Cancer risk factors and prevention
Who gets cancer, and whether the disease could have been avoided, are questions about how much of it is inherited and how much comes from environment and lifestyle. The answers rest on attributable fractions, on migration and twin studies, on the genetics of inherited risk and what a genetic test can tell, and on the evidence linking diet, obesity and supplements to cancer, from which recommendations for prevention are drawn.
Why prevention matters
Despite significant progress in tumour diagnosis and treatment, cancer remains a major cause of death worldwide. Widespread population screening programmes for breast, prostate, cervical and colorectal cancer had significantly improved early detection and enhanced survival, but cancer still killed almost 8 million people in 2008, 13% of all human deaths. The disease is difficult to treat, if not impossible to cure, has a dramatic effect on quality of life, and is lethal, particularly when it is not diagnosed at an early stage or is aggravated by comorbidities. Its treatment options, whether surgical removal, chemotherapy or radiation therapy, are limited, expensive and coupled with adverse effects, such as chemotherapy-induced nausea and vomiting, immunosuppression and myelosuppression, and cardiac, hepatic and renal toxicity. Because cancer is difficult to manage, preventing it is the first and best strategy.
Cancer treatment was also becoming increasingly expensive, and personalised or stratified medicine in particular is expensive to develop and deliver, which raises the obvious question of whether cancer is preventable. Cancer prevention through diet and lifestyle changes was gaining importance as understanding grew of the potential of dietary patterns and single foods to avoid carcinogenesis.
Inherited and environmental shares of cancer
Cancer is a complex, multifactorial disease. Approximately 5–10% of cancer cases are thought to be entirely hereditary, and the remainder results from an interaction between biological or environmental insults and genetic predisposition. Common environmental factors that contribute to cancer death include diet and obesity together (30–35%), smoking (25–30%), infections (15–20%), ionizing and non-ionizing radiation (up to 10%), stress, lack of physical activity and environmental pollutants. Hence most forms of cancer have their roots in environment and lifestyle and, as such, are preventable.
Another estimate relates about 18% of cancers worldwide to infectious diseases and has genetic mutations causing under 3–10% of all cancers, which leaves the question whether the rest, more than 70%, can be prevented.
A study funded by Cancer Research UK examined about 134,000 cancers occurring in the United Kingdom in 2010 and estimated how many could be attributed to sub-optimal past exposure to fourteen lifestyle and environmental risk factors. The fourteen factors were responsible for 42.7% of cases, 45.3% in men and 40.1% in women. Smoking was by far the top factor for both sexes, and second came a lack of fruit and vegetables for men and overweight for women.
Evidence from migration and twin studies
The correlation between lifestyle and cancer is evidenced by the large variation in rates of specific cancers between countries and by the changes in incidence observed when people migrate to other countries. Immigrants develop the cancer risk of their new country, often within one generation. Further evidence comes from studies in monozygotic twins, which showed that inherited genetic factors make only a minor contribution to susceptibility to most types of neoplasm. These findings indicate that lifestyle and environmental factors have the principal role in causing sporadic cancer.
Genetic, inherited and hereditary cancer
All cancers are genetic, in that they occur in dividing cells and involve mutations in genes, but not all cancers are inherited, because for a cancer to be inherited the defective gene must be in the germ line, the cells passed on to one's children.
Cancer is multifactorial, involving an interplay between genes and environment, so having a gene mutation does not always mean that a person will get cancer. By 2011 two breast cancer genes, BRCA1 and BRCA2, had been identified, responsible for 5% to 10% of breast cancers, and even within these genes there are different mutations, some more common in certain ethnic groups such as Ashkenazi Jews. The remaining cases were attributed to an unidentified gene or constellation of genes, under the catch-all term BRCA3.
Epigenetics, what happens to change genes after they are formed, has a role in cancer, and a lot can happen in nurturing. There is a need to look beyond genes themselves to socioeconomic factors and environmental exposures, which can make a big difference in health and wellness.
Genetic risk assessment and testing
As the Human Genome Project progressed, increasing attention was being paid to screening for genetic diseases, particularly cancer. The vast majority of cancers are sporadic rather than hereditary, so genetic testing is not appropriate for most people, and the first job in a genetic risk programme is to work out who is at risk. One genetic counsellor reports that people tend to come in asking for that genetic test for cancer, but that it is not that simple, and that her task is a complicated one, involving both assessment and communication of risk.
