Breast cancer epidemiology and demographics

, Assistant Editor(s)-In-Chief: Jack Khouri

Overview
Epidemiological risk factors for a disease can provide important clues as to the etiology of a disease. The first work on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.

Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors.
 * 1) Lesions to DNA such as genetic mutations.  Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer.  Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
 * 2) Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
 * 3) Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells, for example in the angiogenesis necessary to promote new blood vessel growth near new cancers.
 * 4) Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and p53.

Although many epidemiological risk factors have been identified, the cause of any individual breast cancer is often unknowable. In other words, epidemiological research informs the patterns of breast cancer incidence across certain populations, but not in a given individual. Approximately 5% of new breast cancers are attributable to hereditary syndromes, while no etiology is known for the other 95% of cases.

The primary risk factors that have been identified are sex, age, childbearing, hormones, a high-fat diet, alcohol intake, obesity, and environmental factors such as tobacco use and radiation.

Age
The risk of getting breast cancer increases with age. A woman who lives to age 90 has a lifetime risk of about 14.3%, or one in seven. The probability of breast cancer rises with age, but breast cancer tends to be more aggressive when it occurs in younger people. One type of breast cancer that is especially aggressive and that occurs disproportionately in younger people is inflammatory breast cancer. It is initially staged as Stage IIIb or Stage IV. It also is unique because it often does not present with a lump, so it is often undetected by mammography or ultrasound. It presents with the signs and symptoms of a breast infection like mastitis, and the treatment is usually a combination of surgery, radiation, and chemotherapy.

Sex
Men have a lower risk of developing breast cancer (approximately 1.08 per 100,000 men per year), but this risk appears to be rising.

Heredity
In 5% of breast cancer cases, there is a strong inherited familial risk. Two autosomal dominant genes, BRCA1 and BRCA2, account for most of the cases of familial breast cancer. Family members who harbor mutations in these genes have a 60% to 80% risk of developing breast cancer in their lifetimes. Other associated malignancies include ovarian cancer and pancreatic cancer. If a mother or a sister was diagnosed breast cancer, the risk of a hereditary ‘’’BRCA1’’’ or ‘’’BRCA2’’’ gene mutation is about 2-fold higher than those women without a familial history. In addition to the BRCA genes associated with breast cancer, the presence of NBR2, near breast cancer gene 1, has been discovered, and research into its contribution to breast cancer pathogenesis is ongoing. Commercial testing for ‘’’BRCA1’’’ and ‘’’BRCA2’’’ gene mutations has been available since at least 2004. Genetic testing for BRCA gene mutations is conducted exclusively by Myriad Genetics, located in Salt Lake City.

Diet
Dietary influences have been proposed and examined, and recent research suggests that low-fat diets may significantly decrease the risk of breast cancer as well as the recurrence of breast cancer. Another study showed no contribution of dietary fat intake on the incidence of breast cancer in over 300,000 women. A randomized controlled study of the consequences of a low-fat diet, the Women's Health Initiative, failed to show a statistically significant reduction in breast cancer incidence in the group assigned to a low-fat diet, although the authors did find evidence of a benefit in the subgoup of women who followed the low-fat diet in a strict manner. Another randomized trial, the Nurses' Health Study II, found increased breast cancer incidence in premenopausal women only, with higher intake of animal fat, but not vegetable fat. Taken as a whole, these results point to a possible association between dietary fat intake and breast cancer incidence, though these interactions are hard to measure in large groups of women.

In a study published in the Journal of the American Medical Association, biomedical investigators found that Brassica vegetable intake (broccoli, cauliflower, cabbage, kale and Brussels sprouts) was inversely related to breast cancer development. The relative risk among women in the highest decile of Brassica vegetable consumption (median, 1.5 servings per day) compared to the lowest decile (virtually no consumption) was 58%. That is, women who consumed the most Brassica vegetables were 58% less likely to develop breast cancer.

