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Breast Cancer Risk Factors

Published on | Eric Brown

Genetic Pic

A very common questions that patients have is “why did I get breast cancer?”.  Unfortunately, there are rarely satisfying answers.  Here is a terrific article published in 2010 by the National Institute of Health, on breast cancer risk factors.  There is a lot of very helpful information:

The etiology of the majority of breast cancers is multifactorial, including both genetic and environmental factors, and it is possible that many of the factors responsible are as yet unrecognized. The existence of non-genetic determinants of breast cancer is indicated by the large variations of breast cancer among different countries and over time within countries.

Hormonal factors

It is well known that hormones play a major role in the aetiology of breast cancer. The recognized hormonal risk factors for breast cancer appear to be related to the cumulative exposure of the breast to estrogens and possibly to progestins. One of the most important risks is associated with late menopause (after age 55 years). Other risk factors for breast cancer have also been identified, such as early menarche, nulliparity or late age at first pregnancy.

The effect of exogenously administered estrogens and progestins, in the form of oral contraceptives, has been extensively studied, but evidence for an increase in risk of breast cancer has not been conclusively demonstrated. Studies of hormone replacement therapy have shown a small but statistically significant increase in the risk of breast cancer related to the duration of estrogen [1] exposure.

Women in China and Japan have low serum levels of ovarian estrogens compared with Western women and this may explain the differences in geographical risk seen in Western and Asian populations, although the low steroid concentrations may, in turn, be explained by dietary factors.

Family history

Family history of breast cancer is known to be an important risk factor for the disease [2]There are different levels of risk in women with family histories of breast cancer, one due to a genetically inherited predisposition to breast cancer and the other to increased familial incidence of the disease [3] The risk for a woman with a first-degree relative with breast cancer is approximately two or three times higher than that for a woman with no family history. To date, mutations of three genes, p53, BRCA-1 and BRCA-2, have been associated with a genetic predisposition to breast cancer, although it is anticipated that additional genes will be identified in the future [3, 4, 5] Familial characteristics suggestive of a genetic predisposition to breast cancer are: multiple relatives with breast cancer (usually >3); a history of breast and ovarian cancer; early-onset breast cancer and bilateral breast cancer [3] .

Germline mutations in cancer susceptibility genes have been identified in individuals of all races and ethnic groups. Differences among ethnic groups for cancer risks have been identified, and a proportion of these differences may result from founder mutations within these genes. One such group is the Ashkenazi Jews, among whom three BRCA1 and BRCA2 mutations have been extensively studied. Mutations in the BRCA1 and BRCA2 genes account for approximately 3 to 10% of breast cancers in the general population, but for a much higher proportion in those of Ashkenazic Jewish descent. However, the overall increased risk of breast or ovarian cancer among Askenazi Jewish women is not higher than that for non-Jewish Caucasian women [6, 7] .

Understanding Inherited Breast and Ovarian Cancer

Breast and ovarian cancer are topics of concern for all women – regardless of family history. Each year, close to 200,000 cases of breast cancer and about 25,000 cases of ovarian cancer are diagnosed. While the majority of breast and ovarian cancers are not caused by inherited risk factors, research has shown that about 10 percent of these cases are hereditary.

Inherited Cancer Risk Factors

Many people are unaware of their inherited risk, though they may be aware of a cancer history in their family. Whether or not you’ve had cancer, a family history of early onset breast and/or ovarian cancer at any age can point to the presence of hereditary cancer risk. Your risk for breast and ovarian cancer may also be heightened if you are of Ashkenazi or Eastern European Jewish heritage.  How is this risk inherited? We’re all born with two copies of about 30,000 different genes, one copy of each gene from our mother and the other from our father. Two genes in particular, BRCA1 and BRCA2, normally work to prevent breast and ovarian cancer. But in some cases, we can inherit a BRCA1 or BRCA2 alteration from either parent. This alteration or mutation interferes with the normal activity of the gene, making us more susceptible to breast and ovarian cancer. A person with one of these gene mutations has a higher risk of developing these cancers and also may pass that gene mutation on to his or her children.

