Heather K. Neilson

State of the epidemiological evidence on physical activity and cancer prevention

BACKGROUND Physical activity is a modifiable lifestyle risk factor that has the potential to reduce the risk of most major cancer sites. METHODS We examined the strength, consistency, dose-response and biological plausibility of an association between physical activity and risk of colon, breast, endometrium, lung, prostate, ovarian, gastric, rectal, pancreatic, bladder, testicular, kidney and haematological cancers. We also estimated the population-attributable risk (PAR) for physical inactivity and cancer in 15 European countries. RESULTS There is convincing or probable evidence for a beneficial effect of physical activity on the risk of colon, breast and endometrial cancers. The evidence is weaker for ovarian, lung and prostate cancers and generally either null or insufficient for all remaining cancers. Several hypothesised biological mechanisms include a likely effect of physical activity on insulin resistance, body composition, sex steroid hormones and a possible effect on vitamin D, adipokines, inflammation and immune function. Somewhere between 165,000 and 330,000 cases of the six major cancers (breast, colon, lung, prostate, endometrium and ovarian) could have been prevented in 2008 in Europe alone if the population had maintained sufficient levels of physical activity. CONCLUSION There is strong and consistent evidence that physical activity reduces the risk of several of the major cancer sites, and that between 9% and 19% of cancer cases could be attributed to lack of sufficient physical activity in Europe. Public health recommendations for physical activity and cancer prevention generally suggest 30-60 min of moderate or vigorous-intensity activity done at least 5d per week.

Physical Activity and Postmenopausal Breast Cancer : Proposed Biologic Mechanisms and Areas for Future Research

Convincing evidence now supports a probable preventive role for physical activity in postmenopausal breast cancer. The mechanisms by which long-term physical activity affect risk, however, remain unclear. The aims of this review were to propose a biological model whereby long-term physical activity lowers postmenopausal breast cancer risk and to highlight gaps in the epidemiologic literature. To address the second aim, we summarized epidemiologic literature on 10 proposed biomarkers, namely, body mass index (BMI), estrogens, androgens, sex hormone binding globulin, leptin, adiponectin, markers of insulin resistance, tumor necrosis factor-α, interleukin-6, and C-reactive protein, in relation to postmenopausal breast cancer risk and physical activity, respectively. Associations were deemed “convincing,” “probable,” “possible,” or “hypothesized” using set criteria. Our proposed biological model illustrated the co-occurrence of overweight/obesity, insulin resistance, and chronic inflammation influencing cancer risk through interrelated mechanisms. The most convincing epidemiologic evidence supported associations between postmenopausal breast cancer risk and BMI, estrogens, and androgens, respectively. In relation to physical activity, associations were most convincing for BMI, estrone, insulin resistance, and C-reactive protein. Only BMI and estrone were convincingly (or probably) associated with both postmenopausal breast cancer risk and physical activity. There is a need for prospective cohort studies relating the proposed biomarkers to cancer risk and for long-term exercise randomized controlled trials comparing biomarker changes over time, specifically in postmenopausal women. Future etiologic studies should consider interactions among biomarkers, whereas exercise trials should explore exercise effects independently of weight loss, different exercise prescriptions, and effects on central adiposity. (Cancer Epidemiol Biomarkers Prev 2009;18(1):11–27)

Physical Activity and Breast Cancer Prevention

Breast cancer is the most commonly diagnosed invasive malignancy and the second leading cause of cancer death in women. This chapter considers epidemiologic evidence regarding the association between physical activity and breast cancer risk from 73 studies conducted around the world. Across these studies there was a 25% average risk reduction amongst physically active women as compared to the least active women. The associations were strongest for recreational activity, for activity sustained over the lifetime or done after menopause, and for activity that is of moderate to vigorous intensity and performed regularly. There is also some evidence for a stronger effect of physical activity amongst postmenopausal women, women who are normal weight, have no family history of breast cancer, and are parous. It is likely that physical activity is associated with decreased breast cancer risk via multiple interrelated biologic pathways that may involve adiposity, sex hormones, insulin resistance, adipokines, and chronic inflammation. Future research should include prospective observational epidemiologic studies relating proposed biomarkers to breast cancer risk and also randomized controlled trials to examine how physical activity influences the proposed biomarkers. Exercise trials will provide more clarity regarding the appropriate type, dose, and timing of activity that relate to breast cancer risk reduction.

Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225 min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81–0.93), HOMA-IR (TER=0.86, 95% CI=0.80–0.93), and leptin (TER=0.82, 95% CI=0.78–0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13–1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Physical Activity and Survival After Prostate Cancer

BACKGROUND Despite the high global prevalence of prostate cancer (PCa), few epidemiologic studies have assessed physical activity in relation to PCa survival. OBJECTIVE To evaluate different types, intensities, and timing of physical activity relative to PCa survival. DESIGN, SETTING, AND PARTICIPANTS A prospective study was conducted in Alberta, Canada, in a cohort of 830 stage II-IV incident PCa cases diagnosed between 1997 and 2000 with follow-up to 2014 (up to 17 yr). Prediagnosis lifetime activity was self-reported at diagnosis. Postdiagnosis activity was self-reported up to three times during follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards models related physical activity to all-cause and PCa-specific deaths and to first recurrence/progression of PCa. RESULTS AND LIMITATIONS A total of 458 deaths, 170 PCa-specific deaths, and, after first follow-up, 239 first recurrences/progressions occurred. Postdiagnosis total activity (>119 vs ≤42 metabolic equivalent [MET]-hours/week per year) was associated with a significantly lower all-cause mortality risk (hazard ratio [HR]: 0.58; 95% confidence interval [CI], 0.42-0.79; p value for trend <0.01). Postdiagnosis recreational activity (>26 vs ≤4 MET-hours/week per year) was associated with a significantly lower PCa-specific mortality risk (HR: 0.56; 95% CI, 0.35-0.90; p value for trend = 0.01). Sustained recreational activity before and after diagnosis (>18-20 vs <7-8 MET-hours/week per year) was associated with a lower risk of all-cause mortality (HR: 0.66; 95% CI, 0.49-0.88). Limitations included generalisability to healthier cases and an observational study design. CONCLUSIONS These findings support emerging recommendations to increase physical activity after the diagnosis of PCa and would inform a future exercise intervention trial examining PCa outcomes. PATIENT SUMMARY In a 17-yr prostate cancer (PCa) survival study, men who survived at least 2 yr who were more physically active postdiagnosis or performed more recreational physical activity before and after diagnosis survived longer. Recreational physical activity after diagnosis was associated with a lower risk of PCa death.

Inflammatory Marker Changes in a Yearlong Randomized Exercise Intervention Trial among Postmenopausal Women

Chronic low-grade inflammation is a possible risk factor for cancer that may be modifiable with long-term exercise. Very few randomized controlled trials (RCT) have studied the isolated effects of exercise on low-grade inflammation exclusively in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial, a 2-armed RCT in healthy postmenopausal women, examined how 1 year of moderate to vigorous aerobic exercise, compared with usual inactivity, influenced circulating inflammatory markers. Baseline, 6-month, and 12-month serum was analyzed by direct chemiluminescent immunoassays to measure high sensitivity C-reactive protein (CRP) and ELISAs to measure interleukin 6 (IL-6) and TNF-α. Intention to treat analyses were conducted with linear mixed models. Statistically significant differences in CRP were observed over 12 months for exercisers versus controls (treatment effect ratio = 0.87, 95% CI = 0.79–0.96, P = 0.005), but not in IL-6 or TNF-α. A statistically significant trend (Ptrend = 0.021) of decreasing CRP with increasing exercise adherence and stronger intervention effects on CRP in women with higher baseline physical fitness (Pheterogeneity = 0.040) was found. The intervention effect on CRP became statistically nonsignificant with adjustment for dietary fiber intake change and seemed to be mediated by fat loss. Low-grade inflammation may be lowered with exercise, but confounding by dietary intake occurred and should be considered in future studies. Further trials are needed to corroborate our findings about the optimal dose of exercise required to lower CRP levels and effect modification of CRP changes by levels of body fatness and fitness. Cancer Prev Res; 5(1); 98–108. ©2011 AACR.

