therapy; SD, standard deviation. * Corresponding author. Tel.: +216 73219502; GSM: +216 97867155; fax: +216 73226702. E-mail addresses: [email protected] (M. Awatef), [email protected] (G. Olfa), [email protected] (C. Rim), [email protected] (K. Asma), [email protected] (M. Kacem), [email protected] (H. Makram), [email protected] (B.F. Leila), [email protected] (L. Amel), [email protected] (B.A. Slim). 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.02.011
the few known modifiable factors. The past 20 years of epidemiological research has generated a large body of evidence describing the benefits of physical activity in relation to breast cancer risk [3], and has been shown that physical activity may reduce the risk of breast cancer [4–9]. With reference to a recent study published on 2010 [3], 73 separate studies published to date has been focused on the aetiological role of physical activity in relation to breast cancer risk. More than three quarters of these studies have observed a beneficial effect of physical activity on breast cancer risk. More evidence for a protective effect of physical activity against breast cancer in a report from the International Agency for Research on Cancer, who has estimated that one fourth to one third of cancer cases, may be attributable to the combined effects of elevated body weight and inadequate physical activity [10]. In order to provide further information on the relation between physical activity and breast cancer risk among Tunisian women, we considered data from a case–control study of breast cancer, including detailed information on lifetime physical activities with all parameters (duration, intensity, frequency). Physical activity was quantified in terms of estimated metabolic equivalents. To develop a better understanding of potential mechanisms linking physical activity to the relative risk of
M. Awatef et al. / Cancer Epidemiology 35 (2011) 540–544
breast cancer, we assessed the interplay between physical activity and other risk factors for breast cancer, including weight gain, breastfeeding and parity.
2. Materials and methods After the hospital approvals were obtained, histological confirmed breast cancer cases were ascertained from November 2006 to April 2009 from Farhat Hached University Hospital, Sousse, Tunisia. The cases were limited to 25–75-year-old women without previous diagnoses of other cancers. A total of 400 female breast cancer cases were identified from participating hospitals, and all of them participated in the study and were included in the analyses. Controls were 400 patients, admitted to the hospitals in the same catchment area as cases, free of any cancer diagnosis and without earlier physical limitation. The major diagnostic categories were eye diseases (20%); tooth extraction, nose and throat conditions (12%); stomach flu or other digestive infections (8%); surgery such as appendicitis, strangulated hernia, haemorrhoids, or other conditions (17%); lower back pain and disk problems (9%); diabetes (18%); irregular heart rates and other acute circulatory conditions (11%); acute urinary tract infection (5%). A total of 98% (400/408) of the controls identified initially participated in the study. Selection of controls was restricted to patients whose current hospital admission was for a condition diagnosed within 1 year of the interview to reduce the proportion of controls who might have modified their habits as a result of having a chronic disease. Efforts were made to frequency match the cases and controls by age (within 5-year intervals). The study was approved by the Ethic Committee of Farhat Hached University Hospital, Sousse, Tunisia, and all participants provided informed consent. The participants were interviewed by the same interviewer in an area of each hospital allocated for the study, using a structured questionnaire. They were asked about their activity performed at various levels of intensity, including activities performed at work, leisure, and around the home. The following activities were ascertained: work activities (time spent sitting, standing, and walking); sports and conditioning activities (school sports, teams); individual activities (walking, cycling); activities performed at home (major cleaning, light daily housework, quiet inactivity). For each activity, women were asked to report the number of years spent in activity, months per year, days per week and hours per day. The same questionnaire was also used to collect information on other potential confounding factors, including personal and family history of breast cancer up to the reference year (the year before diagnosis for the cases or the year before selection into the study for the controls), dietary intake during the reference year, menstrual and reproductive history, oral contraceptives use and hormone replacement therapy (HRT). The intensity of physical activity is quantified using a specific metabolic equivalent (MET) values assigned to each activity, abstracted from Ainsworth et al.’s Compedium of Physical Activities [11,12]. The averages MET-hours/week/year spent in physical activity over a woman’s lifetime were calculated by multiplying the number of hours/week/year a woman practised a particular activity by the MET score described to that activity. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for various levels of lifetime physical activity, calculated by using SAS statistical software [13], were derived using unconditional logistic regression. Data were stratified by menopausal status to replicate prior analyses performed in western studies, which have suggested that physical activity may affect pre- and post-menopausal women differently.
