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Exercise: Powering up

Physical activity has numerous proven benefits, and its long-contested ability to keep cancer at bay is now being put to the test.

In the spring of 2006, Janice Hayes-Cha was recovering from a gruelling series of treatments for breast cancer. She had both breasts and both ovaries removed, to shut off her body's supply of oestrogen, which can fuel the growth of breast cancers. The busy mother of four was at the time executive director of the MassGeneral Institute for Neurodegenerative Disease in Boston, Massachusetts. The surgical procedures, plus four months of chemotherapy and two months of radiotherapy, left her physically and emotionally exhausted.

To help her cope, Hayes-Cha — then in her early 40s — resumed an old habit: exercise. “Before I had cancer, I'd found that exercise was really important for preventing depression and anxiety,” she says. So she began running, just ten minutes a day at first, gradually building up the distance. By autumn, she was in good enough shape to complete a half marathon around Boston's Emerald Necklace archipelago of parks. Today, she is still exercising as much as an hour a day, five or six days a week — and there is no evidence of cancer.

For women like Hayes-Cha, exercise could be offering far more than an emotional boost. Epidemiological studies have found that certain groups of women who exercise after being diagnosed with breast cancer are less likely to die from the disease. Physically active women might also be less likely to develop breast cancer in the first place.

Women raise more than their heart rates in a fundraising event by Susan G. Komen Race for the Cure. Credit: T.FOXX/ALAMY

No sweat

The evidence for a positive association between exercise and breast cancer prevention is mounting. Over the past two decades, the cumulative findings1 from 73 epidemiological studies suggest that the most physically active women are about 25% less likely to develop breast cancer than their least active counterparts.

The strongest association appears to be for women who engage in regular recreational exercise at least at a moderate level (meaning that they raise a sweat and feel breathless but can still talk). And it's never too late to start. Being active after the age of 50 is associated with a 17% lower risk of breast cancer, whereas for those under 50, the reduction in risk is only 8% (ref. 1).

Christine Friedenreich, an epidemiologist at the Southern Alberta Cancer Research Institute in Calgary, Canada, who reviewed the 73 studies, says that there is “convincing” evidence that exercise can prevent breast cancer. What's more, she says, exercise is a large area of “unmet potential, because a lot of people are not following the recommended physical activity guidelines”.

In the United States, federal guidelines recommend at least 150 minutes of moderate aerobic exercise or 75 minutes of vigorous aerobic exercise each week, along with muscle-strengthening exercises at least twice a week — a goal that's met by less than 1 in 5 adults. “If more women followed the physical activity guidelines,” says Friedenreich, “we could potentially reduce breast cancer incidence by as much as 20 to 30 per cent.

After the fact

For those who have received a diagnosis of breast cancer, there is also evidence that exercise can improve disease outcomes. A meta-analysis2 of six studies that included more than 12,000 women with breast cancer concluded that taking up exercise after diagnosis cuts the risk of dying from the disease by 34% (and of dying from any cause by 41%), within the 9–18-year time frame of the studies.

By contrast, in the same meta-analysis, women who exercised before diagnosis were 18% less likely to die in a given period than inactive women, but there was no difference in the rate of breast cancer deaths.

In two of the six studies, there was an indication that only women with a body mass index (BMI) greater than 25 benefited from exercise after diagnosis. The two studies that took into account the oestrogen-receptor (ER) status of the tumours found that women with ER-positive tumours were the only subgroup to benefit from post-diagnosis exercise. While not conclusive, these associations do suggest pathways that might be involved in mitigating cancer risk.

According to epidemiologist Melinda Irwin, director of the Yale Cancer Center's Cancer Survivorship Program in New Haven, Connecticut, two groups of hormones are thought to influence breast cancer risk — sex hormones (particularly the oestrogens, namely oestradiol and oestrone) and insulin.

Three randomized, controlled trials have now assessed how exercise affects the serum levels of sex hormones and insulin, and therefore the potential mechanisms of breast cancer development. All three included women whose age and physical activity levels gave them an above-average risk of breast cancer. The 1999 Physical Activity for Total Health (PATH) study enrolled 173 sedentary, overweight, postmenopausal women; the 2007 Sex Hormones And Physical Exercise (SHAPE) trial studied 189 sedentary postmenopausal women; and most recently the 2010 Alberta Physical Activity and Breast Cancer Prevention (ALPHA) trial included 320 sedentary postmenopausal women. All three trials involved moderate-to-vigorous-intensity exercise interventions, ranging from 150 to 225 minutes a week, over 12 months.

