Megan S. Farris

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.

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.

Anthropometric measurements and survival after a prostate cancer diagnosis

Background:Evidence regarding the role of anthropometrics in prostate cancer survival is inconsistent. We examined the associations between anthropometric measures and survival outcomes.Methods:Men diagnosed with prostate cancer (n=987) were recruited into a population-based case–control study between 1997 and 2000 then a prospective cohort study between 2000 and 2002 where anthropometric measurements (weight, height, body mass index, waist circumference, waist-hip ratio) were taken and participants were followed up to 19 years for survival outcomes. Cox proportional hazards were used to examine these associations.Results:Survival analyses suggested no clear pattern of associations between post-diagnosis anthropometric measurements and all-cause mortality, prostate-specific mortality, first recurrence/progression or new primary cancer.Conclusions:We did not find a significant trend relating anthropometrics to survival outcomes after prostate cancer diagnosis. Continued assessment of objective measurements of body composition over the life-course is warranted to determine true associations between anthropometrics and survival after prostate cancer.

Effects of prescribed aerobic exercise volume on physical activity and sedentary time in postmenopausal women: a randomized controlled trial

BackgroundPhysical activity has emerged as an important lifestyle factor for primary prevention of numerous diseases, including postmenopausal breast cancer. No study to date has assessed the acute and long-term effects of year-long aerobic exercise programs differing in prescribed exercise volume on physical activity and sedentary time in postmenopausal women. Therefore, we aimed to examine the effects of two moderate-vigorous intensity exercise doses on total, light and moderate-vigorous intensity physical activity times, and sedentary time in postmenopausal women during the year-long intervention and one year later.MethodsThe Breast Cancer and Exercise Trial in Alberta (BETA) was a two-center, two-arm, 12-month randomized controlled trial that included 400 previously inactive postmenopausal women randomized to either 150 (MODERATE) or 300 (HIGH) minutes/week of aerobic exercise. Physical activity and sedentary time were assessed at baseline, 6- (intervention mid-point), 12- (prior to end of intervention) and 24-months (follow-up) with waist-mounted accelerometers (Actigraph GTX3®). Self-reported activity and sedentary time at baseline, 12- and 24-months was also assessed (Past Year Total Physical Activity Questionnaire and SIT-Q). Intention-to-treat analyses were conducted using linear mixed models and adjusted for baseline variables.ResultsBoth physical activity interventions led to increases in objective and subjective measures of total and moderate-vigorous intensity/recreational physical activity time, coupled with decreases in sedentary time, at 6- and 12-months compared to baseline. Additionally, greater increases in accelerometry-derived total physical activity time at 6- and 12-months, and self-reported recreational activity time at 12-months, compared to baseline were noted in the HIGH versus MODERATE groups. Decreases in total, light and moderate-vigorous intensity physical activity time, and an increase in sedentary time, in both groups were noted at 24-months compared to 12-months. A decrease in light intensity physical activity time in both groups at 24-months compared to baseline was also noted.ConclusionThese findings have important health implications, suggesting that total physical activity time can be increased with greater volumes of prescribed exercise, but that additional support and resources could be used to promote the maintenance of these high levels of aerobic exercise participation following study completion.Trial registrationclinicaltrials.gov identifier: NCT01435005 (BETA Trial). Registred September 15th 2011 (retrospectively registered).

Post-diagnosis alcohol intake and prostate cancer survival: A population-based cohort study: Alcohol consumption and prostate cancer mortality

Alcohol consumption has been declared a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) and is a potential risk factor for several types of cancer mortality. However, evidence for an association with prostate cancer survival remains inconsistent. We examined how alcohol consumption post‐diagnosis was associated with survival after prostate cancer diagnosis. Men diagnosed with prostate cancer (n = 829) in Alberta, Canada between the years 1997 and 2000 were recruited into a population‐based case–control study and then followed for up to 19 years for survival outcomes. Pre‐ and post‐diagnosis alcohol consumption, clinical characteristics and lifestyle factors were collected through in‐person interviews shortly after diagnosis and again 2–3 years post‐diagnosis. Cox proportional hazards were used to examine how post‐diagnosis alcohol consumption was associated with all‐cause and prostate cancer‐specific mortality (competing risk analysis too), in addition to first recurrence/progression or new primary cancer. Most participants reported drinking alcohol (≥once a month for 6 months) post‐diagnosis (n = 589, 71.0%). Exceeding Canadian Cancer Society (CCS) alcohol consumption recommendations (≥2 drinks/day) post‐diagnosis was associated with prostate cancer‐specific mortality relative to non‐drinkers (aHR: 1.82, 95% CI: 1.07–3.10) with borderline evidence of a linear trend. Interestingly, those in the highest quartile of drinks/week pre‐ and post‐diagnosis also had a twofold increase for prostate‐specific mortality (aHR: 2.67, 95% CI: 1.28–5.56) while controlling for competing risks. Our results support post‐diagnosis alcohol consumption was associated with increased mortality after prostate cancer diagnosis, specifically for prostate cancer‐related death. Future studies focused on confirming this burden of disease are warranted.