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Variables considered as confounders were: age, education (illiterate, elementary school, secondary school and higher education), marital status (never married, married, widowed, divorced), body mass index (BMI) at reference year (<21, 21–24, 25 kg/m2), age at menarche (13, 14–15, 16 years), age at first full-term pregnancy (<20, 20–25, 26 years), number of pregnancies (0, 1, 2, 3), duration of breastfeeding (0, <6, 6 months), use of oral contraceptives (never, ever), post-menopausal HRT use (never, ever), menopausal status (pre-menopausal, post-menopausal), age at last menstrual period (<45, 45–50, 51 years) and family breast cancer history (no, yes). Categorical tests for trend were conducted by using a likelihood ratio statistic in a logistic regression model, and the MET score was used as a continuous variable. 3. Results The statistical comparison between cases and controls showed no significant difference in terms of education, marital status, age at menarche, age at first full-term pregnancy, pregnancy number, hormone use, age at menopause (Table 1). Compared to controls,
Table 1 Selected demographic characteristics of breast cancer cases and controls in Tunisia. Cases (n = 400) Education Illiterate 229 Elementary school 116 Secondary school 43 High education 12 P value Marital status Never married 46 Married 285 Widowed 51 Divorced 18 P value Age at menarche 13 166 14–15 157 16 77 P value Age at first full term pregnancy Nullipared 11 <20 57 20–25 281 26 51 P value Pregnancy number 0 12 1 159 2 117 3 112 P value Oral contraceptive use Never 259 Ever 141 P value Age at menarche <45 27 45-50 114 51 57 P value 2 Body mass index (kg/m ) <21 49 21-24 159 25 192 P value
Controls (n = 400)
206 67 83 44
30 321 36 13
189 120 91
4 75 283 38
7 150 121 122
ORa (95% CI)
1.00 4.07 (2.09–7.92) 6.34 (3.13–12.85) 0.10
1.00 1.10 (0.47–2.58) 0.64 (0.30–1.33) 0.37 1.00 1.49 (1.08–2.04) 0.96 (0.66–1.39) 0.23
1.00 1.30 (0.89–1.91) 1.76 (1.02–3.04) 0.11
1.00 0.91 (0.65–1.27) 0.86 (0.61–1.21) 0.69
203 97
1.00 1.56 (0.39–4.28) 0.37
31 112 35
1.00 1.16 (0.65–2.08) 1.87 (0.96–3.63) 0.13
66 150 184
1.00 1.52 (1.02–2.25) 1.35 (0.92–2.01) 0.41
OR, odds ratio; CI, confidence interval. a Odds ratios for each selected characteristic were adjusted for all other selected characteristics listed in this table.
M. Awatef et al. / Cancer Epidemiology 35 (2011) 540–544
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Table 2 Mean values of lifetime total physical activity in cases and controls. Type of physical activity, time specific measure
Mean value (S.D.) Hours/week/year
Total activity
MET-hours/week/year
Cases
Controls
P value
Cases
Controls
P value
46.9 (16.6)
53.2 (15.2)
<0.001
137.9 (58.1)
152.1 (60.9)
0.002
MET, metabolic equivalent; SD, standard deviation.
Table 3 Odds ratios for breast cancer according to lifetime total physical activity. Physical activity (hours/week/year) Total physical activity
Cases (numbers)
Controls (numbers)
<40 40–50
162 136
95 148
>55
102
157
Ptrend
OR (95% CI)
Physical activity (MET-hours/week/year)
Age adjusted
Multivariable adjusted
1.00 0.53 (0.35–0.82) 0.37 (0.23–0.56) <0.001
1.00a 0.39 (0.22–0.69) 0.27 (0.18–0.52) 0.001
Cases (numbers)
Controls (numbers)
<110 110–150
147 128
106 129
>150
125
165
OR (95% CI)
Age adjusted
Multivariable adjusted
1.00 0.70 (0.45–1.06) 0.52 (0.33–0.79) 0.004
1.00a 0.59 (0.34–1.10) 0.42 (0.26–0.73) 0.004
OR, odds ratio; CI, confidence interval; MET, metabolic equivalent. a Adjusted for age, BMI, breastfeeding, parity.
cases had a higher BMI (26.88 4.91 kg/m2 for cases and 25.62 4.17 kg/m2 for controls). The distribution of cases and controls according to lifetime total physical activity is given in Table 2. The cases had lower lifetime averages for total physical activity for both measurements (hours/week/year and MET-hours/week/year) of physical activity (Ptrend < 0.001 and Ptrend = 0.002, respectively). High risk reductions were found in total physical activity for both measurements (hours/week/year and MET-hours/week/year) of physical activity for the highest versus the lowest level of activity (Table 3). The statistical significant trends of breast cancer decreasing risk with increasing levels of activity were found in both measurements (hours/week/year and MET-hours/week/year) of physical activity (Ptrend = 0.001 and 0.004, respectively). The breast cancer risk associated with lifetime physical activity was stratified by menopausal status (Table 4). Among premenopausal women, the total physical activity was not significantly associated with reduced risk. On the contrary, for postmenopausal women a significant 56% reduction in breast cancer risk, when adjusted on five-year age-groups, was observed. The risk was further reduced to 68% after multivariate adjustment. BMI and parity were mainly responsible for that reduction. Evidence for trends in decreasing risk with increasing physical activity for these women were found significant in both analyses (Ptrend = 0.001, adjusted for five-year age-groups, and Ptrend = 0.002, multivariate adjusted).