Physical Activity and Cancer Outcomes: A Precision Medicine Approach

There is increasing interest in applying a precision medicine approach to understanding exercise as a potential treatment for cancer. We aimed to inform this new approach by appraising epidemiologic literature relating postdiagnosis physical activity to cancer outcomes overall and by molecular/genetic subgroups. Across 26 studies of breast, colorectal, and prostate cancer patients, a 37% reduction was seen in risk of cancer-specific mortality, comparing the most versus the least active patients (pooled relative risk = 0.63; 95% confidence interval: 0.54–0.73). Risks of recurrence or recurrence/cancer-specific death (combined outcome) were also reduced based on fewer studies. We identified ten studies of associations between physical activity and cancer outcomes by molecular or genetic markers. Two studies showed statistically significant risk reductions in breast cancer mortality/recurrence for the most (versus least) physically active estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) patients, while others showed risk reductions among ER−PR− and triple-negative patients. In colorectal cancer, four studies showed statistically significant risk reductions in cancer-specific mortality for patients with high (versus low) physical activity and P21 expression, P27 expression, nuclear CTNNB1−, PTGS2 (COX-2)+, or IRS1 low/negative status. One prostate cancer study showed effect modification by Gleason score. As a means to enhance this evidence, future observational studies are needed that will measure physical activity objectively before and after diagnosis, use standardized definitions for outcomes, control for competing risks, assess nonlinear dose–response relations, and consider reverse causality. Ultimately, randomized controlled trials with clinical cancer outcomes and a correlative component will provide the best evidence of causality, relating exercise to cancer outcomes, overall and for molecular and genetic subgroups. Clin Cancer Res; 22(19); 4766–75. ©2016 AACR.

Effects of a High vs Moderate Volume of Aerobic Exercise on Adiposity Outcomes in Postmenopausal Women: A Randomized Clinical Trial

IMPORTANCE Body fat increases postmenopausal breast cancer risk. Physical activity may decrease risk through adiposity changes, but the optimal dose of activity is unknown. OBJECTIVE To compare the effects of 300 vs 150 min/wk of moderate to vigorous aerobic exercise on body fat in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS The Breast Cancer and Exercise Trial in Alberta was a 12-month, 2-armed, 2-center randomized dose-comparison trial conducted from June 2010 through June 2013. Participants were 400 inactive postmenopausal women with body mass index 22 to 40, disease-free, nonsmokers, and nonusers of exogenous hormones. INTERVENTIONS Five d/wk of aerobic exercise (3 d/wk supervised, 2 d/wk unsupervised) for 30 min/session (moderate-volume) or 60 min/session (high volume) achieving 65% to 75% of heart rate reserve for at least 50% of each session. Participants were asked not to change usual diet. MAIN OUTCOMES AND MEASURES Total body fat, measured from dual energy x-ray absorptiometry scans, was the primary outcome. Other measures included subcutaneous and intra-abdominal fat from computed tomography scans, weight, and waist and hip circumferences. RESULTS Of 400 women, 384 provided baseline and follow-up adiposity measurements. Median (interquartile range) adherence at full prescription for the high- and moderate-volume groups was 254 (166-290) and 137 (111-150) min/wk, respectively. Mean reductions in total fat were significantly larger in the high- vs moderate-volume group (least-squares mean difference, -1.0% [95% CI, -1.6% to -0.4%], P = .002). Subcutaneous abdominal fat and waist to hip ratio decreased significantly more in the high-volume group (least-squares mean difference, -10.8 [95% CI, -19.5 to -2.2] cm², P = .01, and -0.01 [95% CI, -0.02 to 0.00], P = .04, respectively). Changes in weight and intra-abdominal fat were not significantly different between groups (least-squares mean difference, -0.7 [95% CI, -1.6 to 0.2] kg, P = .11, and -1.5 [95% CI, -5.9 to 2.9] cm², P = .50, respectively). Some dose-response effects were stronger for obese women. CONCLUSIONS AND RELEVANCE In previously inactive postmenopausal women, a 1-year prescription of moderate to vigorous exercise for 300 min/wk was superior to 150 min/wk for reducing total fat and other adiposity measures, especially in obese women. These results suggest additional benefit of higher-volume aerobic exercise for adiposity outcomes and possibly a lower risk of postmenopausal breast cancer. TRIAL REGISTRATION clinicaltrials.gov: NCT01435005.