Reply to ‘Comment on ‘Anthropometric measurements and survival after prostate cancer diagnosis”

We thank Dal Maso et al. for their thought-provoking response to our recently published manuscript on the association between anthropometric measurements and survival after prostate cancer. We found no associations between anthropometry and prostate cancer prognosis and specifically, no associations with body mass index (BMI). Furthermore, we did not find any statistically significant interactions between smoking status and the association of BMI and survival, however, we did not present these analyses stratified by smoking status. Dal Maso et al. noted the potential for residual confounding by tobacco smoking status of this association and suggested that we consider this issue. Hence, we present here the additional analyses of the associations between anthropometric measures and prostate cancer outcomes stratified by smoking status. To recap the main design aspects of our study, we had 987 incident, stage T2 or greater prostate cancer cases who were initially enrolled into a population-based case–control study between 1997 and 2000 who we followed up for all outcomes until 2017. BMI, along with other anthropometric measures were directly measured by interviewers shortly after prostate cancer diagnosis and 2–3-year postdiagnosis, along with several other lifestyle and prognostic factors. All-cause mortality and prostate cancer-specific mortality were determined for all participants on an ongoing basis through record linkage. To reanalyse our data by categories of smoking status and BMI, we performed a stratified analysis by smoking status (never, former, and current) in a Cox proportional hazards regression model. This analysis was completed for all-cause mortality and prostate cancer mortality at both time points: (1) shortly after diagnosis to within 6 months and (2) 2–3-year postdiagnosis. Smoking status was defined as: (1) never smokers (<100 cigarettes smoked over lifetime) and (2) former smokers (included both exoccasional and excurrent smokers who had stopped smoking for at least 1 month before the interview); current smokers (included occasional and regular smokers). All adjustments for possible confounding factors that we previously reported were done in these additional analyses. Tests for trend were also estimated for age-adjusted and multivariable adjusted models. Table 1 presents the associations between BMI within 6-month postdiagnosis and all-cause mortality and prostate cancer-specific mortality by all smoking and BMI groups. The only statistically significant association found was an increased risk of prostatespecific mortality for obese men (BMI ≥ 30) relative to normal weight men (BMI < 25) who were former smokers at the time of diagnosis in the age-adjusted model (HR= 1.73, 95% CI: 1.02–2.92) with evidence of a trend (p= 0.007). This association, however, was attenuated in the multivariable adjusted model and no longer statistically significant (HR= 1.33, 95% CI: 0.76–2.31) and was not observed for all-cause mortality or for other categories of smokers. For the analyses done with the data collected at 2–3-year postdiagnosis, no statistically significant results were found for any of the associations between BMI and prostate cancer outcomes stratified by smoking status. Although there was a slightly increased risk of all-cause mortality amongst obese never smokers, as that found by Dal Maso et al. when compared with overweight or normal weight nonsmokers in our study, the risk estimates were not statistically significant and there was no evidence for trends across BMI categories. Indeed, the slightly elevated risks for allcause mortality observed among obese never smokers were of similar magnitude to those found for obese current smokers compared to other BMI categories at both time points assessed in our study. Hence, it appears from our analysis, that there was no strong effect modification of the association between obesity and smoking on these prostate cancer outcomes in our study. The results from these stratified analyses need to be interpreted with caution given the small number of deaths in each analysis. We agree with Dal Maso et al. that the association between obesity and prostate cancer survival is complex and requires careful consideration of the multiple and correlated factors that influence survival and that these need to be considered in future analyses of this topic.