4. Discussion The results from this study mainly revealed an inverse association between lifetime total physical activity and breast cancer risk for all women. The relationship, however, was more consistent when all women’s activities were measured by average hours/week than by average MET-hours/week. According to menopausal status, statistically significant reduced risk of breast cancer was found only for post-menopausal women; this may be due to the limited number of pre-menopausal women, which prevents the study to have sufficient statistical power to evaluate the effect of physical activity on their risk. A potential inverse association between lifelong physical activity and breast cancer risk is biologically plausible. Several mechanisms have been proposed to explain the observed association as reviewed by other studies [14,15], these included a positive effect of the activity on: endogenous sex steroid hormone production, fat tissue storage, levels of peptide hormones and growth factors such as insulin and insulin like growth factor I (IGF-I) and on improving the immune and antioxidant systems. However, the relationship between lifetime physical activity and breast cancer risk according to menopausal status has been inconsistent in the literature. As in our study, a study in Canada that used similar measurement of activity-MET-hours/week/year suggests that
Table 4 Odds ratios for breast cancer according to lifetime total physical activity and menopausal status. Physical activity (MET-hours/week/year)
Total physical activity <110 110–150 >150 Ptrend
Pre-menopausal women Cases (numbers)
34 23 34
Controls (numbers)
41 47 46
Post-menopausal women OR (95% CI)
Cases (numbers)
Age adjusted
Multivariable adjusted
1.00 0.62 (0.26–1.47) 0.88 (0.40–1.99) 0.79
1.00a 0.46 (0.13–1.43) 0.43 (0.12–1.38) 0.43
OR, odds ratio; CI, confidence interval; MET, metabolic equivalent. a Adjusted for BMI, breast-feeding, parity.
114 104 91
Controls (numbers)
65 83 118
OR (95% CI) Age adjusted
Multivariable adjusted
1.00 0.72 (0.49–1.18) 0.44 (0.26–0.70) 0.001
1.00a 0.61 (0.34–1.10) 0.32 (0.22–0.71) 0.002
M. Awatef et al. / Cancer Epidemiology 35 (2011) 540–544
lifetime total physical activity may be protective only for postmenopausal breast cancer (OR = 0.70, 95% CI: 0.52–0.94, Ptrend = 0.003) [16]. Furthermore, the case control study by Kruk [17] that included women aged 35–75 years, showed similar results to what we report. The researcher found a large risk reduction for lifetime total physical activity only among post-menopausal women (OR = 0.31, 95% CI: 0.21–0.70, Ptrend = 0.002). In contrast, the results from a study by Magnusson et al. [18] of pre-menopausal women showed that women spending an average of more than 1 h/week in sports in the lifetime period of 10– 30 years had not experienced decreased breast cancer risk compared to less active ones. This observation is generally in line with the results from a case control study of pre-menopausal women in Germany which reported no association between total physical activity during adolescence and early adulthood and breast cancer [19]. Several reports revealed risk reduction in both pre-menopausal and post-menopausal women, among them the study conducted in San Francisco which founded similar risk reductions for specific types of activities in both menopausal groups. The risk for the highest tertile of average lifetime activity was OR = 0.74, 95% CI: 0.52–1.05, and 0.81, 95% CI: 0.64–1.02 (multivariable adjusted ORs). Lifetime activity has been shown to be importantly associated with breast cancer risk both in this study and in others, this being in agreement with the observation that fat mass reduction by physical activity may prevent breast cancer development, especially in post-menopausal women. In fact, blood fatty acids are particularly sensitive to oxidation by free oxidant species, leading to radicals’ generation and macromolecules oxidation enhancement [20]. Physical activity may affect breast cancer risk not only by decreasing the endogenous oestrogen level due to the decreased body fat [21–24], but also by increasing the amount of circulating sex-oestrogen-binding globulin reducing its ability to influence the targeted tissue. Furthermore, physical activity delays menarche and reduces the number of ovulate cycles [15]. In interpreting the results from our current study, several potential limitations need to be considered. A potential concern is the study sample size that is relatively small, particularly after stratification by menopausal status. Another potential limitation for our study was the use of hospital-based cases and controls. While every effort was made to include all cases admitted to the study hospitals, we did not attempt to ascertain breast cancer patients who may not have come to this hospital. Therefore, the generalization of our results may be limited because of the hospital-based study design. To avoid selection bias, the cases were selected among the women admitted to the study hospital, but the controls were chosen for non-cancerous conditions. Furthermore, control chosen was counted a limit for this study, in particular for conditions that are directly related to physical activity. In fact, regular physical activity prevents or delays the development of high blood pressure, reduces blood pressure in people with hypertension and reduces the risk of developing diabetes. Physical activity can also lower blood cholesterol levels which then decrease the risk of developing cardio-vascular diseases [25]. Despite these limitations, the study contributes to our understanding of breast cancer in this population and provides some of the first data on associations between physical activity and breast cancer in Tunisia. In fact, our results emphasized the measurement of extensive information on three parameters of physical activity: duration, frequency and intensity. In addition, self-reported activity intensity led to similar results as that of the assigned exertion intensity levels, expressed in MET-hours/week/