A systematic literature review of vitamin D and ovarian cancer

OBJECTIVE We assessed the evidence supporting a reduction in risk for ovarian cancer occurrence or mortality with greater vitamin D exposures. STUDY DESIGN This review followed standard guidelines for systematic literature reviews. The diverse study designs precluded a quantitative metaanalysis. Therefore studies are summarized via tables and abstracted information. RESULTS Approximately half of the ecologic and case-control studies reported reductions in incidence or mortality with increasing geographic latitude, solar radiation levels, or dietary/supplement consumption of vitamin D, whereas the other half reported null associations. The cohort studies reported no overall risk reduction with increasing dietary/supplement consumption of vitamin D or with plasma levels of vitamin D prior to diagnosis, although vitamin D intakes were relatively low in all studies. CONCLUSION There is no consistent or strong evidence to support the claim made in numerous review articles that vitamin D exposures reduce the risk for ovarian cancer occurrence or mortality.

Moderate-vigorous recreational physical activity and breast cancer risk, stratified by menopause status: a systematic review and meta-analysis

Objective: Physical inactivity increases postmenopausal and possibly premenopausal breast cancer risk, although different biologic mechanisms are proposed. Our primary objective was to estimate breast cancer risk associated with high versus low levels of moderate-vigorous recreational activity, separately for premenopausal and postmenopausal women. Methods: We conducted a systematic review of literature published to July 2015. Included reports were cohort or case-control studies relating moderate-vigorous recreational physical activity (metabolic equivalent ≥3.0) to breast cancer incidence, exclusively (≥90%) in premenopausal or postmenopausal women. We appraised study quality and performed meta-analyses using random effects modeling. Subgroup meta-analyses were based on tumor subtype, race, body mass index, parity, hormone therapy use, family history of cancer, and statistical adjustment for body fatness. Dose-response relations were examined. Results: Pooled relative risks (RRs, 95% CI) for women with higher versus lower levels of moderate-vigorous recreational activity were RR = 0.80 (0.74-0.87) and RR = 0.79 (0.74-0.84) for premenopausal (43 studies) and postmenopausal (58 studies) breast cancer, respectively, with high heterogeneity. Inverse associations were weaker among postmenopausal cohort studies (RR = 0.90 [0.85-0.95]) and studies that statistically adjusted for nonrecreational (eg, occupational, household) activity (RR = 0.91 [0.77-1.06] premenopausal, RR = 0.96 [0.86-1.08] postmenopausal). Risk estimates with versus without body fatness adjustment did not vary by menopause status, although other subgroup effects were menopause-dependent. Among studies of overweight/obese women, there was an inverse association with postmenopausal but not premenopausal breast cancer (RR = 0.88 [0.82-0.95] and RR = 0.99 [0.98-1.00], respectively). Dose-response curves were generally nonlinear. Conclusions: Although risk estimates may be similar for premenopausal and postmenopausal breast cancer, subgroup effects may be menopause-dependent.