Testing can clarify risk, determine the best way to manage it, whether by lifestyle changes, early screening or prophylactic surgery, and help determine the risk of other family members. Its risks include psychological distress, guilt about the possibility of passing a mutation on to one's children, loss of privacy, and fear of insurance discrimination. Against that fear, the 2008 Genetic Information Nondiscrimination Act provides protection from insurance and employment discrimination on the basis of genetic testing results. The same counsellor holds that this protection is a huge message to send to the general public, because fear may be preventing some people from learning their risk and taking appropriate steps to manage it.
A test result indicates the probability of developing cancer, not the certainty, and this can be hard for people to understand. Not every mutation has been identified, so a person who does not carry a known mutation may still be at risk of that cancer from other factors. The results of testing can have implications for both the person tested and his or her family. Genetic counselling is a balancing act between providing patients with the information they need to make informed decisions and overmanaging them.
Diet and cancer
The pioneering work pointing to a link between diet and cancer was published by Doll and Peto, who estimated that approximately 30–35% of cancer deaths in the United States were linked to diet. In the 1970s, people in many Western countries were noted to have diets high in animal products, fat and sugar together with high rates of colorectal, breast, prostate, endometrial and lung cancer. People in developing countries, by contrast, usually had diets based on one or two starchy staple foods, with low intake of animal products, fat and sugar, and low rates of those cancers. Diets high in processed or red meat and low in fruit, vegetables and whole grains have been linked to a number of cancers.
In theory, the link between diet and cancer is simple. Sporadic cancer arises from mutations caused by carcinogens or free radicals. A major source of carcinogens is food: the food itself, contaminants such as aflatoxins, dioxins and pesticides, additives such as nitrates and nitrites, and preparation at high temperature, such as frying and barbecuing, which generates nitrosamines, heterocyclic amines and polycyclic aromatic hydrocarbons. Several food carcinogens have been shown to activate inflammatory pathways, including those involving nuclear factor-kappa B. Some nutrients, chiefly antioxidants found in fruits, vegetables, cereals, spices and teas, minimise oxidative damage to DNA caused by free radicals. Nutrients also interact with other molecules within cells, particularly proteins, including enzymes, and lipids, and some of these are then able to regulate the expression of genes such as oncogenes and tumour suppressor genes and the activity of enzymes that control cell proliferation, differentiation and programmed cell death.
The extent to which diet contributes varies greatly with the type and anatomical site of the cancer. Diet was thought to account for 70% of colorectal cancer cases, and consumption of red meat, fat and alcohol was associated with increased risk. Heavy consumption of red or processed meat, such as sausages, bacon and hot dogs, was a risk factor for several cancers, especially gastrointestinal but also prostate, bladder and breast. Epidemiological association studies had linked grilled meat to increased risk of oesophageal and stomach, colon, pancreatic and breast cancer, which could be due to carcinogens present in foods cooked at high temperatures.
Obesity
The key link between diet and cancer seems to be obesity, a condition fostered by diets based on high-fat meat products. A prospective cohort study of 900,000 US adults published in 2003 found body mass index significantly associated in both sexes with higher rates of death from cancer of the oesophagus, colon and rectum, liver, gallbladder, pancreas and kidney, and from non-Hodgkin's lymphoma and multiple myeloma. The same study found significant trends of increasing risk with higher BMI for death from stomach and prostate cancer in men and from breast, uterine, cervical and ovarian cancer in women. Caloric restriction, on the other hand, has been shown to reduce cancer incidence in animals and in humans.
The correlation might have several causes. Obese people usually eat a diet rich in processed food, saturated and trans fatty acids, refined sugar, and red and processed meat products, which are a good source of carcinogens, and they eat less fruit, vegetables and grain, and they are less physically active. They also present comorbidities such as diabetes and cardiovascular disease that may contribute to a bad state of health, for instance by activating inflammatory signalling cascades and raising systemic chronic inflammation.
