Kiwi scientists are shedding new light on how fat feeds cancer cells – work that has important implications for the role of weight loss and exercise in cancer prevention and treatment.
She’s always understood the importance of keeping active and sticking to a healthy weight as ways of reducing her risk of disease, so her diagnosis of breast cancer in February 2018, just four months after her older sister had received the same news, was a big shock.
But Clifton’s active lifestyle is helping scientists better understand the complex role and interaction of weight, exercise and inflammation. She’s one of 12 breast cancer patients – half of whom were in the control group of women with low or normal weight, the other half obese – who took part in a pilot study that researchers hope will help them to tease apart those links and their role in cancer.
When doctors asked if she’d take part in the trial, which would measure her activity together with inflammatory and other markers in the blood over the six-month course of her chemotherapy, she jumped at the opportunity. “One in eight women get breast cancer, so I said I would help in any way I could.”
It’s been recognised for many years that being overweight or obese is a risk factor for many cancers. “There is strong evidence that being overweight or obese increases the risk for cancers of the oesophagus, pancreas, liver, colo-rectum, breast (post-menopause), endometrium and prostate,” says Shayne Nahu, the Cancer Society’s advocacy and well-being manager.
It also makes it harder to treat these cancers, though the reasons for that are yet to be fully explained. Internationally, studies suggest obesity promotes the spread of breast cancer and makes chemotherapy less effective. It’s associated with chronic low-grade inflammation, which is also linked to the development and spread of the disease. Now, work by a team of scientists at the Mackenzie Cancer Research Group at the University of Otago, Christchurch, is providing insights through several studies that have put both cancer cells and cancer patients under the microscope.
The Mackenzie Group’s principal investigator and clinical oncologist, Bridget Robinson, says international research suggests obesity might be a risk factor for 5-10% of cancers. In New Zealand, more than a third of breast cancer patients are obese. Although that’s roughly the same rate as obesity in the general population, their weight is associated with outcomes that are 30% worse than for women with a normal body mass index (BMI).
“When we first started,” says Robinson, “it was very hard to show that obesity and exercise actually mattered. But gradually the evidence has increased, so it really does now seem to be important to the extent there are guidelines for cancer patients recommending they keep active after diagnosis.”
It’s now accepted that regular exercise decreases inflammation, and increasing physical activity can improve survival rates in early breast cancer. One study, the Women’s Health Initiative Dietary Modification Trial in the United States, which involved nearly 50,000 post-menopausal women, showed even a 5% weight loss could reduce the incidence of breast cancer. “You don’t need to change much to reduce your risk.”
However, the time when patients might most need to keep exercising and watching their weight is when they’ll probably feel least like doing it. That’s borne out in the results of a new study by Mackenzie Group PhD student Rebekah Crake, supervised by clinical oncologist Dr Matthew Strother, which measured markers of inflammation and the metabolism of chemotherapy drugs in patients whose exercise levels were monitored by fitness trackers. People with a BMI of over 30 – the point at which we’re deemed to be obese – have higher levels of markers of inflammation in their bloodstream. Prolonged low-level inflammation can reduce the ability of the enzymes in the liver to metabolise medicines.
The activity levels of all the women dropped markedly after three weeks of chemotherapy. Clifton, who was regularly managing about 15,000 steps a day before her mastectomy and chemotherapy in February 2018, was one of the most active participants in the study, but her exercise regime suffered too, not because she was feeling nauseous from treatment, but because she couldn’t play tennis following the operation on her left breast – she is left handed – and avoided the swimming pool because of the risk of infection when her immunity was lowered, as it is by chemotherapy.
Because all the women reduced their activity – they were mostly down to just 1000 or 2000 steps a day in the second phase of chemotherapy – Crake says it wasn’t possible to get a good line on the effect of exercise on drug metabolism. However, she did see variation in the metabolic activity of the liver: one marker of inflammation that is often correlated with obesity was potentially influencing one of the main liver enzymes so that the metabolising of most cancer drugs was reduced. But Crake says, so far, that’s an association rather than a causal link.
