Lee Jones

PhD

Memorial Sloan Kettering Cancer Center

Scientist

PLCO (Learn more about this study)

PLCO-769

Apr 19, 2021

Impact of Exercise on Cancer Pathogenesis

A wealth of epidemiological data demonstrates that regular exercise is associated with substantial reductions in all-cause and cause-specific mortality in the general population. Comparably fewer studies have examined the impact of exercise performed in the period after diagnosis on long-term mortality in patients with adult-onset cancers. For example, a recent systematic review only identified a total of 29 epidemiological studies examining the relationship between post-diagnosis exercise and all-cause mortality in cancer patients. Furthermore, studies included in this review have important limitations including but not limited to the following: small sample sizes (mean, n = 2925; range, 573-11 315), limited follow-up duration, and small number of all-cause mortality events. Due to the timing of exercise assessment and short duration of follow-up, observed reductions in total mortality are likely driven primarily by a reduction in death from recurrence. Thus, whether exercise reduces mortality due to competing (noncancer) causes, a major cause of death in 5-year survivors of cancer, remains to be resolved. In addition, most studies focused on a single cancer site (~40% of all studies were performed in breast cancer). Consequently, to date it has not been possible to compare whether the impact of exercise on cause-specific mortality is uniform across all cancer diagnoses or whether benefit varies as a function of cancer site. Relatedly, while meta-analyses and systematic reviews indicate that post-diagnosis exercise is associated with reductions in all-cause mortality among cancer patients, the results of individual studies are not consistent. Differences in study methodology related to the definition, timing, and most importantly, measurement of exercise exposure (i.e., reliability and validity of study instruments) undoubtedly contribute to the divergent findings. Other contributing factors include differences in study populations relating to demographic characteristics such as age and ethnicity but also medical characteristics, especially tumor subtypes. Few studies have investigated whether the impact of exercise differs based on patient medical (tumor) characteristics.

Relatedly, a wealth of observational data shows that regular non-occupational / recreational physical activity (i.e., exercise) is associated with reduced risk of numerous types of cancer. In a recent report pooling data from 12 prospective studies with self-reported data, including data from PLCO, a higher level of exercise was associated with a reduction in the primary risk of 13 different types of cancer. A growing literature base also shows that exercise in the period following a diagnosis of breast, colorectal or prostate cancer is associated with a reduction in the risk of cancer-specific mortality.

To our knowledge, all observational studies examining the relationship between exercise and the primary risk of cancer or outcomes following a cancer diagnosis have done so using the same methodological / statistical approach: investigators select a fixed timepoint in the follow-up window (e.g., 5 years following initial completion of the exercise survey) and determine the cumulative number of events (e.g., diagnosis of primary cancer or death from cancer) observed during the observation window.

...Various statistical approaches are then performed to examine whether the number (proportion) of events observed, compared to the number at risk, differs among individuals categorized into different exercise classifications based on self-reported data at study entry. In general, the relative risk of being diagnosed with cancer is significantly lower in exercising compared with non-exercising individuals, leading to conclusion that exercise reduces the risk of numerous forms of cancer. However, since this statistical modeling approach assesses the number of events accumulated at a snap-shot in time it provides limited insight into the potential temporal dynamics of the exercise – cancer pathogenesis relationship. As such, it fails to address the fundamental primary prevention question of whether exercise completely prevents the development of a clinically detectable cancer or delays the date of which a diagnosis of clinically detectable cancer occurs. Similarly, it also fails to address the fundamental treatment question of whether exercise after a cancer diagnosis completely prevents cancer progression or delays the time to progression. Indeed, the predominant focus of observational studies studying the exercise – cancer pathogenesis relationship has been the relative risk reduction in incidence and cancer death between exercisers and non-exercisers – largely ignored is the proportion of exercising individuals diagnosed with or dying from cancer. An important but unaddressed question is whether age-standardized incidence rates are similar or different in such a cohort. Our goal is to leverage data from PLCO to address these important knowledge gaps.

Specific Aims
We propose to leverage PLCO data to address two major objectives:

Objective 1: Examine the relationship between exercise and cause-specific mortality in cancer patients
Specific aims are to: (1) the association between exercise exposure evaluated following a cancer diagnosis with cause-specific mortality, (2) the dose-response relationship, and (3) whether the relationship between exercise and cancer-specific mortality outcomes differs based on medical characteristics and tumor features.

Objective 2: To investigate the temporal relationship between exercise and cancer risk and cancer-specific mortality.
Specific aims are to: (1) leverage exercise data collected in individuals at the time of PLCO study entry (i.e., individuals without cancer) examine the age-dependent primary incidence of cancer in exercisers and non-exercisers, and to examine whether this differs as a function of cancer type, and (2) leverage exercise data collected after individuals were diagnosed with cancer during follow-up in PLCO to examine the length of disease-free survival in exercisers and non-exercisers, and examine whether this differs as a function of cancer type.

Objective 3: Examine the relationship between lifestyle and cause-specific mortality in cancer patients
Specific aims are to: (1) the association between lifestyle health index evaluated following a cancer diagnosis with cause-specific mortality, (2) the dose-response relationship, and (3) whether the relationship between lifestyle index and cancer-specific mortality outcomes differs based on medical characteristics and tumor features.