HOW TO PREVENT CANCERS

We know from studies of leukemia and some other cancers that people who were exposed to certain factors (such as to radiation) while in the womb (in utero) can have a greater risk of cancer as children and adults. More recently, interest has shifted from large one-time exposures to carcinogens (such as to atomic bomb radiation) to other more subtle factors, such as: older maternal age, maternal obesity, maternal pre-eclampsia during childbirth, higher child birthweight, and certain infections. Each of these factors is thought to alter a mother’s estrogen levels, which may in turn prime cells in the baby’s body for future cancer risk. On top of its possible effect on estrogen levels, a high birthweight may also be associated with in utero exposure to high levels of growth hormones, which like estrogen, can increase later risk of cancer.

A recent review of the research on this topic found that higher birthweight was associated with a fairly small increase in the risk of breast cancer, especially in premenopausal women. Specifically, the paper found that a 2.2 pound (1 kilogram) increase in birthweight raised the risk of breast cancer later in life by about 15 percent (study link) (1). This means that women who weighed, for example, 10 pounds at birth, had a 15 percent higher risk of breast cancer compared to women who weighed 7 pounds, 13 ounces.

Literature cited
1. Xue, F. and K.B. Michels, Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. Lancet Oncol, 2007. 8(12): p. 1088-100.

A recent study in the British Medical Journal adds further evidence that use of oral contraceptives reduces cancer mortality (full study). In the long term study of over 46,000 women who were followed for up to 39 years, Hannaford and colleagues reported that women who used oral contraceptives (OCs)  had lower mortality from cancers of the ovary, uterine body and colon (Hannaford, Iversen et al. 2010). OC use was not related to breast cancer mortality.

Approximately half of the women who had used OCs had used them for more than 4 years, and the risk of cancer death decreased the longer women had used OCs. These data extend previous work from the Nurses’ Health Study, which showed no overall adverse effect from use of OCs (Colditz and for the NHS research group 1994).

Oral contraceptives are one of the most widely used medications. Use of oral contraceptives (OCs) for 5 years halves a woman’s risk of developing ovarian cancer (see figure) and substantially reduces the risk of endometrial cancer  (Collaborative Group on Epidemiological Studies of Ovarian, Beral et al. 2008).



The protection is long lasting and in high income countries rates of use approach 80 per cent. Adverse effects are largely limited to an increased risk of breast cancer and stroke while women are currently using OCs, a risk which seems to disappear within about ten years of stopping. These side-effects are strongly age-dependent - being more common the older a woman is. Thus use of OCs during late teens and early 20s could be expanded for greater reduction in ovarian and endometrial cancers and overall net public health benefit (Kawachi, Colditz et al. 1994).

Strong scientific evidence supports several other medications as either causing cancer  (e.g. postmenopausal hormone therapy with estrogen plus progestin) (Colditz 2007), or reducing cancer (e.g aspirin and colon cancer) (Chan, Giovannucci et al. 2005).

Postmenopausal hormones
For combination oestrogen plus progestin, the International Agency for Research on Cancer (IARC) has now classified this combination hormone therapy as carcinogenic in humans (2007), and estimates indicate that the reduction in use of hormones after the widespread publicity of the results of the Women’s Health Initiative (stopped early due to excess breast cancer) accounts for approximately a 10 per cent decline in breast cancer incidence among women 40 to 70 years of age (Colditz 2007). Thus for this combination therapy evidence shows that risk rises with duration of use and that acting as a late promoter, removal of the drug leads to a rapid decline in incidence (Colditz 2007), though among women with longer durations of use risk may not return to that of women who have never used combination therapy (Colditz and Rosner 2000).

Other less widespread drugs may also contribute to cancer risk (e.g., DES), but the population impact will be substantially smaller than the examples based on much more widespread use described above.

For some medications that reduce cancer risk, the benefits have been limited to date to those who have had the specific indications to use the medication. Broader population strategies may be developed for more widespread protection, such as could be achieved if all women took oral contraceptives as a chemopreventive for a minimum of 5-years.