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year in regard to the risk of breast cancer. The next specific emphasis of this study included detailed information about a broad range of potential confounding variables gathered and considered in statistical analyses, and the restriction of cases to histological confirmation of breast cancer. In summary, this study provides an evidence of an inverse association between lifetime physical activity and breast cancer risk among post-menopausal women only. It should be noted, however, that despite the tremendous effort that has been made, the relationship between lifetime physical activity and subsequent breast cancer risk among both menopausal groups continues to be as controversial as ever. Considering the fact that physical activity is one of the few potentially modifiable factors in preventing breast cancer, the suggested protective effect from physical activity and the proposed carcinogenic mechanisms merit further investigation. Conflict of interest None. Acknowledgements This work was supported by the research unit ‘‘oncoge´ne´tique clinique’’ Medicine College, Sousse, Tunisia. We would like to thank Mr. Mahmoud Bchir for the English revision. References [1] Ben Abdallah M, Zehani S, Maalej M, Hsairi M, Hechiche M, Ben Romdhane K, et al. Cancer du sein en Tunisie: caracteristiques epidemiologiques et tendance evolutive de l’incidence. La Tunisie Medicale 2009;87:417–25. [2] McPherson K, Steel CM, Dixon JM. Breast cancer epidemiology, risk factors, and genetics. Br Med J 2000;321:624–8. [3] Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. Eur J Cancer 2010;46:2593–604. [4] World Health Organization. Weight control and physical activity. Lyon (France): IARC Press, 2002. [5] Friedenreich CM, Rohan TE. A review of physical activity and breast cancer. Epidemiology 1995;6:311–7. [6] McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams- Campbell LL, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA 2003;290:1331–6. [7] Friedenreich CM. Physical activity and breast cancer risk: the effect of menopausal status. Exerc Sport Sci Rev 2004;32:180–4. [8] Colditz GA, Feskanich D, Chen WY, Hunter DJ, Willett WC. Physical activity and risk of breast cancer in premenopausal women. Br J Cancer 2003;89:847–51. [9] Bernstein L, Patel AV, Ursin G, Sullivan-Halley J, Press MF, Deapen D, et al. Lifetime recreational exercise activity and breast cancer risk among black women and white women. J Natl Cancer Inst 2005;97:1671–9. [10] IRAC Working Group. Weight control and physical activity, vol. 6. Lyon: IRAC Handbook of Cancer Prevention, 2002. [11] Ainsworth BE, Haskell WL, Leon AS, Jacobs DR, Montoye MJ, Sallis JS, et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc 1993;25:71–80. [12] Ainsworth BE, Haskell WL, Whitt MC, Irvin ML, Swartz AM, Starth SJ, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 2000;32(Suppl.):S498–516. [13] SAS Institute SAS/STAT user’s guide. Version 6. Cary, NC: SAS Institute, 1990. [14] Gotay CC. Behaviour and cancer prevention. J Clin Oncol 2005;10:301–10. [15] Friedenreich CM, Orenstein MR. Physical activity and cancer prevention: etiologic evidence and biological mechanisms. J Nutr 2002;132:3456S–64S. [16] Friedenreich CM, Bryant HE, Courneya KS. Case–control study of lifetime physical activity and breast cancer risk. Am J Epidemiol 2001;154:336–47. [17] Kruk J. Lifetime physical activity and the risk of breast cancer: a case control study. Cancer Detect Prev 2007;31:18–28. [18] Magnusson CMK, Roddam AW, Pike MC, Chilvers C, Crossley B, Hermon C, et al. Body fatness and physical activity at young ages and the risk of breast cancer in premenopausal women. Br J Cancer 2005;93:817–24. [19] Steindorf K, Schmidt M, Kropp S, Chang-Claude J. Case–control study of physical activity and breast cancer risk among premenopausal women in Germany. Am J Epidemiol 2003;157:121–30. [20] Kassab A, Leban N, Ferchichi S, Feki M, Ben Limem H, Chaeib L, et al. Oxidant stress and cardiovascular absolute risk in Tunisian type 2 diabetes. Ann Biol Clin 2008;66(2):151–6.
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[21] Bernstein L, Ross RK, Lobo RA, Hanish R, Krailo MD, Henderson BE. The effect of moderate physical activity on menstrual cycle patterns in adolescence: implications for breast cancer prevention. Br J Cancer 1987;55:681–5. [22] McTiernan A, Ulrich C, Slate S, Potter J. Physical activity and cancer etiology: association and mechanisms. Cancer Causes Control 1998;9:487–509. [23] Shephard RJ, Shek PN. Association between physical activity and susceptibility to cancer. Possible mechanisms. Sports Med 1998;26:293–315.
[24] McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irvin ML, Rajan KB, et al. Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomised clinical trial. Cancer Res 2004;64:2923–8. [25] U.S. Department of Health and Human Services. Physical activity and health: a report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 1996.