A significant environmental effect is likely responsible for the different rates of breast cancer incidence between countries with different dietary customs. Researchers have long measured that breast cancer rates in an immigrant population soon come to resemble the rates of the host country after a few generations. The reason for this is speculated to be immigrant uptake of the host country diet. The prototypical example of this phenomenon is the changing rate of breast cancer after the arrival of Japanese immigrants to America.

Alcohol Consumption
Alcohol appears to increase the risk of breast cancer, though meaningful increases are limited to higher alcohol intake levels. Breast cancer constitutes about 7.3% of all cancers. Among women, breast cancer comprises 60% of alcohol-attributable cancers. The UK's Review of Alcohol: Association with Breast Cancer concludes that "studies confirm previous observations that there appears to be an association between alcohol intake and increased risk of breast cancer in women. On balance, there was a weak association between the amount of alcohol consumed and the relative risk."

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) concludes that "Chronic alcohol consumption has been associated with a small (averaging 10 percent) increase in a woman's risk of breast cancer." According to these studies, the risk appears to increase as the quantity and duration of alcohol consumption increases. Other studies, however, have found no evidence of such a link.

The Committee on Carcinogenicity of Chemicals in Food, Consumer Products Non-Technical Summary concludes, "the new research estimates that a woman drinking an average of two units of alcohol per day has a lifetime risk of developing breast cancer 8% higher than a woman who drinks an average of one unit of alcohol per day. The risk of breast cancer further increases with each additional drink consumed per day. The research also concludes that approximately 6% (between 3.2% and 8.8%) of breast cancers reported in the UK each year could be prevented if drinking was reduced to a very low level (i.e. less than 1 unit/week)." A review article from JAMA also found that breast cancer incidence seems to increase with increasing alcohol consumption. It has been reported that "two drinks daily increase the risk of getting breast cancer by about 25 percent" (NCI), but the evidence is inconsistent. The Framingham study has carefully tracked individuals since the 1940s. Data from that research found that drinking alcohol moderately did not increase breast cancer risk (Wellness Facts). Similarly, research by the Danish National Institute for Public Health found that moderate drinking had virtually no effect on breast cancer risk. One study suggests that women who frequently drink red wine may have an increased risk of developing breast cancer.

"Folate intake counteracts breast cancer risk associated with alcohol consumption" and "women who drink alcohol and have a high folate intake are not at increased risk of cancer." Those who have a high (200 micrograms or more per day) level of folate (folic acid or Vitamin B9) in their diet are not at increased risk of breast cancer compared to those who abstain from alcohol. Foods rich in folate include citrus fruits, citrus juices, dark green leafy vegetables (such as spinach), dried beans, and peas. Vitamin B9 can also be taken in a multivitamin pill.

Obesity
Gaining weight after menopause can increase a woman's risk. A recent study found that putting on 9.9kg (22lbs) after menopause increased the risk of developing breast cancer by 18%.

Hormones
Persistently increased blood levels of estrogen are associated with an increased risk of breast cancer, as are increased levels of the androgens androstenedione and testosterone (which can be directly converted by aromatase to the estrogens estrone and estradiol, respectively). Increased blood levels of progesterone are associated with a decreased risk of breast cancer in premenopausal women. A number of circumstances which increase exposure to endogenous estrogens including not having children, delaying first childbirth, not breastfeeding, early menarche (the first menstrual period) and late menopause are suspected of increasing lifetime risk for developing breast cancer.

Hormonal contraceptives may produce a slight increase in the risk of breast cancer diagnosis among current and recent users, but this appears to be a short-term effect. In 1996 the largest collaborative reanalysis of individual data on over 150,000 women in 54 studies of breast cancer found a relative risk (RR) of 1.24 of breast cancer diagnosis among current combined oral contraceptive pill users; 10 or more years after stopping, no difference was seen. Further, the cancers diagnosed in women who had ever used hormonal contraceptives were less advanced than those in nonusers, raising the possibility that the small excess among users was due to increased detection. The relative risk of breast cancer diagnosis associated with current and recent use of hormonal contraceptives did not appear to vary with family history of breast cancer.