Reducing the Risk of Breast and Ovarian Cancer

Here are some of the risk-reducing steps you and your doctor can take if your genetic test indicates a greater-than-average risk of developing an inherited cancer.
Increased Surveillance for Breast Cancer
• Monthly breast self-exams starting between ages 18-21
• Annual or semiannual clinical breast exams starting between ages 25-35
• Annual mammography starting between ages 25-35
• Consider investigational screening-for example: magnetic resonance imaging
Increased Surveillance for Ovarian Cancer
• Annual or semiannual transvaginal ultrasound (TVU) starting between ages 25-35
• Annual or semiannual check-up on serum CA-125 levels
Preventive Drug Therapies for Breast Cancer
Preventive drug therapies may be implemented along with increased surveillance. Specifically, tamoxifen, a selective estrogen receptor modulator (SERM), has been proven to cut in half the risk for women with BRCA mutations.
Preventive Drug Therapies for Ovarian Cancer
Oral contraceptives can reduce the chances of ovarian cancer in women with BRCA mutations, as well as the general population. Research has shown a risk reduction of up to 60 percent in women with BRCA mutations who took oral contraceptives.
Prophylactic Mastectomy
Prophylactic bilateral mastectomy has been shown to reduce breast cancer risk by greater than 90 percent in women with a BRCA mutation or a family history of the disease.
Prophylactic Oophorectomy
Prophylactic bilateral oophorectomy has been shown to reduce ovarian cancer risk by 96 percent in women with a BRCA mutation. It is generally recommended after 35 years of age or after childbearing is completed. If this procedure is performed pre-menopausally, it also reduces the risk of breast cancer by about 50 percent.

Oncogenes

Oncogenes are genes that are normal constituents of cells, however, they may become amplified (multiple copies of the gene produced) in some breast cancers, and this is associated with poor prognosis. The type 2 human epidermal growth factor receptor gene (HER-2/neu or c-erbB-2) is one such gene. Amplification occurs in up to 30% of primary breast cancers and is accompanied by elevated expression of HER-2 mRNA and subsequently HER-2 protein, which is a tyrosine membrane-bound receptor [8, 9, 10] Expression of the HER-2 protein is associated with poor patient prognosis.

Benign breast disease

Various types of benign breast disease exist and can be classified as non-proliferative, proliferative or atypical lesions. Non-proliferative lesions account for the majority of benign breast disease and are not associated with increased risk of breast cancer. Proliferative disease and atypical hyperplasia are less common but are each associated with a small increase in the risk of breast cancer.  Lobular carcinoma in situ (LCIS) is a benign breast lesion associated with a risk of breast cancer development of approximately 1% per year [11, 12] .

Dietary factors and the development of breast cancer

Large increases in the incidence rates of breast cancer have been reported among migrating populations, particularly in those migrating from Japan to the United States [13] This indicates that the development of breast cancer may also be determined by dietary factors and suggests that the potential for prevention exists.

The main dietary changes encountered by individuals migrating from a low-risk to a high-risk area are an increase in animal fat and protein and a corresponding decrease in the intake of complex carbohydrates and fiber. It is thought that it is the combination of reduced intake of whole grain products plus increased animal fat and protein which increase cancer risk.
High fiber diets correlate with high fecal estrogen excretion, low urinary estrogen excretion and low plasma concentrations of estrogens. Conversely, Western-style diets increase plasma concentrations of sex hormones and decrease sex hormone-binding globulin (SHBG) concentrations thus increasing the availability of sex hormones at a tissue level. This is reportedly due to the low formation of mammalian lignans and phytoestrogens from plant precursors by gut bacteria. These diphenolic substances have been shown to have effects on hormone metabolism and production and cancer cell growth.

Data from prospective studies have also confirmed that a relationship exists between alcohol intake and risk of breast cancer [14, 15.] .

Environmental factors and the development of breast cancer

Exposure to industrial environmental factors such as moderate-to-high-dose ionizing radiation increases the risk of breast cancer [16, 17] However, other environmental factors, such as exposure to electromagnetic radiation, occupational exposures and organochlorine pesticides, have not been conclusively linked to an increased risk [18] .

