We performed this study to test the hypothesis that CTNNB1 (β-catenin) status in colorectal cancers interact with patient’s BMI or post-diagnosis physical activity, and modify tumor cell behavior. We found a substantial interactive prognostic associations of tumor CTNNB1 and self-reported BMI or post-diagnosis physical activity. Specifically, nuclear CTNNB1 positivity was associated with significantly better cancer-specific and overall survivalin obese patients, while nuclear CTNNB1 status was not associated with survival among nonobese patients. Furthermore, in stage I-III nuclear CTNNB1-negative cases, high post-diagnosis physical activity (≥18 MET hours/week) was associated with significantly better cancer-specific survival, while physical activity was not associated with survival among stage I-III nuclear CTNNB1-positive cases. These results provide evidence for a possible interactive effect of tumor CTNNB1 and patient’s energy balance status in determining tumor cell behavior. Our data support the hypothesis that progression of WNT-CTNNB1-inactive tumor might be influenced by energy intake and expenditure, whereas WNT-CTNNB1-active tumor might progress independent of energy balance status. Although our data need to be confirmed by independent datasets, tumor CTNNB1 status may serve as a predictive biomarker for response to exercise prescription in clinical practice. Because physical activity is a modifiable lifestyle factor, our data may have considerable clinical implications.
Examining molecular changes or prognostic factors is important in cancer research.32,33
Previous prognostic data on CTNNB1 alterations in colorectal cancer are inconclusive.34-52
Two large studies42,43
(N>540) demonstrated no prognostic role of CTNNB1 alterations. However, none of the previous studies34-52
has examined interactive associations of tumor CTNNB1 and patient’s BMI or physical activity.
A host-tumor interaction that appears to modify tumor cell behavior has been first described between BMI and FASN expression in colon cancer.53
Examining host-tumor interactions has been a novel research paradigm in the evolving interdisciplinary field of “Molecular Pathological Epidemiology (MPE)”.54,55
Investigating whether lifestyle interventions are more or less beneficial based on tumor molecular subtypes provides important information regarding mechanisms of action that can, in turn, inform mechanistically-driven clinical trials to optimize the efficacy of such lifestyle interventions. We have previously examined interactions of several molecular markers with physical activity, and found that the benefit of physical activity may be influenced by tumor CDKN1B (p27) status.31
Specifically, physical activity after colon cancer diagnosis was associated with better cancer-specific survival in CDKN1B-expressing tumors but not in CDKN1B-lost tumors.31
It would be of particular interest to examine interactive effects of CDKN1B, CTNNB1 and physical activity in well-powered trial settings in the future. In addition, further studies are warranted to examine the exact mechanism of how physical activity modulates the CTNNB1 or CDKN1B signaling pathway to influence tumor cell behavior.
Prospective observational data suggest that physically active colorectal cancer survivors have lower rates of cancer recurrence and better survival compared with inactive survivors.14,15,56
Physical activity is a modifiable lifestyle factor, and thus its beneficial effect on cancer survivors has considerable clinical implications. However, as with any other oncological intervention, it is unlikely that all patients will universally gain a benefit from exercise. As evidence grows that nondrug interventions such as physical activity can influence outcome of 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 such an intervention. Thus, it is of particular interest to identify patient characteristics or a tumor biomarker which can predict response to exercise intervention. In the current study, we have found CTNNB1 status as such a candidate predictor. Although our data need to be confirmed by additional studies, nuclear CTNNB1 status may improve the identification of patients who will benefit most from physical activity. Future prospective intervention studies may be warranted.
There are limitations in this study. For example, data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use substantially differed according to CTNNB1 alterations in tumor, since such data were not available for treatment decision making. In addition, our multivariate survival analysis finely adjusted for disease stage (I, IIA, IIB, IIIA, IIIB, IIIC, IV, unknown), on which treatment decision making was mostly based. We recognize that we cannot exclude the possibility that dosing, completion, or dose modification rates of adjuvant therapy might vary according to BMI or physical activity. However, approximately 60% of patients included in our analysis had stage I or stage II disease, for whom surgery alone would generally be the standard care, and no interaction between physical activity and disease stage was observed in our previous analyses of this cohort.56
Thus, we consider that the confounding effects, if any, of different dosing, etc, of adjuvant therapy, would not have been substantial. As another limitation, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, colorectal cancer-specific survival is a reasonable surrogate of colorectal cancer-specific outcome.
There are advantages in utilizing the database of the two prospective cohort studies. Data on anthropometric measurements, physical activity, cancer staging, and other clinical, pathologic, and tumoral molecular variables were prospectively collected, blinded to patient outcome. Cohort participants who developed cancer were treated at hospitals throughout the U.S., and thus more representative colorectal cancer cases in the general U.S. population than patients in one to a few academic hospitals. In addition, we assessed the effect of CTNNB1 alterations independent of other critical molecular events such as BRAF
mutations, LINE-1 hypomethylation, CIMP and MSI, all of which have been associated with colorectal cancer prognosis.23,57,58
In conclusion, our data provide evidence for an interaction between CTNNB1 alterations in colorectal cancer and patient’s energy balance status, which influences tumor cell behavior. Notably, there appear to be substantial modifying effects of tumor CTNNB1 status on the beneficial prognostic role of post-diagnosis physical activity. Physical activity is associated with better cancer-specific survival only in patients with nuclear CTNNB1-negative colorectal cancers, whereas physical activity is not associated with survival in nuclear CTNNB1-positive cases. Our findings may have considerable clinical implications because physical activity is a modifiable lifestyle factor.