At the end of the PATH trial, women in the exercise groups who had lost more than 2% of their body fat (fat being the important factor, rather than weight) also had significantly lower oestrogen levels than women in the control groups. In the ALPHA trial, oestradiol levels also dipped more in the exercisers — a result that held even after adjusting for weight changes, suggesting that exercise might have a positive benefit independent of weight loss. What's more, the PATH and ALPHA trials showed that exercise decreases insulin levels as well.

Hormonal changes might also underlie improved survival after breast cancer diagnosis. In a study3 led by Irwin involving 75 postmenopausal breast cancer survivors, moderate exercise (an average of 129 minutes a week) was associated with decreases in the serum levels of insulin and two related factors: insulin-like growth factor 1 (IGF1) and IGF-binding protein 3 (IGFBP3). By contrast, women in the control group, who exercised only 45 minutes a week, had increased levels of all three factors.

Janice Hayes-Cha (left) with friend Kim Donlan after completing the Covered Bridges Half Marathon in Woodstock, Vermont. Credit: J. DUFFEY

Irwin suspects that exercise exerts its effects through decreasing insulin levels, because “insulin increases cell proliferation” and therefore could facilitate cancer growth. Preliminary research suggests that the diabetes drug metformin might decrease the recurrence of breast cancer, and studies by two other research teams are exploring this possibility. But physical activity could be a superior means to the same end. “Medications often work on a single pathway, while exercise affects multiple pathways,” says Irwin.

Another one of these pathways involves proteins called adipokines, which are produced by fat cells. Several adipokines, including leptin and adiponectin, may be associated with a higher risk of breast cancer — and regular exercise has been shown to decrease their serum levels, as revealed in the PATH and ALPHA trials. The same is true of inflammation, which is thought to raise breast cancer risk by increasing cell proliferation, creating changes in the microenvironment and inducing oxidative stress. Results from the PATH and ALPHA studies showed a post-trial decline in C-reactive protein, a well-established marker of inflammation, in the exercise group. Other researchers are investigating how exercise affects which genes are turned on (see 'An epigenetic connection').

Damage control

Most patients with breast cancer get a course of chemotherapy centred on doxorubicin, which has a heart-damaging side effect. Women diagnosed with late-stage breast cancer are less likely to respond to chemotherapy and more likely to succumb to the cancer, whereas women with early-stage disease often survive the cancer — but might die from heart failure instead, says Lee W. Jones, scientific director of the Duke Center for Cancer Survivorship in Durham, North Carolina.

The good news is that exercise might also help to mitigate this heart damage. Aerobic exercise strengthens the heart's pumping power and helps fight fatigue. “It's also one of the most powerful weapons we have against the oxidative damage that underlies doxorubicin's actions,” says Jones. In a 2011 review of the scientific literature4 by Jones and his colleagues, the collective findings from nine studies in rodents and one in humans suggest that exercise modulates the cardiotoxic effects of doxorubicin by several molecular mechanisms, including promoting the body's ability to temper oxidative damage.

Receiving treatment for cancer can also negatively affect fitness levels. In an as-yet-unpublished study, Jones' team found that fitness levels drop by almost 10% in women who have undergone 12 weeks of chemotherapy. That's about the same decline experienced by the average healthy woman over the course of a decade, he says. In his next study, Jones plans to check the heart and lung function, aerobic capacity and other measures of cardiopulmonary function in breast cancer patients who exercise during and after therapy to see whether it is possible to mitigate this loss.

Jones is also investigating the question of how much exercise might be needed to achieve a positive outcome. In 2010, he launched the Exercise Intensity Trial (EXCITE), enrolling 174 postmenopausal women who have undergone treatment for breast cancer. The women will be randomized into one of three groups: supervised treadmill walking at moderate intensity, or moderate-to-high intensity, or a control activity of stretching exercises, each for 150 minutes a week over 16 weeks. “The goal is to identify the best exercise prescription for breast cancer survivors to optimize cardiovascular health and maybe even minimize breast cancer recurrence,” says Jones.

Breast cancer treatment can leave women feeling fatigued, depressed and powerless. Difficult as those feelings can be, they're not necessarily a barrier to exercising, says Jones, who adds that women are eager to participate in his trials. “Exercise is something that gives control back to the individual. It's something women can do for themselves that is not only likely to lower their risk of recurrence but also makes them feel better. It's very powerful.”

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Corliss, J. Exercise: Powering up. Nature 485, S62–S63 (2012). https://doi.org/10.1038/485S62a

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