Prospective observational data suggest that physically active colon cancer survivors have lower rates of cancer recurrence and improved survival compared to inactive survivors (14
). However, as with any oncological intervention, it is likely that not all patients derive a benefit from exercise. We tested molecular pathways that have been associated with energy balance to determine if a population of colon cancer survivors particularly benefit from physical activity. Surveying a variety of molecular events, we found that the benefit associated with physical activity differed significantly according p27 expression. Patients with loss of p27 did not appear to benefit from physical activity but those with expression of p27 and were physically active (at least 18 MET-hours / week) had a 68% improvement in colon cancer-specific mortality compared to those with p27 expression but not physically active.
Personalized medicine is a growing goal in the treatment of cancer patients (42
). It is clear that individual pharmacological interventions will not impact all patients with the same cancer type. As such, there is growing interest to find markers that better differentiate patients that are likely to benefit from a treatment from patients that have little to no chance of deriving benefit. Similarly, as evidence grows that non-drug therapies can influence patients with established cancer, there is a need to better delineate subpopulations of cancers that may or may not be more likely to be impacted by an intervention. Given the consistent evidence suggesting that physical activity reduces colon cancer recurrences in early stage patients (14
), we hypothesized that certain characteristics of a patient’s tumor may interact with the biological effects of exercise. With the exception of p27, no such interaction was detected for colon cancer-specific or overall mortality. Further, while the p for interaction between p27 and physical activity was statistically significant for colon-cancer specific mortality (p = 0.03), there was no significant interaction for overall mortality (p = 0.37).
In preclinical models, higher levels of p27 expression were detected in chemically-induced malignancies in animals that were energy restricted compared to those not restricted (26
). Such an effect will arrest cell cycle progression. Thus, the interaction detected in our data is consistent with a hypothesis that energy restriction by physical activity could influence p27 expressing tumors by cell cycle arrest inhibiting growth. Excess energy balance may have a much stronger impact on tumor behavior if tumor cells can upregulate p27 to arrest cell cycle, than if tumor cells have lost the ability to upregulate p27, possibly through the constitutive activation of the AKT1 pathway. However, it is not clear why no such benefit was detected for overall mortality. One explanation is that those with p27 expressing tumors clearly derive a benefit from exercise related to their colon cancer but that exercise still is beneficial to all patients irregardless of p27 status and equally protective for overall mortality related to non-cancer related causes (eg. cardiovascular disease). Another possibility is that the finding for colon cancer-specific mortality is by chance alone, a risk of multiple hypothesis testing.
The use of the Nurse’s Health Study and Health Professional Follow-up Study cohorts provides multiple advantages to study molecular-environment interactions. Diet and lifestyle are prospectively collected and entered into a database blind to a patient’s diagnosis. Data are updated every 2 years. Tumor block ascertainment has been fairly high (~60 %). Subjects are treated at hospitals throughout the United States and represent diverse treatment approaches that could be considered generalizable on a population level. However, a limitation of this study is that cancer treatment data are not available for most patients in our cohorts. Nonetheless, it is unlikely that chemotherapy use differed according to molecular characteristics of the tumor beyond typical pathological features like stage of disease and grade of differentiation (which are adjusted for in multivariate models). In addition, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, given the median survival for metastatic colon cancer was approximately 10 to 12 months during much of the time period of this study (44
), colon cancer-specific survival should be a reasonable surrogate for cancer-specific outcomes. Finally, these data are limited to patients that were alive to have their physical activity assessed after diagnosis (median 17 months). As such, conclusions are limited to that population.
In conclusion, this large prospective study of colon cancer patients confirms an association between physical activity and lower colon cancer-specific and overall mortality in colon cancer survivors. However, a molecular signature influencing this association was not clearly detected. While p27 status may be relevant, these findings require confirmation in independent populations of colon cancer patients.