Exercise Alters Breast Tumor Gene Expression

Pam Harrison

September 26, 2019

For the first time, a study has shown that exercise has a direct biological effect on breast tumor gene expression, providing potential insight into previously reported links between exercise and lower mortality risk in breast cancer patients who exercise relative to those who do not.

"We only had observational evidence that exercise has an effect on mortality risk, but [until now] we had no direct evidence that it's exercise per se that's helpful," Jennifer Ligibel, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, told Medscape Medical News.

"So we were trying to establish whether or not there is a biologic basis for what we are seeing in these observational studies, and this is the first study that has shown that exercise can induce changes in a tumor in people. And these findings are similar to what has been seen in animal models, which gives [our findings] more validity," she added.

The study was published online May 23 in Clinical Cancer Research.

The Pre-Operative Health and Body (PreHAB) study was a randomized window-of-opportunity trial carried out to assess the effect of preoperative exercise on tissue and serum biomarkers in women with newly diagnosed breast cancer.

Twenty-seven women were randomly assigned to take part in the exercise intervention; 22 control persons were assigned to a mind-body surgical preparation program in which they were given a book and a relaxation audio guide.

"Participants randomized to the exercise intervention received social/behavioral support to increase physical activity to 220 minutes of exercise per week, including 40 minutes of strength training and 180 minutes of moderate-intensity, aerobic exercise," the researchers explain.

The intervention was delivered in two supervised exercise sessions of 60 to 90 minutes. The remainder of the exercise consisted of unsupervised aerobic training.

At baseline, women were inactive; they reported engaging in, on average, 49 minutes of moderate or vigorous physical activity per week.

The mean time between study enrollment and surgery was 29.3 days.

"Adherence to exercise intervention was excellent, with participants randomized to exercise increasing physical activity by more than 200 minutes/week," the investigators note.

Among the control participants, time spent exercising after randomization increased by only 23 minutes per week, a difference between the two arms that was highly significant (P < .0001), the authors indicate.

Tissue Biomarkers

Tissue samples from baseline biopsy and surgical excisions were available from 39 patients.

Analyses indicated that exercise did not alter proliferation, as reflected by a change in Ki-67 expression in exercise participants compared to control persons. Ki-67 is a proliferative marker linked to breast cancer prognosis. In animal models, exercise has been shown to reduce breast cancer proliferation.

There was no change in expression of apoptotic markers, the investigators add.

On the other hand, paired tissue samples from 32 patients — 16 in each group — showed that tumor gene expression was upregulated in 18 unique pathways between baseline biopsy and surgical excision among women who exercised, whereas no such changes were observed in the mind-body intervention group.

The upregulated pathways were largely related to inflammation and immune regulation and included cytokine-cytokine receptor interactions; the NF-kB signaling pathway; natural killer cell–mediated cell cytotoxicity; antigen processing and presentation; and T-cell receptor signaling.

Whether or not exercise of longer duration or a more intensive exercise regimen would have a greater effect on tumor gene expression is difficult to gauge, especially because women with newly diagnosed breast cancer need to undergo to surgery in a timely fashion.

"You need to balance what's good for the patient and make sure you are dealing with their malignancy in the most optimal way," Ligibel stressed.

However, the highly beneficial effects of exercise on both breast cancer–specific mortality and all-cause mortality seen in observational trials have been seen largely with walking as the main exercise intervention, suggesting that more intensive exercise may not have a greater impact on breast tumors, Ligibel suggested.

Ligibel also noted that after a diagnosis of any cancer, "it's a very stressful, scary time for patients, and our patients were happy to have something positive to focus on other than their upcoming surgery," she said.

"This is very much a hypothesis-generating study, and while it is exciting to see some direct effects from exercise on breast tumors, we need to figure out what the next step is from a research perspective," Ligibel added.

She anticipates a second, larger trial will follow so as to try to replicate the findings in a larger cohort of patients.

Accompanying Editorial

In an accompanying editorial, Graeme Koelwyn, MD, and Lee Jones, MD, both from the Memorial Sloan Kettering Cancer Center in New York City, write that this study provides "novel evidence" that short-term treatment with exercise can modify the breast tumor microenvironment in patients with breast cancer.

However, they remain unconvinced that the current findings support conducting a larger phase 2 randomized trial of exercise in the setting of adjuvant breast cancer because the amount and the nature of the exercise needed to affect cancer outcomes are still not well delineated.

On the other hand, the editorialists indicate that the study did "firmly demonstrate the utility of the presurgical setting as an excellent model to comprehensively develop and test exercise as a candidate antitumor strategy."

A 2014 meta-analysis showed that women who engaged in the highest levels of physical activity after being diagnosed with breast cancer had a 29% lower risk for breast cancer–specific mortality and a 43% lower risk for all-cause mortality compared with inactive patients.

The study was supported by grants from the Susan G. Komen Foundation in collaboration with the Society for Women's Health Research and the American Institute for Cancer Research. Ligibel has disclosed no relevant financial relationships. Financial relationships of the study's coauthors are listed in the original article. Jones holds ownership interests in Pacylex.

Clin Cancer Res. Published online May 23, 2019. Abstract, Editorial

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