Effects of physical activity on colorectal cancer risk among family history and body mass index subgroups: a systematic review and meta-analysis

BackgroundPhysical activity is consistently associated with a reduced risk of colorectal cancer in epidemiologic studies. This association among higher risk subgroups, such as those with a first-degree family history of colorectal cancer or high body mass index remains unclear.MethodsWe searched MEDLINE for studies examining physical activity and colorectal cancer risk among higher risk subgroups through July 11, 2017. Fifteen and three studies were eligible for inclusion for body mass index and first-degree family history of colorectal cancer subgroups, respectively. Estimates of the highest to lowest comparison of physical activity for each subgroup of risk were pooled using random-effects models.ResultsThe pooled associations of physical activity and colorectal cancer risk for those without and with a first-degree family history of colorectal cancer were 0.56 (95% confidence interval (CI) = 0.39–0.80) and 0.72 (95% CI = 0.39–1.32), respectively (pheterogeneity = 0.586). The pooled associations of physical activity and colorectal cancer risk for the low and high body mass index groups were 0.74 (95% CI = 0.66–0.83) and 0.65 (95% CI = 0.53–0.79), respectively (pheterogeneity = 0.389).ConclusionsOverall, a stronger relative risk of physical activity on colorectal cancer risk was observed in the higher body mass index group, although the difference was not statistically significant, suggesting an added benefit of physical activity as a cancer prevention strategy in population groups with strong risk factors for colorectal cancer. Additional research among these subgroups is warranted.

Predictors of Adherence to Different Volumes of Exercise in the Breast Cancer and Exercise Trial in Alberta

BACKGROUND Exercise demonstrates a dose-response effect on many health outcomes; however, adhering to higher doses of exercise can be challenging, and the predictors of adherence may differ based on exercise volume. PURPOSE To examine the predictors of adherence to two different volumes of aerobic exercise within the Breast Cancer and Exercise Trial in Alberta (BETA). METHODS In BETA, we randomized 400 inactive but healthy postmenopausal women to either a moderate volume (150 min/week) or a high volume (300 min/week) of aerobic exercise for 1 year. We collected data on several predictors of exercise adherence at baseline and used linear and mixed-effect models to determine predictors of exercise adherence to exercise volume and overall. RESULTS Adherence was higher in the moderate-volume group (84.5%) compared with the high-volume group (75.2%; p < .001). There were no statistically significant interactions between predictors of exercise adherence and exercise volume. Overall, we found that exercise adherence was predicted by randomization group, body mass index (BMI), employment status, and physical health. Adherence was 8.6% lower in the high-volume versus moderate-volume group, 6.7% lower for women working full time versus not, 0.8% lower per BMI increase of 1 kg/m2, and 0.5% higher per unit of physical health. CONCLUSIONS Adherence to high-volume aerobic exercise was more challenging than for moderate-volume aerobic exercise, but the predictors of adherence were similar. Moreover, few factors were major predictors of exercise adherence in this setting suggesting that well-controlled efficacy trials that produce high adherence rates may reduce the influence of individual characteristics on exercise adherence. TRIAL REGISTRATION NCT1435005.

Psychosocial Outcomes 12 Months Following a Dose–Response Aerobic Exercise Intervention in Postmenopausal Women

BACKGROUND We previously reported no postintervention differences in quality of life and other psychosocial outcomes when comparing 12-month high versus moderate volume of aerobic exercise in postmenopausal women. Here, we report the 24-month follow-up for these outcomes. METHODS At 24-month follow-up, 333 out of 400 postmenopausal women were randomized to a year-long intervention of 150 (moderate) or 300 (high) minutes per week of aerobic exercise returned a battery of self-reported measures assessing quality of life, psychosocial outcomes, and sleep quality, also assessed at baseline and postintervention. Intention-to-treat analyses using linear models were conducted to determine the changes between baseline and 24-month follow-up. RESULTS No significant effects between moderate- and high-volume aerobic exercise groups were observed among any outcomes. There was some evidence of effect moderation by baseline body mass index in relation to quality of life, psychosocial outcomes, and sleep quality, where obese women benefitted from the moderate-volume exercise and nonobese women benefitted from the high-volume exercise prescription. CONCLUSION Although high-volume aerobic exercise did not improve psychosocial outcomes when compared with moderate volume at the 24-month follow-up, we did observe potential effect of moderation between obese and nonobese women. Confirmation of these interactions is warranted in this population.