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Physical activity reduces breast cancer risk: A case–control study in Tunisia Msolly Awatef a,*, Gharbi Olfa a, Chafai Rim a, Kassab Asma b, Mahmoudi Kacem a, Hochlef Makram a, Ben Fatma Leila a, Landolsi Amel a, Ben Ahmed Slim a a b
Department of Medical Oncology, CHU Farhat Hached, Sousse 4000, Tunisia Biochemistry Laboratory, CHU Farhat Hached, Sousse 4000, Tunisia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 November 2010 Received in revised form 13 February 2011 Accepted 16 February 2011 Available online 5 April 2011
Purpose: This study examined the relationship between lifetime history of physical activity and breast cancer risk. Methods: The case–control study was conducted on 400 women with histological confirmed breast cancer operated during the 2006–2009 period at Farhat Hached University Hospital, Sousse, Tunisia, and 400 cancer-free controls, aged 25–75 years. The physical activity was assessed using a structured questionnaire on each activity: type, duration, frequency, and intensity. Odds ratios (ORs), 95% confidence intervals (CI) and a full confounding assessment, included in this analysis, were derived using logistic regression. Results: These cases had lower lifetime averages for total physical activity for both forms of activity measurements (hours/week/year and MET-hours/week/year) and (Ptrend < 0.001 and Ptrend = 0.002, respectively). Significant risk reductions were found in total physical activity for both forms of activity measurements (OR = 0.27, 95% CI: 0.18–0.52, OR = 0.42, 95% CI: 0.26–0.73, respectively) for the highest versus the lowest level of activity (Ptrend = 0.001 and 0.004, respectively). The stratification by menopausal status showed a significant 56% reduction in breast cancer risk for postmenopausal women (Ptrend = 0.001, adjusted for age). The risk was further reduced to 68% (Ptrend = 0.002, multivariate adjusted). Among pre-menopausal women, the total physical activity was not significantly associated with reduced risk, ORs were 0.88 (95% CI: 0.40–1.99, age adjusted) and 0.43 (95% CI: 0.12– 1.38, multivariate adjusted). Conclusion: These data are in concordance with the majority of previous reports which involved physical inactivity as an important risk factor for breast cancer. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Physical activity Case–control study
1. Introduction Breast carcinoma is the most common malignancy diagnosed among women in Tunisia. It accounts for 20–25% of malignant tumours in Tunisian women with an annual incidence of about 2.15 cases per 10,000 women [1]. Extensive research has been conducted on the etiology of this disease. The majority of them have been carried more of interest on hormonal, family history, reproductive and dietary factors showing that the risk is increased by obesity in postmenopausal women, early menarche, late menopause and excessive alcohol consumption [2]. However, most of risk factors are not easily modifiable. Physical activity is one of
Abbreviations: MET, metabolic equivalent; OR, odds ratios; CI, confidence interval; BMI, body mass index; HRT, hormonal releasing therapy; SD, standard deviation. * Corresponding author. Tel.: +216 73219502; GSM: +216 97867155; fax: +216 73226702. E-mail addresses: [email protected] (M. Awatef), [email protected] (G. Olfa), [email protected] (C. Rim), [email protected] (K. Asma), [email protected] (M. Kacem), [email protected] (H. Makram), [email protected] (B.F. Leila), [email protected] (L. Amel), [email protected] (B.A. Slim). 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.02.011
the few known modifiable factors. The past 20 years of epidemiological research has generated a large body of evidence describing the benefits of physical activity in relation to breast cancer risk [3], and has been shown that physical activity may reduce the risk of breast cancer [4–9]. With reference to a recent study published on 2010 [3], 73 separate studies published to date has been focused on the aetiological role of physical activity in relation to breast cancer risk. More than three quarters of these studies have observed a beneficial effect of physical activity on breast cancer risk. More evidence for a protective effect of physical activity against breast cancer in a report from the International Agency for Research on Cancer, who has estimated that one fourth to one third of cancer cases, may be attributable to the combined effects of elevated body weight and inadequate physical activity [10]. In order to provide further information on the relation between physical activity and breast cancer risk among Tunisian women, we considered data from a case–control study of breast cancer, including detailed information on lifetime physical activities with all parameters (duration, intensity, frequency). Physical activity was quantified in terms of estimated metabolic equivalents. To develop a better understanding of potential mechanisms linking physical activity to the relative risk of
M. Awatef et al. / Cancer Epidemiology 35 (2011) 540–544
breast cancer, we assessed the interplay between physical activity and other risk factors for breast cancer, including weight gain, breastfeeding and parity.
2. Materials and methods After the hospital approvals were obtained, histological confirmed breast cancer cases were ascertained from November 2006 to April 2009 from Farhat Hached University Hospital, Sousse, Tunisia. The cases were limited to 25–75-year-old women without previous diagnoses of other cancers. A total of 400 female breast cancer cases were identified from participating hospitals, and all of them participated in the study and were included in the analyses. Controls were 400 patients, admitted to the hospitals in the same catchment area as cases, free of any cancer diagnosis and without earlier physical limitation. The major diagnostic categories were eye diseases (20%); tooth extraction, nose and throat conditions (12%); stomach flu or other digestive infections (8%); surgery such as appendicitis, strangulated hernia, haemorrhoids, or other conditions (17%); lower back pain and disk problems (9%); diabetes (18%); irregular heart rates and other acute circulatory conditions (11%); acute urinary tract infection (5%). A total of 98% (400/408) of the controls identified initially participated in the study. Selection of controls was restricted to patients whose current hospital admission was for a condition diagnosed within 1 year of the interview to reduce the proportion of controls who might have modified their habits as a result of having a chronic disease. Efforts were made to frequency match the cases and controls by age (within 5-year intervals). The study was approved by the Ethic Committee of Farhat Hached University Hospital, Sousse, Tunisia, and all participants provided informed consent. The participants were interviewed by the same interviewer in an area of each hospital allocated for the study, using a structured questionnaire. They were asked about their activity performed at various levels of intensity, including activities performed at work, leisure, and around the home. The following activities were ascertained: work activities (time spent sitting, standing, and walking); sports and conditioning activities (school sports, teams); individual activities (walking, cycling); activities performed at home (major cleaning, light daily housework, quiet inactivity). For each activity, women were asked to report the number of years spent in activity, months per year, days per week and hours per day. The same questionnaire was also used to collect information on other potential confounding factors, including personal and family history of breast cancer up to the reference year (the year before diagnosis for the cases or the year before selection into the study for the controls), dietary intake during the reference year, menstrual and reproductive history, oral contraceptives use and hormone replacement therapy (HRT). The intensity of physical activity is quantified using a specific metabolic equivalent (MET) values assigned to each activity, abstracted from Ainsworth et al.’s Compedium of Physical Activities [11,12]. The averages MET-hours/week/year spent in physical activity over a woman’s lifetime were calculated by multiplying the number of hours/week/year a woman practised a particular activity by the MET score described to that activity. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for various levels of lifetime physical activity, calculated by using SAS statistical software [13], were derived using unconditional logistic regression. Data were stratified by menopausal status to replicate prior analyses performed in western studies, which have suggested that physical activity may affect pre- and post-menopausal women differently.