Crake, 25, whose mother, Julie, has twice been treated for breast cancer, says her family history influenced her decision to explore genetics and breast cancer for her honours degree in 2015. She and the Mackenzie team – funded by the Mackenzie Charitable Foundation since 2010 – are now preparing an ethics application for a second, larger clinical trial, which will introduce exercise as an intervention in one group of women and compare their progress and outcomes during chemotherapy with a control group.
For cancer patients who are obese, the problem of how they metabolise chemotherapy drugs could be compounded because they’re not getting enough of the chemo for their size in the first place. Strother says there are guidelines for clinicians on dosages for patients on a height-weight basis but he says doctors can get nervous, because of the toxicity of the cancer drugs, about giving as much as recommended. “It does cause a gut check because you get used to operating within your normal parameters and you suddenly go, ‘Whoa, that’s a lot of drug.’” He says some reviews in ovarian and breast cancer have shown that if doctors arbitrarily reduce doses because of their discomfort at the amounts recommended, patients have worse outcomes than expected.
Strother, who has a background in clinical pharmacology, says he’s usually less timid about giving the bigger doses, unless there is a clear reason not to do so. It’s an issue doctors would be unlikely even to discuss with their patients, he says. “Even in the context of clinical trials, we have to be careful of the language we use because there is such stigma and sensitivity in the population as a whole over obesity. A clinical conversation with a morbidly obese patient about dose and their size is probably a difficult one to have.” During chemotherapy, patients tend to lose “massive amounts of muscle”, while their proportion of fat remains largely unchanged.
Clinical trials of chemotherapy drugs also often exclude obese patients because they have other conditions, such as diabetes, that rule them out, so it is difficult to get good evidence in that group. “In drug trials, obesity is a sub-population that has never been discretely reported, and I feel like there is an enormous black hole that needs better data so we could say, here is the average colon- or breast-cancer presentation, here’s their weight and here’s how that population did in relation to those in other strata of weight.
“For oncology in particular, the majority of clinical research is driven by the financial gain and desire of the pharmaceutical industry and it has elected to eliminate meaningful groups from lots of its research and these groups need to be studied better to improve outcomes.”
Back to basics
To find out more about how our fat cells might interact with and influence the development of cancer cells, Crake, supervised by senior Mackenzie Group researchers Margaret Currie and Dr Elisabeth Phillips, went back to basics in the laboratory, growing the two types of cells in a co-culture. Imagine a petri dish with the fat cells growing on the bottom, and on a porous plastic mini-tray above them, the cancer cells. In the body, the two cells interact both directly, when touching each other, and indirectly through factors in the blood and factors they are both secreting into the micro-environment around them.
The group believes that in obese women, tumours develop in a “nest of fat”, an environment that supports the growth, speed and survival of the cancer cell. “Our idea is that perhaps the fat in the original site actually primes those breast cancer cells to spread by providing energy and metabolism to fuel that metastasis,” says Currie.
Other researchers have targeted particular proteins or molecules to investigate, but Crake’s work used a technique called mass spectrometry that enabled her to look at all the proteins in the breast cancer cells grown with fat – something the researchers say has not been done anywhere else in the world. She found the expression and abundance of a small number of proteins significantly changed after three days in the co-culture.
In simple terms, it means the fat cells are feeding the breast cancer cells by releasing molecules that the tumour cells are then using to generate energy – effectively turbo-changing the cancer, allowing it to grow and spread more rapidly. And it’s a two-way street. Once the cancer is established, it starts releasing factors itself that tell the fat cells to feed it more to increase its energy supply, thereby increasing its aggressiveness. Currie and Phillips say Crake’s work has given researchers a huge database of potential targets to study further.
