How obesity causes cancer, and may make screening and treatment harder

Today, almost two in every three Australian adults are overweight or obese, as is one in four children. Obesity is a disease itself and a risk factor linked to ischaemic heart disease (the leading cause of premature deaths today in Australia), stroke (the third leading cause), and musculoskeletal conditions (the second major cause of disability), among others.

This rising obesity burden is the outcome of a host of factors, many of which are beyond the control of the individual. It is having a devastating impact on the health of the nation. What’s often overlooked though, is the link between obesity and cancer.

Cancer is a disease of altered gene expression that originates from changes to the DNA caused by a range of factors. These include inherited mutations, DNA damage, inflammation, hormones, and external factors including tobacco use, infections (for example viruses such as HPV), radiation, chemicals, and carcinogenic agents in food.

Strong evidence also links obesity to a number of cancers. These include oesophageal adenocarcinoma; bowel cancer (the third leading cause of preventable death in Australia); cancer of the liver, gall bladder and bile ducts; pancreatic cancer; postmenopausal breast cancer; endometrial cancer; kidney cancer; and multiple myeloma (cancer in the plasma in the blood).

This is just the tip of the iceberg, as highly suggestive evidence exists for a further eight cancers.

How does obesity increase the risk of cancer?

There are many complex ways obesity is thought to cause or increase the risk of cancer.

Increased body fat is associated with increased inflammation in the body, increased release of oestrogens (in part from the fat cells themselves), and decreased insulin sensitivity associated with raised insulin production.

Insulin, “insulin-like growth factor-1” (IGF1) and leptin are all elevated in obese people, and can promote the growth of cancer cells.

Secretion of the hormone insulin is usually tightly controlled and a healthy part of our body’s sugar regulation processes. But it can be significantly elevated in people with obesity-related pre-diabetes or diabetes due to insulin resistance.

This state of elevated insulin levels in the blood can act as a growth signal for tumour cells, and increases the risk of cancers of the colon and endometrium (the lining of the uterus), and likely of the pancreas and kidney.

Insulin-like growth factors (IGFs) regulate cell growth, differentiation and death, and IGF-1 has been associated with prostate, breast and bowel cancers.

Leptin, a hormone implicated in hunger and satiety, can stimulate proliferation of many pre-cancer and cancer cells. Increased leptin levels in obese people are associated with bowel and prostate cancers.

Sex steroid hormones including oestrogens, testosterone, and progesterone are crucial to healthy body development and sexual function, but are also likely to play a role in obesity and cancer. Increased levels of sex steroids are strongly associated with risk of developing endometrial and postmenopausal breast cancers, and may contribute to other cancers such as bowel cancer.

Fat tissue is the main site of oestrogen production in the body for men and postmenopausal women (while in premenopausal women the ovaries are the major producer). Obesity can predispose premenopausal women to polycystic ovarian syndrome, which causes elevated testosterone and therefore could contribute to cancer risk.

Obesity also causes inflammation in the body, meaning the body’s immune system is consistently more active than is normal in healthy weight people.

Evidence for a role of sex hormones and chronic inflammation in affecting the relationship between obesity and cancer is strong, and the evidence for a role of insulin and IGF is moderate. There are a range of other mechanisms still under investigation.

Where does obesity lie on cancer-risk scale?

Overall, obesity-associated cancers represent up to 8.2% of all cancers in the UK, compared to smoking which is responsible for approximately 19%.

Of all deaths from cancer in the USA, excess body weight is close behind smoking as the attributable cause, at 20% versus 30% respectively.

Does obesity affect the screening and detection of cancer?

Focusing on just two types of cancer, breast cancer in women and prostate cancer in men, some evidence suggests that obesity can delay the identification of cancer through screening - but does not reduce the importance or accuracy of screening tools or programs.

For breast cancer, the most common form of cancer in women in Australia, the good news is that screening accuracy is similar across weight status. The Swiss national health survey found the accuracy of mammography is maintained in obese women - with similar ability of the tests to detect cancers, but reduced ability to ensure the positive result definitely means cancer. This meant obese women had a 20% higher false positive rate than normal weight individuals, but does not suggest any cancers were missed.

The troubling news though is, studies suggest obese women with breast cancer detected through mammogram tend to present to their doctors later, and when the cancer is more serious, than their healthy weight counterparts. The exact reasons for this are not clear but may include possible difficulties in breast self-examination and delayed health-seeking. Such findings reinforce the crucial importance of strategies to encourage appropriate cancer screening and timely medical follow-up among overweight and obese women.

For prostate cancer, the most common form of cancer in Australia, large studies suggest a link between obesity and decreased risk of low-grade or early prostate cancer, but increased risk of advanced disease.

The reasons for this are again thought to be numerous, but one potential reason may be linked to greater difficulty in diagnosing prostate cancer in overweight men. While this is thought to possibly delay diagnosis and treatment, it is unlikely entirely to explain the links between obesity and prostate cancer risk.

What risks does obesity pose in the treatments of cancer?

Obesity can impact cancer treatments and their success. Obese patients have a significantly higher risk of heart attack following surgery, as well as risk of wound infection, nerve injury, and urinary infection. Obesity alone increases the risk of poorer health outcomes following surgery, and morbid obesity increases the risk of death.

In cancer treatments, one study has shown significantly increased surgical complications and prolonged hospital stay with morbid obesity in bowel cancer. Another suggests obesity may reduce chemotherapy efficacy in breast cancer, with lower disease-free survival rates.

Is this risk reversible?

By 2025 it’s estimated that more Australians will be obese than normal weight. At the same time, cancer is a leading contributor to early deaths and disability in Australia and the major cause of years lost from people’s lifespans.

The question is not whether obesity can cause cancer; it is how we can better prevent or mitigate this important risk factor. Reassuringly, there is suggestive evidence that weight loss may reduce or reverse many of the above processes and their associated risks.

While obesity is just one of the drivers of the cancer burden in Australia, it is one that is preventable and in doing so, would bring other enormous health benefits.