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Variables considered as confounders were: age, education (illiterate, elementary school, secondary school and higher education), marital status (never married, married, widowed, divorced), body mass index (BMI) at reference year (<21, 21–24, 25 kg/m2), age at menarche (13, 14–15, 16 years), age at first full-term pregnancy (<20, 20–25, 26 years), number of pregnancies (0, 1, 2, 3), duration of breastfeeding (0, <6, 6 months), use of oral contraceptives (never, ever), post-menopausal HRT use (never, ever), menopausal status (pre-menopausal, post-menopausal), age at last menstrual period (<45, 45–50, 51 years) and family breast cancer history (no, yes). Categorical tests for trend were conducted by using a likelihood ratio statistic in a logistic regression model, and the MET score was used as a continuous variable. 3. Results The statistical comparison between cases and controls showed no significant difference in terms of education, marital status, age at menarche, age at first full-term pregnancy, pregnancy number, hormone use, age at menopause (Table 1). Compared to controls,
Table 1 Selected demographic characteristics of breast cancer cases and controls in Tunisia. Cases (n = 400) Education Illiterate 229 Elementary school 116 Secondary school 43 High education 12 P value Marital status Never married 46 Married 285 Widowed 51 Divorced 18 P value Age at menarche 13 166 14–15 157 16 77 P value Age at first full term pregnancy Nullipared 11 <20 57 20–25 281 26 51 P value Pregnancy number 0 12 1 159 2 117 3 112 P value Oral contraceptive use Never 259 Ever 141 P value Age at menarche <45 27 45-50 114 51 57 P value 2 Body mass index (kg/m ) <21 49 21-24 159 25 192 P value
Controls (n = 400)
206 67 83 44
30 321 36 13
189 120 91
4 75 283 38
7 150 121 122
ORa (95% CI)
1.00 4.07 (2.09–7.92) 6.34 (3.13–12.85) 0.10
1.00 1.10 (0.47–2.58) 0.64 (0.30–1.33) 0.37 1.00 1.49 (1.08–2.04) 0.96 (0.66–1.39) 0.23
1.00 1.30 (0.89–1.91) 1.76 (1.02–3.04) 0.11
1.00 0.91 (0.65–1.27) 0.86 (0.61–1.21) 0.69
203 97
1.00 1.56 (0.39–4.28) 0.37
31 112 35
1.00 1.16 (0.65–2.08) 1.87 (0.96–3.63) 0.13
66 150 184
1.00 1.52 (1.02–2.25) 1.35 (0.92–2.01) 0.41
OR, odds ratio; CI, confidence interval. a Odds ratios for each selected characteristic were adjusted for all other selected characteristics listed in this table.
M. Awatef et al. / Cancer Epidemiology 35 (2011) 540–544
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Table 2 Mean values of lifetime total physical activity in cases and controls. Type of physical activity, time specific measure
Mean value (S.D.) Hours/week/year
Total activity
MET-hours/week/year
Cases
Controls
P value
Cases
Controls
P value
46.9 (16.6)
53.2 (15.2)
<0.001
137.9 (58.1)
152.1 (60.9)
0.002
MET, metabolic equivalent; SD, standard deviation.
Table 3 Odds ratios for breast cancer according to lifetime total physical activity. Physical activity (hours/week/year) Total physical activity
Cases (numbers)
Controls (numbers)
<40 40–50
162 136
95 148
>55
102
157
Ptrend
OR (95% CI)
Physical activity (MET-hours/week/year)
Age adjusted
Multivariable adjusted
1.00 0.53 (0.35–0.82) 0.37 (0.23–0.56) <0.001
1.00a 0.39 (0.22–0.69) 0.27 (0.18–0.52) 0.001
Cases (numbers)
Controls (numbers)
<110 110–150
147 128
106 129
>150
125
165
OR (95% CI)
Age adjusted
Multivariable adjusted
1.00 0.70 (0.45–1.06) 0.52 (0.33–0.79) 0.004
1.00a 0.59 (0.34–1.10) 0.42 (0.26–0.73) 0.004
OR, odds ratio; CI, confidence interval; MET, metabolic equivalent. a Adjusted for age, BMI, breastfeeding, parity.
