Researchers have found a link between chemotherapy-induced changes to gut bacteria and the unhealthy weight gain seen in breast cancer patients, pointing the way to potentially help survivors avoid obesity-related illness later in their lives.
In newly published research, a cross-disciplinary team at the University of Alberta tracked 40 early-stage breast cancer patients — half of whom received chemotherapy and half who were prescribed hormone treatment only. They found that the patients treated with chemotherapy lost muscle mass and gained abdominal fat, which has been linked to heart disease, diabetes and even cancer recurrence. The chemo patients also exhibited signs of inflammation and significant changes to the number and variety of bacteria in their guts.
"Changes in the bacterial populations within the gut directly correlate with unhealthy weight gain and increased body fat composition in breast cancer patients who were treated with chemotherapy," says lead author John Walker, associate professor in the Faculty of Medicine & Dentistry and head of medical oncology for northern Alberta at the Cross Cancer Institute.
You're not what you eat
Obesity has been linked with several kinds of cancer, including breast cancer, and oncologists have long observed that cancer treatment seems to make it worse. Many people lose weight after a cancer diagnosis, but that trend is reversed in breast cancer patients who undergo chemotherapy. Studies have shown that while 50 per cent of breast cancer patients are overweight or obese before their diagnosis, that rate goes up to 67 per cent after treatment.
Changes to diet or exercise patterns during treatment are simply not significant enough to explain that difference, since they affect all patients who are treated for cancer, Walker notes.
"People tend to be a little less active during and after chemotherapy but they also tend to significantly reduce their caloric intake," he says. "Our study shows there is a more nuanced explanation. There's something unique about this modulation of the gut microbiome for breast cancer patients who receive chemotherapy."
"The old saying that 'you are what you eat' is just flat-out wrong," adds co-investigator Gane Ka-Shu Wong, professor in the departments of medicine and biological sciences, who did molecular studies on gut bacteria and immune markers for the paper. "You are what you eat, subject to whatever the bacteria and enzymes in your body do to that food."
Unintended consequences of chemo
Changes to the gut microbiota, known as dysbiosis, have been linked to chronic illnesses such as cardiovascular disease, Type 2 diabetes and obesity. This study on breast cancer patients was conceived after oncology professor John Mackey, former head of clinical trials at the Cross Cancer Institute, read a Scientific American article about the relationship between gut bacteria and obesity while on a plane trip home from a conference. He wondered whether chemotherapy might be unintentionally harming patients' gut flora as well.
Walker notes it is not surprising that chemotherapy drugs have bacteria-killing effects, since some are derived from antibiotics and all are metabolized through the liver and then the gut.
The 40 patients in the study were all diagnosed with early-stage breast cancer. Following genetic analysis of their tumours they were prescribed either chemotherapy or hormone therapy or both. Hormone therapy interferes with the production or absorption of estrogen, which feeds some kinds of tumours, while chemotherapy kills or slows the growth of cancer cells by disrupting cell division. The patients who received only hormone therapy served as an ideal control group for those who received chemotherapy or both treatments, says Walker.
The study participants provided stool and blood samples, before their tumours were surgically removed, before and after treatment, and one year after diagnosis. Their blood samples were examined for markers of inflammation, and the stool samples were checked for changes at a molecular and a microbial level. Patients in the chemo group exhibited immune-related inflammation in their colons and changes in the abundance of 47 different gut microbes. The same effects were not observed in the non-chemo patients.
"It wasn't just the gut bacteria that were disturbed by the chemotherapy, but the immune system went crazy in ways that could also contribute to the obesity effect," says Wong.
Patients also underwent full-body X-rays, known as DEXA or DXA scans, to monitor their body composition. DXA is considered more accurate than the commonly used body mass index, which is a simple ratio between weight and height.
"Pretty much anybody who's a competitive bodybuilder or an Olympic athlete — even Arnold Schwarzenegger in his prime — would be considered obese by the BMI definition," explains Wong. "What you really need to measure is muscle versus fat. And DXA is the gold standard for that."
The team reports that patients who were treated with chemotherapy gained an average of 0.15 per cent of their total body mass per month, whereas the hormone-only group lost an average of 0.19 per cent of their body mass each month. The weight gain was more pronounced in patients who were pre-menopausal and under the age of 60.
"An unparalleled success story"
Both researchers say the fact that so many women survive long enough to worry about obesity-related health problems can be viewed as good news, because now the goal is not just survival but long-term wellness.
"Breast cancer is an unparalleled success story in medicine. We see cure rates over 90 per cent today, so survivorship is now equally important," Walker says. "We want to ensure that in survival, our patients aren't then dealing with the metabolic consequences of weight gain during treatment."
"We know that obesity is an epidemic and it is a factor in so many diseases including cancer," he points out.
Walker and Wong agree more research needs to be done to better understand the impact of chemotherapy on gut bacteria and its potential role in obesity for breast cancer survivors. While chemotherapy will likely always be considered the most effective treatment, they say followup treatment could address weight gain. For example, fecal transplants studied by U of A gastroenterology professor Karen Madsen show promise in restoring healthy gut microbiota and treating obesity. New widely available diabetes medications such as Ozempic, known as GLP-1 agonists, are also proving effective in treating obesity.
Walker says it will take cross-disciplinary expertise to look at these problems in a new light. For this project, he collaborated with Wong, oncologist Anil Abraham Joy, Madsen and gastroenterology professor Dina Kao, who founded the Edmonton Fecal Microbiota Program, as well as scientists at the Cross Cancer Institute Clinical Trial Unit.
"I was so thrilled with the milieu that I suddenly found myself in during this project. I was sort of the hub of the wheel. When you cross disciplines and draw these groups together, you're going to be able to do some truly excellent research," he says.
"Our campus competes with any campus on the planet in terms of our ability to do this research. All the expertise is right here."
The five-year study was funded by Alberta Innovates and the Alberta Cancer Foundation, and supported by the Cancer Research Institute of Northern Alberta.
