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Exercise habits prior to breast cancer diagnosis significantly affected the risk of recurrence in premenopausal women with certain tumor types in a large prospective cohort study.

The relationship was non-linear -- i.e., past a certain point, more exercise was not associated with greater benefit, reported Ines Vaz-Luis, MD, PhD, of Gustave Roussy Institute in Villejuif, France, and colleagues in the .

They analyzed data on 10,359 patients enrolled in the multicenter Cancer Toxicities (CANTO) study and followed for 5.4 years. Exercise was assessed via questionnaire and quantified and standardized into "metabolic equivalent of task–hours per week" (MET-h/wk).

Patients who reported having at least 5 MET-h/wk pre-diagnosis -- the equivalent of 1.5 hours a week of moderate exercise -- had an 18% lower risk for distant recurrence (HR 0.82, 95% CI 0.61-1.00) compared with patients who exercised less. However, at a threshold above 25 MET-h/wk, the equivalent of 5 hours a week of moderate exercise, there was no additional risk reduction.

The benefit was found primarily in premenopausal patients with HR-negative/HER2-negative tumors (HR 0.59, 95% CI 0.38-0.92) and HR-negative/HER2-positive tumors (HR 0.37, 95% CI 0.14- 0.96), the investigators said.

"Our data suggest the hypothesis that exercise doses below and above a homeostatic zone (therapeutic range) confer suboptimal recurrence benefit, and potential antitumor effects of exercise may be confined to only certain subtypes in primary breast cancer," the team concluded.

Vaz-Luis, who is director of the Cancer Survivorship Research Group, elaborated on the findings and the implications in the following interview.

Why did you decide to examine the effect of exercise on recurrence rather than survival?

Vaz-Luis: We know that higher levels of exercise, both before and after diagnosis, are associated with reduced all-cause and breast cancer-specific mortality. However, the impact on recurrence has been less studied. The impact of exercise on disease recurrence examined in this study provided an opportunity to rigorously evaluate the exercise-tumor progression link.

What mechanisms might be involved?

Vaz-Luis: Our data indicated that exercise doses exceeding a relatively modest amount (approximately 90 minutes of moderate exercise per week) were associated with greater risk reductions, but this benefit was observed only up to a certain limit (around 5 hours of moderate exercise per week). Beyond this threshold, no additional benefits were noted. This phenomenon may be linked to the adaptive response of cells and organisms to moderate stress.

The cellular signaling pathways and molecular mechanisms that mediate responses to exercise may depend on the dose. Understanding the cell-autonomous and/or cell-nonautonomous molecular mechanisms underpinning these responses would be of great interest.

Exercise doses below and above an optimal range may confer suboptimal benefits. Further research is necessary to validate these findings and hypotheses, starting with validation in independent data sets or experimental models.

Can you speculate about why the effect was seen only in certain tumor types?

Vaz-Luis: In our study, the exercise-recurrence link was observed in the triple-negative [TN] and hormone receptor (HR)–/HER2+ subtypes, but not in the HR+ subtypes. This suggests that the exercise-tumor progression relationship may vary based on tumor biology. However, it is also possible that the short follow-up period prevented us from capturing additional late recurrence events in the HR+ group.

The observed benefit in TN tumors supports growing preclinical data indicating that exercise significantly inhibits tumor progression in mouse models of TN breast cancer.

Why do you think the benefit was observed only in premenopausal women?

Vaz-Luis: The benefit of exercise in reducing the risk of relapse was evident only in the premenopausal population. Most studies evaluating breast cancer recurrence or mortality have not found significant differences based on menopausal status.

The differing categorization of exercise levels across studies and the short follow-up period of our study might explain this discrepancy, especially considering that the majority of postmenopausal women are diagnosed with HR+/HER2– breast cancer.

Do you have any thoughts on what to advise patients about exercise based on your findings?

Vaz-Luis: Our study suggests that exercise may be linked to a reduced risk of recurrence in primary breast cancer in a nonlinear manner, highlighting the need to incorporate exercise programs into patient care pathways. Additionally, the impact of exercise on recurrence may differ by tumor subtype and menopausal status and could be influenced by exercise dose.

Therefore, trials are necessary to assess whether exercise therapy has biological antitumor effects and if these effects vary based on tumor molecular characteristics. These trials will inform the design of larger, definitive studies and help tailor exercise guidelines for oncology.

While we await these definitive data, all cancer survivors should be advised to engage in physical exercise according to international guidelines since there is consistent benefit in other symptoms, improved quality of life, and reduced risk of adverse events that exist beyond the potential direct anti-tumoral effect.

Read the study here.