cases had a higher BMI (26.88 4.91 kg/m2 for cases and 25.62 4.17 kg/m2 for controls). The distribution of cases and controls according to lifetime total physical activity is given in Table 2. The cases had lower lifetime averages for total physical activity for both measurements (hours/week/year and MET-hours/week/year) of physical activity (Ptrend < 0.001 and Ptrend = 0.002, respectively). High risk reductions were found in total physical activity for both measurements (hours/week/year and MET-hours/week/year) of physical activity for the highest versus the lowest level of activity (Table 3). The statistical significant trends of breast cancer decreasing risk with increasing levels of activity were found in both measurements (hours/week/year and MET-hours/week/year) of physical activity (Ptrend = 0.001 and 0.004, respectively). The breast cancer risk associated with lifetime physical activity was stratified by menopausal status (Table 4). Among premenopausal women, the total physical activity was not significantly associated with reduced risk. On the contrary, for postmenopausal women a significant 56% reduction in breast cancer risk, when adjusted on five-year age-groups, was observed. The risk was further reduced to 68% after multivariate adjustment. BMI and parity were mainly responsible for that reduction. Evidence for trends in decreasing risk with increasing physical activity for these women were found significant in both analyses (Ptrend = 0.001, adjusted for five-year age-groups, and Ptrend = 0.002, multivariate adjusted).
4. Discussion The results from this study mainly revealed an inverse association between lifetime total physical activity and breast cancer risk for all women. The relationship, however, was more consistent when all women’s activities were measured by average hours/week than by average MET-hours/week. According to menopausal status, statistically significant reduced risk of breast cancer was found only for post-menopausal women; this may be due to the limited number of pre-menopausal women, which prevents the study to have sufficient statistical power to evaluate the effect of physical activity on their risk. A potential inverse association between lifelong physical activity and breast cancer risk is biologically plausible. Several mechanisms have been proposed to explain the observed association as reviewed by other studies [14,15], these included a positive effect of the activity on: endogenous sex steroid hormone production, fat tissue storage, levels of peptide hormones and growth factors such as insulin and insulin like growth factor I (IGF-I) and on improving the immune and antioxidant systems. However, the relationship between lifetime physical activity and breast cancer risk according to menopausal status has been inconsistent in the literature. As in our study, a study in Canada that used similar measurement of activity-MET-hours/week/year suggests that
Table 4 Odds ratios for breast cancer according to lifetime total physical activity and menopausal status. Physical activity (MET-hours/week/year)
Total physical activity <110 110–150 >150 Ptrend
Pre-menopausal women Cases (numbers)
34 23 34
Controls (numbers)
41 47 46
Post-menopausal women OR (95% CI)
Cases (numbers)
Age adjusted
Multivariable adjusted
1.00 0.62 (0.26–1.47) 0.88 (0.40–1.99) 0.79
1.00a 0.46 (0.13–1.43) 0.43 (0.12–1.38) 0.43
OR, odds ratio; CI, confidence interval; MET, metabolic equivalent. a Adjusted for BMI, breast-feeding, parity.
114 104 91
Controls (numbers)
65 83 118
OR (95% CI) Age adjusted
Multivariable adjusted
1.00 0.72 (0.49–1.18) 0.44 (0.26–0.70) 0.001
1.00a 0.61 (0.34–1.10) 0.32 (0.22–0.71) 0.002
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lifetime total physical activity may be protective only for postmenopausal breast cancer (OR = 0.70, 95% CI: 0.52–0.94, Ptrend = 0.003) [16]. Furthermore, the case control study by Kruk [17] that included women aged 35–75 years, showed similar results to what we report. The researcher found a large risk reduction for lifetime total physical activity only among post-menopausal women (OR = 0.31, 95% CI: 0.21–0.70, Ptrend = 0.002). In contrast, the results from a study by Magnusson et al. [18] of pre-menopausal women showed that women spending an average of more than 1 h/week in sports in the lifetime period of 10– 30 years had not experienced decreased breast cancer risk compared to less active ones. This observation is generally in line with the results from a case control study of pre-menopausal women in Germany which reported no association between total physical activity during adolescence and early adulthood and breast cancer [19]. Several reports revealed risk reduction in both pre-menopausal and post-menopausal women, among them the study conducted in San Francisco which founded similar risk reductions for specific types of activities in both menopausal groups. The risk for the highest tertile of average lifetime activity was OR = 0.74, 95% CI: 0.52–1.05, and 0.81, 95% CI: 0.64–1.02 (multivariable adjusted ORs). Lifetime activity has been shown to be importantly associated with breast cancer risk both in this study and in others, this being in agreement with the observation that fat mass reduction by physical activity may prevent breast cancer development, especially in post-menopausal women. In fact, blood fatty acids are particularly sensitive to oxidation by free oxidant species, leading to radicals’ generation and macromolecules oxidation enhancement [20]. Physical activity may affect breast cancer risk not only by decreasing the endogenous oestrogen level due to the decreased body fat [21–24], but also by increasing the amount of circulating sex-oestrogen-binding globulin reducing its ability to influence the targeted tissue. Furthermore, physical activity delays menarche and reduces the number of ovulate cycles [15]. In