Higher fitness tied to lower breast cancer risk in 15,199 women, including those at high genetic risk

Some women learn that breast cancer runs in their family, and a growing number learn it from a genetic test that adds up many small inherited risks. Either way the question that follows is the same: does anything in their own hands change the odds?

A study of 15,199 postmenopausal women in the UK offers one partial answer. Women who were fitter on a stationary-bike test were less likely to develop breast cancer over about 11 years, and the fitter they were, the lower their risk. Among women whose genes put them at high risk, being fitter went with a smaller share of the extra risk those genes carried, most clearly in women aged 60 and over. The study was led by Kumpei Tanisawa of the Faculty of Sport Sciences, Waseda University, in Japan, with colleagues at Xi’an Jiaotong University in China. It was published on October 6 in Medicine & Science in Sports & Exercise.

What a polygenic risk score for breast cancer measures

Faults in genes such as BRCA1 and BRCA2 raise breast cancer risk sharply, but they are rare and account for only a small proportion of cases. Much of the rest of inherited risk is spread across common gene variants, each nudging risk a little up or down. A polygenic risk score adds those nudges together.

The best-known version, built in 2019 from the data of women of European ancestry from 69 studies, more than 94,000 of them with breast cancer, uses 313 variants. That origin leaves open how well the new results apply to women of other backgrounds. Its developers found that the lifetime risk of overall breast cancer in the top centile, the highest-scoring 1% of women, was 32.6%. The spread is wide: for the kind of breast cancer whose cells carry receptors for the hormone estrogen, the estimated lifetime absolute risk by age 80 years ranged from 2% in the lowest-scoring 1% of women to 31% in the highest. Compared with women in the middle of the range, the top 1% had 4.37 times the risk of that kind and 2.78 times the risk of the kind without the receptors. The developers argued that sorting women by risk based on polygenic risk scores could improve screening and prevention strategies.

Fitness is the other half of the question. Cardiorespiratory fitness is how well the heart, lungs and muscles take up and use oxygen during sustained effort, and it rises with regular exercise. Earlier studies had found that fitter women get less breast cancer, but the authors note that whether fitness modifies the association between genetic risk and breast cancer remains unclear. That is the gap Tanisawa’s team set out to fill.

How fitness and genetic risk were tested together

The women all came from UK Biobank, a long-running study of half a million British adults. A subset of participants took a fitness test, a submaximal cycle ergometer test introduced in 2009: a ride on an exercise bike at moderate effort, from which maximal fitness was estimated using heart-rate measurements. The researchers took the postmenopausal women who had done the test and whose genetic data allowed a breast cancer risk score.

The team followed them through health records and compared breast cancer rates across levels of fitness and of genetic risk, with models adjusted for established breast cancer risk factors. Over a median follow-up of 10.7 years, 547 of the 15,199 women developed breast cancer, about 3.6%.

How fitness and inherited risk combined

Each factor on its own behaved as expected. Higher fitness was associated with lower risk of breast cancer in a dose-response manner, meaning risk fell step by step as fitness rose, and a higher genetic score went with higher risk.

The question was how the two combined, and the answer depends on how risk is counted. Measured in relative terms, as a percentage cut in risk, fitness looked about equally protective whatever a woman’s genes; the authors found no statistical sign that the link differed by genetic risk on that scale.

Measured in absolute terms, the picture changed. Women with a high genetic score start from a higher baseline, so the same relative cut removes more actual cases. On that additive scale, high fitness went with a smaller excess breast cancer risk conferred by a high genetic score. In other words, the extra risk that came with a high genetic score was smaller in fitter women, by more than a simple adding-up of the two factors would predict. The statistic behind that finding had a wide range around it, from a large offset to a small one, though the whole range pointed the same way.

The difference between the two scales matters for prevention, which is judged by cancers avoided. If a fit woman at high genetic risk sheds more absolute risk than a fit woman at low genetic risk, then high-risk women are where fitness would prevent the most cancers, if the link turns out to be causal.

The offsetting was particularly evident among women aged 60 and over. That is a subgroup result, and subgroup results are the ones most often not repeated in later studies.

What earlier UK Biobank studies found about fitness and breast cancer

The overall link between fitness and breast cancer is not new, and some of the earlier evidence comes from the same cohort. Another team that studied fitness and breast cancer in postmenopausal UK Biobank women reported in 2023 that high estimated fitness was associated with a 24% lower risk. But that link held only among those classified as having overweight or a higher share of body fat, so those authors concluded that fitness may protect against breast cancer after menopause only in women with raised body fat.

A larger 2023 study of 72,572 UK Biobank participants who had the bike test found that fitness was linked to slightly lower breast cancer risk, along with lower endometrial and colorectal cancer. A step up in fitness of about half the usual spread between people was associated with lower risks of breast cancer, by about 4%. Its authors also used a method called Mendelian randomization, which treats gene variants linked to fitness as a natural experiment, and found the same direction. After adjusting for body fat, both the observational and genetic associations were attenuated, which suggests that much of fitness’s link to cancer may run through body composition.

Genetic studies of physical activity point the same way. A 2022 Mendelian randomization study in the British Journal of Sports Medicine found that greater genetically predicted overall activity was associated with lower breast cancer risk, evidence that is harder to explain by healthier people simply choosing to exercise. Genetically predicted vigorous activity was associated with lower risk of breast cancer diagnosed before or around menopause, a group the new study did not include.

The idea that habits matter even for women with high genetic risk also has precedent. A 2020 UK Biobank study grouped postmenopausal women by a lifestyle score built from healthy weight, regular exercise, limited hormone therapy, no oral contraceptive use and less frequent drinking, and by genetic risk. Women in the highest genetic risk group had about two and a half times the risk of those in the lowest, and within each genetic group a healthier lifestyle went with lower risk.

Where body fat fits into the fitness results

Body fat is the hardest part of this story to untangle. The authors of the 2023 fitness and cancer study wrote that relationships with adiposity are complex and may mediate the link, meaning body fat may be one of the routes by which fitness acts. If fitness lowers breast cancer risk partly by keeping body fat down, then adjusting for body fat hides part of a real effect. If body fat simply travels with low fitness, it is a rival explanation. Whether body fat is treated as a rival explanation or as part of the pathway changes how any fitness study should be read, and the two earlier UK Biobank studies both found it central to the fitness link.

What the fitness and breast cancer study leaves unsettled

This was an observational study, so it shows that fitness and lower breast cancer risk went together, not that one caused the other. Fitness was measured once, on a single test, and a woman’s fitness can change over a decade.

The key interaction finding rests on one measure with a wide range, and the clearest effect came from a subgroup, women 60 and over. The bike test was offered to 75,087 participants during baseline data collection, a fraction of UK Biobank’s half a million, so the women studied are a subset of an already selected group. A 2017 comparison found evidence of a “healthy volunteer” selection bias in UK Biobank: its participants smoke less and live in less deprived areas than the population. And the genetic score was built in women of European ancestry, so the results may not carry over to women of other backgrounds.

What the fitness results mean for women at high genetic risk

The authors’ conclusion is that higher fitness “was associated with lower breast cancer risk and attenuation of excess breast cancer risk conferred by elevated polygenic risk, particularly among older women.” They write that the results support the potential role of fitness in breast cancer prevention tailored to each woman’s level of risk. No such strategy was tested.

How a particular woman’s breast cancer risk is assessed and managed is decided with her doctor.

For postmenopausal women with a high inherited risk score, this observational study links greater fitness to a smaller share of that extra risk, a finding that still needs confirming in other groups of women.