Common denominators between obesity and cancer include neurochemicals, hormones such as insulin-like growth factor 1, insulin and leptin, sex steroids, inflammation and insulin resistance. Hyperglycaemia has been shown to activate nuclear factor-kappa B, and several cytokines produced by adipocytes, such as leptin, tumour necrosis factor and interleukin-1, are known to activate it too. Another possible link is the mammalian target of rapamycin (mTOR), a protein kinase that is activated by high cellular nutrient and energy levels and regulates cell growth, proliferation, motility and survival. mTOR is more active in obese and overweight people, a state thought to increase the probability of carcinogenesis. Its counteractor, AMP-activated protein kinase (AMPK), is implicated in preventing metabolic disorders, decreased AMPK activity has been associated with increased carcinogenesis risk, and treatment with the AMPK activator metformin reduces cancer incidence in people with type 2 diabetes. AMPK is emerging as a metabolic tumour suppressor and a promising target for cancer prevention and therapy.
Foods and phytochemicals
A presumed anti-cancer diet has been extensively discussed, and the topic crossed from science into the lay community, fostered by the publication of several books, among them Foods that Fight Cancer, Beating Cancer with Nutrition, The Cancer-Fighting Kitchen, The Everything Cancer-Fighting Cookbook and Beyond the Magic Bullet — The Anti-Cancer Cocktail.
Diets rich in fruit, vegetables, whole grains and spices have been linked to reduced risk of cancers of the colon, rectum, stomach, liver, oral cavity, pharynx and other sites, including breast and prostate. An expert review lists 100 fruits, vegetables, cereals and spices with the potential to prevent cancer. According to that review, the protective role of fruits and vegetables against cancers at various anatomical sites is now well supported, with more than 25,000 different phytochemicals identified that may have anti-cancer activity, among them beta-carotene, lycopene, resveratrol, quercetin, silymarin, indole-3-carbinol and sulphoraphane from fruits and vegetables, and catechins, curcumin, diallyl disulphide, capsaicin, gingerol, anethol and eugenol from spices and teas.
Most of the evidence of chemopreventive efficacy for these compounds had come from cell and animal studies. Their advantage over synthetic drugs is that they are regarded as safe and usually target multiple cell signalling pathways.
Catechins interact with more than ten genes involved in the cellular response to oxidative stress, and they are 100 times more powerful than vitamin C and 25 times more powerful than vitamin E in antioxidant and growth-inhibitor potential. Coffee has been reported to correlate inversely with liver cancer. Whole grains contain dietary fibre and chemopreventive antioxidants such as tocotrienols, phenolic acids, lignans and phytic acid, and whole-grain intake was found to reduce the risk of several cancers, including carcinomas at different sites, lymphomas and leukaemias, by 30–70%.
The most evident correlation between dietary fibre and reduced cancer risk has been observed for colorectal cancer. A meta-analysis of 25 prospective cohort and case–control studies, published in November 2011, confirmed a protective effect of dietary fibre on colorectal cancer incidence and found that the risk reduction varies by fibre type, the greatest benefit being for legume fibre (relative risk 0.62) and cereal fibre (relative risk 0.90).
Some isoflavones, such as genistein, daidzein and equol, have been linked to lower breast cancer incidence, but there is also controversy over whether isoflavones, being phytoestrogens, might instead contribute to hormone-dependent cancers. Their effects on early breast cancer markers differ between pre- and post-menopausal women, and human and animal studies have yielded conflicting results, possibly because isoflavone metabolism differs between humans and rodents.
Lignans are the most important class of phytoestrogens in the Western diet. Found in flaxseed, sesame seed and rye bran, they are converted by intestinal microflora into enterodiol and enterolactone, and they bind oestrogen receptors and interfere with the cancer-promoting effects of oestrogen on breast tissue. A meta-analysis associated high lignan intake with significantly reduced breast cancer risk in post-menopausal women, but an epidemiological study did not confirm this. Colorectal cancer risk was inversely associated with enterolactone and total enterolignans in women but not in men, and enterolignan intake correlated positively with prostate cancer risk, a correlation attenuated after adjustment for dairy intake.
Nutrient supplements
Foods containing certain nutrients have been shown to be beneficial against cancer, but intake of the isolated nutrients has failed to confer the same benefits, and harmful effects have been reported with supplementation of certain compounds.