Aspirin
Aspirin has been extensively studied in observational studies that address duration of use, dose, and magnitude of risk reduction. This evidence is consistent with evidence from randomized primary prevention trials showing that the use of 300 mg or more of aspirin a day for 5 years or more is effective in preventing colon cancer; reducing risk by approximately 25 per cent (Flossmann and Rothwell 2007). A latency of about 10 years is observed between onset of use of aspirin and the reduction in cancer. Like all chemoprevention strategies, risks and benefits must be balanced (Glasziou and Irwig 1995). To date, the risk-benefit considerations of cardiovascular disease, bleeding complications, stomach pain and heart burn caused by aspirin have precluded recommendations for aspirin use as a widespread prevention strategy (Gralow, Ozols et al. 2008).

Selective estrogen receptor modulators (SERMs)
Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have been shown in randomized controlled prevention trials to reduce incidence of pre-invasive and invasive breast cancer (Fisher, Costantino et al. 1998; Martino, Cauley et al. 2004). While tamoxifen increases risk of uterine cancer, this is not so for raloxifene and the risk profile for raloxifene looks considerably safer (Chen, Rosner et al. 2007).

Based on these risks and benefits of therapy, we have estimated the potential for risk reduction among women over age 50 who are postmenopausal. Our estimates indicate that if the trade-off of excess adverse events versus cases of breast cancer prevented must be less than 1, then approximately 30 per cent of the 27 million women between ages 50 and 69 in the United States have benefits exceeding risks, and would achieve a 50 percent reduction in the burden of breast cancer by taking a SERM. This is a population benefit of 42,900 fewer cases of invasive breast cancer among the more than 7 million women with sufficiently high risk to justify chemoprevention (Chen, Rosner et al. 2007).

The reduction in breast cancer risk observed in the chemoprevention randomized trials is very rapid; within 2 years of beginning SERM therapy, incidence curves have clearly separated. This is consistent with the pharmacologic action of these agents inhibiting estrogen receptors. Importantly these agents show protection against estrogen receptor (ER) positive breast cancers (risk reduction up to 76 per cent) and no protection against receptor negative cancers (Martino, Cauley et al. 2004).

While statistical models to predict and classify risk of breast cancer have been developed and validated, to date, prediction of receptor positive tumors is no more accurate than prediction of risk overall (Colditz, Rosner et al. 2004).  Refining risk stratification and developing tools to aid women in considering trade-offs of risks and benefits of chemoprevention therapy are necessary next steps to informed choices for prevention for women at elevated risk of breast cancer.

Conclusions
While all drugs have risks and benefits, some of the agents described here have the potential to substantially reduce risk of cancer. Balancing risks and benefits remains an important decisions that should be reviewed with a heath care provider.


Literature cited

While stomach (or gastric) cancer is the fourth most common cancer globally (it is the most common cancer in China and nearly half of global cases occur there), it is much less common in developed countries, including the US (where it is not in the ten most common cancer diagnoses). Stomach cancer constitutes less than 2% of cancer cases diagnosed in the US. The absolute risk of stomach cancer in the US is quite low with approximately 5 cases per 100,000 individuals (in contrast with colon cancer where the incidence is approximately 45 cases per 100,000 individuals).




What are risk factors for stomach cancer?
The leading cause of stomach cancer is infection with helicobacter pylori (H pylori), a bacteria. Rates of H pylori infection have declined significantly in developed countries, contributing to the decline in stomach cancer rates. Also contributing to the decline in the developed world is the use of refrigeration (instead of salt) to reserve foods, significantly reducing individual salt intake. Salt and salty food intake are likely causes of stomach cancer. There is also good evidence that intake of non-starchy (e.g. green leafy vegetables, tomatoes) and allium (i.e. onions and garlic) vegetables reduce risk of stomach cancer. Evidence also indicates that a high intake of fruit protects against stomach cancer. As with many cancers, tobacco use is a clear risk factor for stomach cancer.