The inequity of obesity
Tackling cancer by addressing obesity is an equity issue, says Diana Sarfati, the recently appointed interim national director of cancer control. She says obesity is the fastest-growing driver of inequity in cancer. “The differences in cancer incidence between Māori and Pacific, non-Māori and Pacific and low and high deprivation are being driven by differences in rates of obesity.”
Obesity plays a bigger role in some cancers, including uterine, post-menopausal breast cancer and cancers of the bowel and stomach, than others. “People who have high BMIs have higher rates of those cancers, and given that our population generally is getting bigger, it’s becoming a more important risk factor.”
But Sarfati says any public campaigns to tackle obesity in the cancer context must take care not to imply that individuals are in some way to blame for their illness. In March, Cancer Research UK was taken to task for an advertising campaign highlighting the obesity-cancer link which was condemned as “harmful and misleading”. The ads, including billboards saying “obesity is a cause of cancer too”, led to accusations the charity was fat-shaming. In a letter to the chief executive of Cancer Research, a group of doctors and scientists said that implying individuals were largely in control of and responsible for their body size (and therefore cancer) “supports a culture of blame and plays into prejudices and negative stereotypes that drive the social exclusion, marginalisation and inequality of an already stigmatised population. It is absolutely terrifying that a cancer charity might inadvertently be causing people not to engage with public health initiatives.”
Sarfati says achieving equity in outcomes is one of the new cancer control agency’s most important objectives, so reducing obesity will be one way of helping to achieve that. But University of Auckland professor of nutritional and global health Boyd Swinburn describes some of our efforts to tackle the issue as “pathetic”. “It’s not so much knowing what we need to change,” he says, “but the big question is how do we get change?”
The health star rating system, which indicates levels of saturated fat, energy, sugar and salt in products on shop shelves, is still not mandatory and even after five years, only 20% of food manufacturers use it. “It’s pretty pathetic if consumers want to make healthy food choices and the environment is not really helping them to do that.” The Government has repeatedly ruled out imposing a sugar tax, particularly on soft drinks, despite calls for the move by Swinburn and other doctors and academics.
He says the evidence linking obesity with cancer has been getting stronger in recent years but cancer societies and funding organisations have been reluctant to pick up the cancer-obesity story and “run with it” because of the sensitivities around stigmatisation and victim-blaming. “If someone has a heart attack and goes into hospital for a stent or surgery, people get that it is a multi-factorial thing related to your genes, your behaviour and your environment; that it’s not purely you to blame for your heart attack. But for obesity, people lump a huge amount of blame on the choices individuals make and lack of willpower.”
One way of reducing the sensitivity, he says, would be to make height and weight measurements of children, for example, routine in general practice. At present, he says, if a GP brings up a child’s weight when they come in about a sore throat, for example, parents might feel affronted and believe they’re being criticised. But if a child is obese and the matter is not even raised, he says, “it’s sending a very powerful message that it doesn’t matter. If I had my wish, it would be a standard thing every time a child or adult came into contact with the health system that they got weighed, just like if I go to the doctor at the age of 66, I would expect to have my blood pressure taken. At least then we are taking it seriously, we have the data, and we can see the trends over time.”
A better start
It’s information parents and caregivers want to know, according to new research by the Liggins Institute in Auckland, as part of the A Better Start National Science Challenge. Its survey of almost 2000 caregivers of children aged five and under, published in December, has found 62% want to know if their child is at risk of obesity and 77% would be worried about the diagnosis. The researchers say early prediction information means parents and caregivers can better manage the child’s health and lifestyle from a young age. A Better Start director Wayne Cutfield says if the information was delivered sensitively to “minimise distress”, it could be a useful tool for interventions to reduce obesity.
Swinburn says most people tend to pay more attention to messages about the risk of cancer than heart disease or diabetes “because it’s way scarier. The fear wakes people up. People do not want to get cancer. That’s why it’s really important for the cancer organisations to be front and centre of this whole battle.”