An increased risk of lung cancer among smokers taking beta-carotene supplements was reported in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial and in the Beta-Carotene and Retinol Efficiency Trial (CARET), at 20 mg and 30 mg respectively. In the ATBC trial, beta-carotene had little or no effect on the incidence of cancers other than lung cancer, but total mortality was 8% higher among participants who received it, primarily through more deaths from lung cancer and ischaemic heart disease. The effect is specific to the supplementation dose, since no lung damage was detected in people exposed to cigarette smoke who ingested a physiological dose of 6 mg, in contrast to the pharmacological 20–30 mg. The harm also seems to be specific to smoke exposure.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) initially found no reduction in prostate cancer risk from either selenium at 200 µg/day as L-selenomethionine or vitamin E at 400 IU/day of all-rac-alpha-tocopheryl acetate, and a statistically non-significant increase in risk with vitamin E. Follow-up data at 7 to 12 years, published in October 2011, found that dietary supplementation with vitamin E significantly increased prostate cancer risk among healthy men (hazard ratio 1.17, p = 0.008). The vitamin E dose used was twelve times the recommended intake of 33 IU daily. For vitamin C the position was less clear: three randomised trials of oral vitamin C in cancer patients at the Mayo Clinic were negative, and whether vitamin C has clinically significant antitumour activity remained under debate.
Drug prevention
The National Surgical Adjuvant Breast and Bowel Project, one of the cancer cooperative clinical trials groups funded by the National Cancer Institute, carries out national and international research studies in breast and colon cancer, and its breast cancer studies demonstrated the effectiveness of tamoxifen in preventing breast cancer.
Recommendations for prevention
A report compiled by the World Cancer Research Fund and the American Institute for Cancer Research in 2007 presents a clear correlation between lifestyle and cancer risk. The 670-page report covered food, nutrition, physical activity, body composition and the prevention of cancer worldwide, and in it an expert panel of over 100 scientists from 30 countries summarised five years of research into eight general and two special recommendations. In summary, they are to keep body weight within the normal range, be physically active, eat mostly foods of plant origin, limit energy-dense foods, red meat, processed meat, salt, alcohol and sugary drinks, and aim to meet nutritional needs through diet alone rather than through dietary supplements. The list sounds easy, but it perhaps has too many items for most people to follow.
Many cases of sporadic cancer are preventable. Prevention through dietary and lifestyle change remains an active research subject because of the potential of an effective intervention to decrease cancer incidence at low cost and with a large positive effect on health economics globally. Effective prevention involves smoking cessation, minimal consumption of fat, red meat and processed meat, increased intake of fruit, vegetables and whole grains, avoidance of alcohol, caloric restriction, physical activity, avoiding prolonged sun exposure, vaccination and regular check-ups. Increased consumption of fat, red meat and processed meat has been clearly associated with increased cancer risk.
Inconsistent results across many studies had not conclusively established an inverse association between fruit and vegetable intake and overall cancer risk. It has been claimed that fruit, vegetables and dietary fibre in themselves have a very marginal effect on cancer incidence, if any, except for cancers caused by smoking and alcohol, where the effect might be residual confounding by those same factors. A diet rich in fruit and vegetables helps avoid obesity, metabolic syndrome and cardiovascular disease, and supplies antioxidants and other phytochemicals with chemopreventive activity. Evidence is accumulating that active phytochemicals have synergistic effects that mono-supplementation of isolated compounds cannot achieve. The use of nutritional supplements in well-nourished individuals is not supported by the evidence.
Not all the substances present in fruits, vegetables, spices and teas have been studied, and many have not been identified, so future research should focus on whole dietary patterns and other lifestyle factors.
Public education and responsibility
Prevention can begin at a young age. In heart disease, identified risk factors, improved technologies and medications, and a focus on prevention and education have led to a decline in death rates, and even children know what they should do to prevent it: one physician's son, served bacon, asked whether she was trying to kill him. That physician believes the same can be done in educating the public about cancer risk, especially since cancer is multifactorial and develops over time.
After the Cancer Research UK study was published, the United Kingdom's shadow health minister criticised the government's approach to tackling lifestyle-related health problems as completely inadequate, a criticism that, in one journal editor's view, could equally have been made of any government in the world.
Cancer has often carried a stigma of being the fault of the victim. The talk therapy movement, a popular alternative therapy of the 1970s, epitomised it: it blamed the negative attitude of people with the disease for their plight and held that correcting that attitude through psychotherapy could cure their cancer. Few people support that concept today, but lifestyle and diet, certain elements of which are related to cancer incidence, are personal choices.