Interactions among risk factors

The majority of women have multiple risk factors, each of which may relate to either an increase in risk or to a protective effect. This leads to considerable difficulty in assessing overall risk, since it is not yet known how the individual risk factors within a combination interact and whether they are additive or multiplicative. A further complication is that some factors for the risk of breast cancer may be more important for premenopausal women than for postmenopausal women and vice versa, hence the influence of individual risk factors on the overall risk may not be constant over time. Gail et al have developed a model to predict the risk of breast cancer development in women at a given age over a defined time period [19]Data were used from 4,496 matched pairs of cases and controls in the Breast Cancer Diagnosis and Demonstration Project. The model employed a number of risk factors: age at menarche, age at first live birth, number of first-degree relatives with breast cancer and number of previous breast biopsies. The Gail model is a clinically useful tool for the identification of a woman’s level of risk of breast cancer over time, after correcting for other competing causes of mortality. However, it should be noted that even women who have a combination of factors associated with the highest risk of breast cancer development will not necessarily develop breast cancer.

Conclusions: Risk factors in breast cancer

The magnitude of the increase in risk of breast cancer associated with the various risk factors is poorly understood and knowledge of the interactions among them limited. A high concentration of endogenous estrogen is well established as a major contributory cause of breast cancer and many known risk factors operate via this pathway. To date, however, our knowledge of risk factors is incomplete and approximately half of the women who develop breast cancer have no identifiable factors indicating increased risk.

References

1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047–1059.
2. Weber B, Garber J. Familial breast cancer. In: Harris J, Lippman M, Morrow M, Hellman S (eds.). Diseases of the Breast. Lippincott-Raven, 1996; 168.
3. Morrow M. Breast cancer: who and why? In: Jordan VC (ed.). Tamoxifen for the treatment and prevention of breast cancer. Melville, New York: PRR, 1999; 187–205.
4. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA-1. Science 1994; 266: 66–71.
5. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA-2, to chromosome 13 q 12-13. Science 1994; 265: 2088–2090.
6. Neuhausen SL. Ethnic differences in cancer risk resulting from genetic variation. Cancer 1999; 86 (Suppl 11): 2575-2582
7. Schubert EL, Mefford HC, Dann JL, et al.BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and ovarian cancer. Genet Test 1997; 1: 41-46
8. Slamon DJ, Clark DJ, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177-182
9. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707-712
10. Hung M-C, Lau Y-K. Basic science of HER-2/neu: A review. Seminars in Oncol 1999; 26 (Suppl 12): 51-59
11. Salvadori B, Bartoli C, Zurrida S, et al. Risk of invasive cancer in women with lobular carcinoma in situ of the breast. Eur J Cancer 1991; 27: 35–37.
12. Page DL, Kidd TE, Dupont WD, et al. Lobular neoplasia of the breast: Higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol 1991; 22: 1232–1239.
13. Buell P. Changing incidence of breast cancer in Japanese-American women. J Natl Cancer Inst 1973; 51: 1479–1483.
14. Gapstur S, Potter J, Sellers T, et al. Increased risk of breast cancer with alcohol consumption in postmenopausal women. Am J Epidemiol 1992; 136: 1221–1231.
15. Friedenreich C, Howe G, Miller A, et al. A cohort study of alcohol consumption and risk of breast cancer. Am J Epidemiol 1993; 137: 512–520.
16. Miller A, Howe G, Sherman G. Mortality from breast cancer after irradiation of the thymus in infancy. N Engl J Med 1989; 321: 146.
17. Hancock S, Tucker M, Hoppe R. Breast cancer after treatment of Hodgkin’s disease. J Natl Cancer Inst 1993; 85: 25–31.
18. Morrow M. Breast cancer: who and why? In: Jordan VC (ed.). Tamoxifen for the treatment and prevention of breast cancer. Melville, New York: PRR, 1999; 187–205.
19. Gail M, Brinton L, Byar D, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989; 81: 1879–1886.


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