Among pre-menopausal women with estrogen receptor (ER)-positive breast cancer, those who are obese have a one third higher risk of dying than those who are normal weight, according to the results of a study presented at the American Society of Clinical Oncology Annual Meeting (Abstract 503).
In the study, though, featured in an ASCO “presscast” news conference for the media in advance of the meeting, there was so such relationship for post-menopausal women with ER-positive cancer or for women with ER-negative disease.
“Obesity substantially increases blood estrogen levels only in post-menopausal women, so we were surprised to find that obesity adversely impacted outcomes only in pre-menopausal women,” said the study's lead author, Hongchao Pan, PhD, a researcher in the Clinical Trial Service Unit and Epidemiological Studies Unit at the University of Oxford. “This means we don't understand the main biological mechanisms by which obesity affects prognosis.”
Other studies have found that being overweight was somewhat protective against breast cancer before menopause, he said.
About two-thirds of breast cancers are hormone receptor-positive, either ER-positive or progesterone receptor-positive, according to information from the American Cancer Society. The new findings suggest that obesity, thought by some researchers to be protective before menopause, places women of any age at higher risk. “Studies have provided convincing evidence that obesity is associated with an increased risk of developing breast cancer after menopause, but not before,” Pan noted.
Hatem Soliman, MD, Assistant Member in the Women's Oncology and Experimental Therapeutics Departments of Moffitt Cancer Center, said, “Obesity is a red flag—similar to those of smoking and other quality metrics for oncologists in practice. We should be more proactive and add dietitians, exercise trainers, and medical weight-loss clinics to a multidisciplinary care team to actively tackle this serious medical problem.”
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) study reported at the ASCO meeting included 80,000 women with early breast cancer in 70 clinical trials. Obesity was found to be associated with a 34 percent higher risk of breast cancer-related death only among the 20,000 pre-menopausal women with ER-positive disease. Obesity had little effect in post-menopausal ER-positive disease or in ER-negative disease.
For the study, which was funded by Cancer Research UK, the Medical Research Council, and the British Heart Foundation, Pan and his colleagues compared the records from women who received the same treatment in the same clinical trial. Body-mass index (BMI) was used to define normal weight, overweight, and obesity (20–25 kg/m2, 25–30 kg/m2, and ≥30 kg/m2, respectively). To assess the independent effects of BMI on prognosis, the researchers adjusted the findings for age, surgery type, trial treatment, HER-2, nodal status, and tumor grade and diameter.
After a mean follow-up of eight “woman-years,” among the 20,000 pre-menopausal patients with ER-positive disease, the breast cancer mortality rate was found to be one-third higher in obese women than in women of normal weight. This would, for example, change a 10-year breast cancer mortality risk of 15 percent into a 10-year risk of 20 percent, Pan explained. In contrast, obesity had little effect on breast cancer outcome either among the 40,000 post-menopausal women with ER-positive disease or among the 20,000 with ER-negative disease.
“There was no apparent effect of obesity in women with ER-negative disease, and little independent effect of obesity in post-menopausal ER-positive disease,” and there was heterogeneity between the obesity effects in pre-and post-menopausal woman.
The findings translate into a 21.5 percent increase in the 10-year breast cancer mortality risk for the subgroup of pre-menopausal, ER-positive patients who were obese, versus 16.6 percent risk in their counterparts of normal weight—a five percent difference.
Pan speculated that previous studies had too few breast cancer patients of ER-negative status to rule out the association between obesity and mortality risk.
‘Growing Body of Evidence’
Commenting on the study during the presscast, ASCO 2013–2014 President Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, said the study is part of the growing body of evidence showing that patients who are obese generally fare worse with cancer—“in this case, younger women with breast cancer.
“With some two-thirds of our nation's adult population now obese or overweight, there's simply no avoiding obesity as a complicating factor in cancer care.”
He said he was surprised that the effect was less clear in post-menopausal than in pre-menopausal patients, but that the bottom line remains that obesity overall is a negative prognostic feature.
New ASCO Resources
He noted that ASCO is working to support physicians and patients in addressing this challenge, releasing two resources in May to help physicians manage the complications of obesity in patients with cancer: “Obesity and Cancer: A Guide for Oncology Providers,” available at asco.org/obesity; and a complementary guide for patients, available at cancer.net/obesity.
“We urge researchers to examine new strategies for reducing obesity's cancer-related toll,” he said.
Soliman noted that oncologists have been dealing with this issue for some time in guidelines for optimal chemotherapy dosing: “Because of concerns for excessive toxicity based on actual body weight, we have been trying to do more chemotherapy dosing based on adjusted body weight in morbidly obese patients.” Body fat also has an effect on aromatase inhibitors because of peripheral conversion of sex steroids. For women with a high amount of fat tissue, these drugs may be less effective in some settings, he said.
Soliman too said he was surprised by the higher risk of death among pre-menopausal women as compared with post-menopausal women. “The hypothesis has been that in women who are post-menopausal, estrogen comes from peripheral tissue,” he said. “Fat generally causes more problems in post-menopausal women as opposed to pre-menopausal women, whose ovaries still are pumping out estrogen.”
The reason for this result could be due to multiple factors, he continued. “Young women are more often treated with chemotherapy than older women are, and younger ones tend to have biologically more aggressive tumors. The impact of chemotherapy under-dosing may play a role.”
He said he was also surprised by the ER-negative finding: “Under-treatment with chemotherapy could also have an impact on the ER-negative subset. The study does raise questions as to what mechanism is in play in this subgroup of women with breast cancer who also have obesity.
“My sense is that morbidly obese women have metabolic derangements, such as insulin resistance and changes in cholesterol, which can have an impact on cancer growth. This could play a role in making breast cancer recurrence higher. Fat is a hormonally active organ and stimulates breast cancer growth.”
This new data should not alter practice, though, he said, since “in my practice, I already deal with obesity and counsel women with breast cancer on the importance of losing weight and getting down to a healthier BMI.”
He noted that women with breast cancer struggle even more with weight gain after they receive treatment with chemotherapy and other medications that affect hormones.
Soliman suggests that oncologists consider recommending more drastic measures, such as bariatric surgery, for dramatic weight loss in a woman with a history of early breast cancer who is morbidly obese: “Dramatically losing weight helps patients with diabetes or hypertension get off drugs. One could argue that there could be significant benefits for women with early-stage breast cancer as well,” he said. “We have been trying diet and exercise for a long time now. The question is, in women with BMI over 35 kg/m2, could we push for insurance coverage of bariatric surgery?”
More specific data are needed, of course, he said, before oncologists could claim that bariatric surgery reduces the risk of death for women with breast cancer. He suggests comparing a cohort of women with breast cancer who had bariatric surgery for other reasons with a matched group to see whether the surgery reduced their breast cancer recurrence. “If we look at it more closely, there might be enough data available as part of a registry, and we could then follow these women for recurrence,” he said.
“Obesity ranks as a significant modifiable risk factor. If women with breast cancer lost weight, this would alleviate morbidity, and mortality. But we don't yet have a good handle on how to holistically tackle this problem.”