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. The largest meta-analysis (1997) of data from 51 observational studies, indicated a relative risk of breast cancer of 1.35 for women who had used HRT for 5 or more years after menopause. The estrogen-plus-progestin arm of the Women's Health Initiative (WHI), a randomized controlled trial, which randomized more than 16,000 postmenopausal women to receive combined hormone therapy or placebo, was halted early (2002) because health risks exceeded benefits. One of the adverse outcomes prompting closure was a significant increase in both total and invasive breast cancers (RR = 1.24) in women randomized to receive estrogen and progestin for an average of 5 years. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.

Tobacco
Most studies have not found an increased risk of breast cancer from active tobacco smoking, although a number of studies suggest an increased risk of breast cancer in both active smokers and those exposed to secondhand smoke compared to women who reported no exposure to secondhand smoke.

Radiation
Women who have received high-dose ionizing radiation to the chest (for example, as treatments for other cancers) have a relative risk of breast cancer between 2.1 to 4.0.

Impact of environmental estrogenic mimics
Although environmental exposures are not generally cited as risk factors for the disease (except for diet, pharmaceuticals and radiation), a substantial and growing body of evidence indicates that exposures to certain toxic chemicals and hormone-mimicking compounds including chemicals used in pesticides, cosmetics and cleaning products contribute to the development of breast cancer. A recent Canadian study concluded that female farm workers are three times more likely to have breast cancer. The increasing prevalence of these substances in the environment may explain the increasing incidence of breast cancer, though direct evidence is sparse.

Dioxins
Although not well-quantified, there has long been a concern about risk associated with environmental estrogenic compounds, such as dioxins.

Light levels
Researchers at the National Cancer Institute and National Institute of Environmental Health Sciences have concluded a study that suggests that artificial light during the night can be a factor for breast cancer.

Viral breast cancer pathogenesis research
Humans are not the only mammals susceptible to breast cancer. Some strains of mice, namely the house mouse (Mus domesticus) are prone to breast cancer which is caused by infection with the mouse mammary tumour virus (MMTV or "Bittner virus" for its discoverer Hans Bittner), by random insertional mutagenesis. This finding is taken to mean that a viral etiology of human breast cancer is at least possible, though there is no definitive evidence to support the claim that MMTV causes human breast cancer. For example, there may be critical differences between cancer pathogenesis in mice and people. The understanding of the role of MMTV or other viruses in human breast cancer is preliminary as of May 2007.

Abortion
Studies in rats led to speculation that abortion may increase the risk of breast cancer because of hormones initiating breast tissue growth in early pregnancy. Some early interview and record based case-control studies indicated a possible correlation, but more recent record based studies  and a large meta-analysis study do not support this association. The subject was examined by a National Cancer Institute (NCI) workshop in 2003, in response to the Bush Administration's alteration of the NCI's website to emphasize studies indicating a potential link. The NCI expert panel concluded, with the strongest level of evidence, that induced abortion is not associated with an increased breast cancer risk.

Deodorants
Much has been made of the possible contribution of aluminum-containing underarm antiperspirants to the incidence of breast cancer, since the most common location of a breast cancer is the upper outer quadrant of the breast. Aluminum salts, such as those used in anti-perspirants, have recently been classified as metalloestrogens. In research published in the Journal of Applied Toxicology, Dr. Philippa D. Darbre of the University of Reading has shown that aluminum salts increase estrogen-related gene expression in human breast cancer cells grown in the laboratory. Fortunately, this in-vitro association between aluminum salts and estrogen activity does not translate into an increased risk of breast cancer in humans. The lack of association between underarm deodorants and breast cancer has been the subject of a number of research articles.

Fertility treatments
There is no persuasive connection between fertility medications and breast cancer.