Can I get tested for stomach cancer?
There is currently no good screening test for stomach cancer. Unfortunately, stomach cancer often shows no outward signs or symptoms in the early stages. However, if you experience any of the following, you should talk with your doctor:

• Indigestion or a burning sensation (heartburn)
• Discomfort or pain in the abdomen
• Nausea or vomiting
• Diarrhea or constipation
• Bloating of the stomach after meals
• Loss of appetite
• Weakness and tiredness
• Vomiting blood

The anti-diabetic drug metformin is associated with reduced cancer incidence. In a UK based study of 4085 type 2 diabetics who used metformin from 1994 to 2003, investigators compared the incidence of cancer in those diebetics to the rate of cancer in diabetics who did not use metformin. The risk of cancer was reduced by 40 percent among those who took metformin (1). In a study of 1353 patients with type 2 diabetes in the Netherlands, during 9.6 years of follow-up, cancer deaths were significantly reduced among those who took metformin (2).

Among mechanisms for such a benefit are the inhibition of cancer cell growth and suppression of erb-2 oncoprotein overexpression and inhibition of mTOR (3-5). A search using the medical literature search engine, PubMed, shows over 800 papers addressing metformin and cancer ranging from human studies, as noted above, to animal models and tissue culture studies. This rapidly expanding area of laboratory and human evidence points to a role for metformin among diabetic patients. The call for clinical trials is well justified (6).

A new study of adolescent diet and subsequent risk of precursor lesions for breast cancer shows that women who had higher intake of fiber earlier in life have lower cancer risk. Data from the Nurses' Health Study show that women in the highest quintile of adolescent fiber intake had a 25% lower risk of proliferative benign breast disease. This significant reduction in risk was seen regardless of the source of fiber. 

Several measures that are currently poorly defined in many of our studies that focus on prevention are now a priority for us to achieve the goal of preventing the majority of cancer. These are summarized below and in a recent article (http://bit.ly/aI2jAr)

Obesity is increasing at epidemic rates around the world (International Agency for Research on Cancer 2002). Within the US, the epidemic is clearly shown spreading across the country (see map).

Comprehensive worksite health promotion addressing occupational health issues, smoking cessation, diet and activity has shown a reduction in cancer risk in blue-collar workers (Sorensen et al. Cancer Causes and Control. 2002). If these results were applied in all similar settings then we would see a substantial reduction in lung cancer in the coming years. See: http://bit.ly/9CVqOW

Media coverage of the obesity epidemic in Australia and the resulting cancer burden nicely emphasizes the role of workplace changes that can help promote wellness - http://bit.ly/ci3NoV.

Growing evidence shows such workplace wellness programs save money and reduce costs for the health system. This is a win-win situation. David Cutler and colleagues write in Health Affairs (Jan 2010): "Amid soaring health spending, there is growing interest in workplace disease prevention and wellness programs to improve health and lower costs. In a critical meta-analysis of the literature on costs and savings associated with such programs, we found that medical costs fall by about $3.27 for every dollar spent on wellness programs and that absenteeism costs fall by about $2.73 for every dollar spent. Although further exploration of the mechanisms at work and broader applicability of the findings is needed, this return on investment suggests that the wider adoption of such programs could prove beneficial for budgets and productivity as well as health outcomes." These data clearly show it is time to act across all types of workplace.

Since we live in communities, we should also remember that school-based programs that help our children grow up healthier are an important adjunct to workplace programs.

Australian population growth projection leads to increasing burden of cancer for health services and for the community. The continuing growth through births and migration lead to projections that the Australian population will substantially increase in size and in age over the next 50 years. By 2056 5% percent or more of the population will be aged 85 or older compared to only 1.6 percent in 2007. Because the risk of cancer increases with age a larger number of older Australians will result in more cases of cancer diagnosed each year, even if the risk at a given age holds steady. Therefore, efforts to reduce risk and prevent cancer must be an even higher priority to avoid this burden on society and the pain and suffering for individuals.

3222.0 - Population Projections, Australia, 2006 to 2101