He wants funding organisations to put more research into studies that look at how best to change diet, nutrition and the food environment, saying it is possible to turn back the obesity tide and the signs of that are already being seen in reducing rates of obesity in pre-schoolers.
US billionaire Michael Bloomberg, the former New York mayor who in November announced he was joining the race to be the Democratic presidential nominee in 2020, has invested US$130 million in an obesity prevention programme that aims to promote healthier food policies in Mexico, Brazil, the Caribbean, South Africa, Colombia and the United States. “They invest in communications to try to galvanise demand for policy action and they fund social lobbying where advocates engage with politicians in the classic way big companies would do if they wanted to get or prevent regulatory change, so we need to learn from that,” says Swinburn.
Someone who knows just how challenging that battle can be, however, is Auckland physician Dr Robyn Toomath who in 2015 wound up the group FOE (Fight the Obesity Epidemic) that she’d formed 14 years before, saying it had failed to frame messages in ways the public could understand. Now, Toomath says there is another opportunity to tackle our obesogenic environment – and that’s through an environmental message. She says the push for locally sourced, fresh produce and fewer processed foods will lead to less of the obesogenic food bought from supermarkets. “Once you start avoiding plastic-wrapped foods you end up with a very different diet.”
Toomath acknowledges one potential downside is that this sort of food is more expensive so could drive even more inequity. “That’s the appeal for public health measures that are across the board, for restricting advertising of junk food and increasing pricing of things like soft drinks.”
The Cancer Society says it’s updating its position statement on obesity and cancer. “There are lots of things that decision-makers can do to promote a healthy diet and increase physical activity,” Shayne Nahu says. The society supports nutrition label standards and food reformulation, restricting food advertising, adopting water-only policies and health-promotion initiatives in schools and workplaces, investing in sustained public awareness programmes and promoting safe “active transport” such as cycling.
Despite her enviably healthy lifestyle, Teresa Clifton has tweaked her habits even further after taking part in the Christchurch research. The glass of red wine she often enjoyed in the evenings is now just an occasional treat and she’s also cut down on sweet treats and portion sizes. “I’ve always been a big eater because all that exercise makes me hungrier.” Clifton says she was given an 80% chance of living another 10 years after surgery, and the percentage has increased because of chemotherapy and the hormone tablets she’ll be taking for the next five years. “I’m positive I’m all clear and I’m just loving life.”
NZ’s waist management
Adults living in the most socio-economically deprived areas are 60% more likely to be obese than adults in the least deprived places. Children living in the most deprived areas are 2.7 times more likely to be obese.
In October, a Unicef report, The State of the World’s Children, found that New Zealand had the second highest rate in the world of children who were overweight or obese – 39%. The US, at 42%, was worst.
Research from the University of Otago published in the Australian and New Zealand Journal of Public Health in March showed the rate of obesity in four-year-olds in most New Zealand communities declined between 2010 and 2016 but often by less than 1%.
The adult obesity rate has increased from 29% in 2011/12 to 30.9%, but has not changed significantly since 2012/13.
‘Exercise may delay the progression of disease and improve survival’
Although the data looks strong, Mackenzie Cancer Research Group PhD student Linda Buss cautions that it’s impossible at this stage to rule out “reverse causation” because the studies were observational rather than experimental. Experimental studies randomise patient groups to rule out other confounding factors. “Maybe cancer patients who exercise more or are more active do so simply because they are less sick.”
Principal investigator Margaret Currie says the strongest data is in support of exercise for improved quality of life and symptom control. “There have been papers showing exercise can have the same effect as chemotherapy in improving cancer outcomes but people don’t understand why. Some studies are starting to unpick the mechanisms, but how we can actually prescribe exercise, at what point, and how much of what sort of exercise for which cancers … none of that is really known yet.”
This article was first published in the January 4, 2020 issue of the New Zealand Listener.