Abstract SY22-01: The role of exercise in cancer progression and mortality: Observational and molecular epidemiologic evidence
Authors: Friedenreich Christine M. 
Published: July 2016

Abstract
The role of physical activity in cancer control has become increasingly recognized over the past 20 years as the evidence for benefit in cancer prevention, treatment, rehabilitation, coping and survival has emerged and become well documented. Several components of physical activity have been investigated in how they relate to cancer control including the type of activity (occupational, household, transportation and recreation), the dose of activity (frequency, duration and intensity), and the timing of activity. We have previously proposed a conceptual framework for physical activity in cancer control that delineates the specific periods from prediagnosis, diagnosis, and post-diagnosis, and the role that activity may have in decreasing the burden of cancer at each time point.
Beginning with the prediagnosis period, the observational epidemiologic evidence for a role of physical activity in reducing cancer risk is fairly well established. With over 300 studies conducted worldwide that have examined some aspect of the role of physical activity in cancer risk reduction, there is now convincing and strong evidence that physical activity reduces the risk of breast, colon, and endometrial cancers and possibly also of lung, ovarian and prostate cancers. The evidence for other cancer sites is emerging with promising evidence for a role in hematologic cancers, gastrointestinal cancers (besides colon), and genitourinary cancers, as well as other rarer cancer sites. For cancer prevention, the focus since the early 2000s has been on understanding the underlying biologic mechanisms that explain how physical activity reduces cancer risk. Randomized, controlled exercise intervention trials in healthy, i.e., cancer-free, populations has demonstrated that aerobic exercise has a direct effect on reducing several biologic pathways that are associated with an increased risk of cancer. The main pathways examined to date have been the effect of physical activity on adiposity, insulin resistance, inflammation, and endogenous sex hormones, as well as other cancer-specific pathways, such as mammographic density. Novel pathways that are being investigated now include an impact on genomic instability (i.e., telomere length), oxidative stress, and DNA methylation. Second generation trials have been conducted that are examining not only the impact of aerobic exercise but also the impact of specific volumes of exercise (e.g. 150 versus 300 minutes/week) as well as different types of exercise (e.g. aerobic versus resistance training). Ultimately, these trials will provide evidence for specific physical activity guidelines for cancer prevention which, to date, have largely been based on the evidence for cardiovascular disease prevention.
With respect to the period around diagnosis and treatment, the role for physical activity, specifically structured aerobic and resistance exercise, in dealing with the side effects of cancer treatment as well as the rehabilitation after treatment is becoming equally well documented. Twenty years ago, there was reluctance and uncertainty in the oncology community to conduct research studies aimed at evaluating the safety and efficacy of exercising cancer patients during treatment. Now there is well documented evidence of improved physical and mental functioning and health with exercise, and safety concerns have been addressed and efficacy of exercise as an adjuvant treatment for cancer established. Widespread exercise prescription during cancer treatment is becoming more readily acceptable and even recommended in many cancer centers worldwide.
The evidence for a role of physical activity in reducing cancer recurrences and cancer-specific mortality is not yet well understood. To date, there have been 60 studies conducted worldwide that examined physical activity done either pre- or post-diagnosis and the impact on cancer outcomes. The majority of these studies have been conducted in either breast (n = 26) or colon cancer survivors (n = 15). Of relevance for clinical oncology is post-diagnosis activity and how changing activity levels might improve quality of life and cancer outcomes. Of these studies, 32 included a measurement of post-diagnosis activity. The strongest evidence for an association between post-diagnosis physical activity and cancer-specific mortality is found for breast and colon cancers for which the average mortality risk decrease is 25% and 32% respectively. There is also some evidence for a dose-response effect between increasing levels of physical activity and decreasing cancer mortality. For prostate cancer, there is new evidence for a strong protective effect of post-diagnosis recreational activity on prostate-specific mortality with reductions of up to 45% in a recent cohort study. For the remaining cancer sites, there is insufficient evidence accumulated to estimate an average reduction in mortality risk given the small number of studies conducted per site (ranging from 1-3 studies). Hence, at present, there is evidence for a consistent and strong effect of post-diagnosis physical activity and decreased risk of breast, colon, and possibly prostate cancers.
Most of these epidemiologic studies had limitations in their design and methods that has likely hampered the assessment of the association between post-diagnosis activity and cancer outcomes. These limitations include a lack of objective assessment of physical activity, no measures of fitness, sedentary behavior (a rapidly emerging risk factor independent of physical activity) or biologic mechanisms. One on-going cohort study, the Alberta Moving Beyond Breast Cancer (AMBER study) has been specifically designed to address the limitations of these observational studies. This cohort is recruiting 1500 newly diagnosed, incident, TI-TIIIc breast cancer cases at diagnosis and measuring health-related fitness, physical activity and sedentary behavior using objective and standardized methods before their cancer treatment, and at 1, 3 and 5 years (questionnaires only at this time point). In addition, blood samples are taken at the first three time points to enable subsequent analyses of biomarkers that may explain how activity is related to survival endpoints. The AMBER cohort will provide the evidence base for clinical practice guidelines regarding the type, timing, and volume of physical activity, sedentary behavior and the levels of health-related fitness needed to be achieve both the quantity and quality of life after breast cancer.
The ultimate study design to examine how post-diagnosis activity is related to survival outcomes is a phase III randomized controlled trial which is being used in the ongoing Colon Health and Life-Long Exercise Trial (CHALLENGE - NCIC-CTG CO.21 Trial). This trial, initiated in Canada and Australia, is recruiting 962 colon cancer survivors for multiple centers worldwide who are being randomized to either a three-year exercise intervention or usual care and then followed for recurrences and mortality outcomes. Correlative studies are also planned to examine underlying biologic mechanisms.
Given the significant progress that has occurred in the past two decades and the availability of new molecular epidemiology platforms to elucidate whether certain patient subtypes are more responsive to physical activity than others, there are now new avenues that can be explored. Specifically, little research has examined how patient and tumor characteristics can be used to add precision to the exercise prescriptions provided for cancer survivors that will increase the possible responsiveness to exercise. Hence, there is potential now to design studies that assess whether patient/survivor subgroups exist that will be more or less responsive to physical activity. Such precision oncology approaches have the promise of optimizing the benefit and safety of exercise prescriptions by being specifically targeted to the individual cancer survivor.
Citation Format: Christine M. Friedenreich. The role of exercise in cancer progression and mortality: Observational and molecular epidemiologic evidence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY22-01.