interpreting the results from our current study, several potential limitations need to be considered. A potential concern is the study sample size that is relatively small, particularly after stratification by menopausal status. Another potential limitation for our study was the use of hospital-based cases and controls. While every effort was made to include all cases admitted to the study hospitals, we did not attempt to ascertain breast cancer patients who may not have come to this hospital. Therefore, the generalization of our results may be limited because of the hospital-based study design. To avoid selection bias, the cases were selected among the women admitted to the study hospital, but the controls were chosen for non-cancerous conditions. Furthermore, control chosen was counted a limit for this study, in particular for conditions that are directly related to physical activity. In fact, regular physical activity prevents or delays the development of high blood pressure, reduces blood pressure in people with hypertension and reduces the risk of developing diabetes. Physical activity can also lower blood cholesterol levels which then decrease the risk of developing cardio-vascular diseases [25]. Despite these limitations, the study contributes to our understanding of breast cancer in this population and provides some of the first data on associations between physical activity and breast cancer in Tunisia. In fact, our results emphasized the measurement of extensive information on three parameters of physical activity: duration, frequency and intensity. In addition, self-reported activity intensity led to similar results as that of the assigned exertion intensity levels, expressed in MET-hours/week/
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year in regard to the risk of breast cancer. The next specific emphasis of this study included detailed information about a broad range of potential confounding variables gathered and considered in statistical analyses, and the restriction of cases to histological confirmation of breast cancer. In summary, this study provides an evidence of an inverse association between lifetime physical activity and breast cancer risk among post-menopausal women only. It should be noted, however, that despite the tremendous effort that has been made, the relationship between lifetime physical activity and subsequent breast cancer risk among both menopausal groups continues to be as controversial as ever. Considering the fact that physical activity is one of the few potentially modifiable factors in preventing breast cancer, the suggested protective effect from physical activity and the proposed carcinogenic mechanisms merit further investigation. Conflict of interest None. Acknowledgements This work was supported by the research unit ‘‘oncoge´ne´tique clinique’’ Medicine College, Sousse, Tunisia. We would like to thank Mr. Mahmoud Bchir for the English revision. References [1] Ben Abdallah M, Zehani S, Maalej M, Hsairi M, Hechiche M, Ben Romdhane K, et al. Cancer du sein en Tunisie: caracteristiques epidemiologiques et tendance evolutive de l’incidence. La Tunisie Medicale 2009;87:417–25. [2] McPherson K, Steel CM, Dixon JM. Breast cancer epidemiology, risk factors, and genetics. Br Med J 2000;321:624–8. [3] Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. Eur J Cancer 2010;46:2593–604. [4] World Health Organization. Weight control and physical activity. Lyon (France): IARC Press, 2002. [5] Friedenreich CM, Rohan TE. A review of physical activity and breast cancer. Epidemiology 1995;6:311–7. [6] McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams- Campbell LL, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA 2003;290:1331–6. [7] Friedenreich CM. Physical activity and breast cancer risk: the effect of menopausal status. Exerc Sport Sci Rev 2004;32:180–4. [8] Colditz GA, Feskanich D, Chen WY, Hunter DJ, Willett WC. Physical activity and risk of breast cancer in premenopausal women. Br J Cancer 2003;89:847–51. [9] Bernstein L, Patel AV, Ursin G, Sullivan-Halley J, Press MF, Deapen D, et al. Lifetime recreational exercise activity and breast cancer risk among black women and white women. J Natl Cancer Inst 2005;97:1671–9. [10] IRAC Working Group. Weight control and physical activity, vol. 6. Lyon: IRAC Handbook of Cancer Prevention, 2002. [11] Ainsworth BE, Haskell WL, Leon AS, Jacobs DR, Montoye MJ, Sallis JS, et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc 1993;25:71–80. [12] Ainsworth BE, Haskell WL, Whitt MC, Irvin ML, Swartz AM, Starth SJ, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 2000;32(Suppl.):S498–516. [13] SAS Institute SAS/STAT user’s guide. Version 6. Cary, NC: SAS Institute, 1990. [14] Gotay CC. Behaviour and cancer prevention. J Clin Oncol 2005;10:301–10. [15] Friedenreich CM, Orenstein MR. Physical activity and cancer prevention: etiologic evidence and biological mechanisms. J Nutr 2002;132:3456S–64S. [16] Friedenreich CM, Bryant HE, Courneya KS. Case–control study of lifetime physical activity and breast cancer risk. Am J Epidemiol 2001;154:336–47. [17] Kruk J. Lifetime physical activity and the risk of breast cancer: a case control study. Cancer Detect Prev 2007;31:18–28. [18] Magnusson CMK, Roddam AW, Pike MC, Chilvers C, Crossley B, Hermon C, et al. Body fatness and physical activity at young ages and the risk of breast cancer in premenopausal women. Br J Cancer 2005;93:817–24. [19] Steindorf K, Schmidt M, Kropp S, Chang-Claude J. Case–control study of physical activity and breast cancer risk among premenopausal women in Germany. Am J Epidemiol 2003;157:121–30. [20] Kassab A, Leban N, Ferchichi S, Feki M, Ben Limem H, Chaeib L, et al. Oxidant stress and cardiovascular absolute risk in Tunisian type 2 diabetes. Ann Biol Clin 2008;66(2):151–6.
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