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Risk factors for breast cancer

There are few well established risk factors for breast cancer and these do not account for the major international differences or allow for practical preventive measures (Table 2). Genetic factors are responsible for only a small percentage of cases.(6) Environmental factors have been speculated as playing a major role since incidence rates vary greatly between countries and rates among migrants moving from both low- and high-risk countries converge to the rate of the destination country.(7) However, the environmental factors responsible for this variation are at present unknown.

Table 2. Established risk factors for breast cancer in women

Factor High-risk group Low-risk group
  Relative risk >4.0 Relative risk <1.0
Age Old Young
Country of birth North America, Northern Europe Asia, Africa
Mother and sister with history of breast cancer, especially if diagnosed at an early age Yes No
Biopsy-confirmed atypical hyperplasia and a history of breast cancer in a first degree relative Yes No
  Relative risk=2.1B4.0 Relative risk <1.0
Nodular densities on the mammogram Densities occupying >75% of breast volume Parenchyma composed entirely of fat
History of cancer in one breast Yes No
Mother or sister with history of breast cancer, diagnosed at an early age Yes No
Biopsy-confirmed atypical hyperplasia without a family history of breast cancer Yes No
Radiation to chest Yes No
  Relative risk=1.1B2.0 Relative risk <1.0
Socio-economic status High Low
Place of residence Urban Rural
Race/ethnicity
breast cancer at >45 years
breast cancer at <45 years
White
Black
Hispanic, Asian
Hispanic, Asian
Religion Jewish Seventh-day Adventist, Mormon
Oophorectomy before age 40 No Yes
Nulliparity, breast cancer at >40 years of age Yes No
Age at first full-term pregnancy >30 years <20 years
Age at menarche <11 years >15 years
Age at menopause >55 years <45 years
History of primary cancer in endometrium, ovary Yes No
Obesity
breast cancer at >50 years
breast cancer at <50 years
Obese
Thin
Thin
Obese

Demographic factors

Age is the most recognised risk factor for breast cancer, and incidence increases with age. Women of high socio-economic status are at greater risk of breast cancer than women of low socio-economic status with possible reasons including differences in reproductive factors, lifestyle factors, and greater numbers of higher educated women attending mammography screening.

Family history

The risk of breast cancer is doubled among women with a first-degree relative diagnosed with breast cancer before the age of 40 years. (8)

The risk associated with an affected second degree relative is lower, at 1.2- to 1.5-fold. Genetic and familial factors are described in greater detail below.

Medical history

Women with biopsy-confirmed benign breast disease are at increased risk of subsequent breast cancer. The risk of invasive breast cancer depends on the specific type of benign breast disease. High relative risks (RR) are found for benign proliferative disease with atypical hyperplasia (2.5–5.3), particularly if there is a family history of breast cancer, and moderate risks are associated with proliferative disease without atypia (RR 1.6–2.2). Women with lobular carcinoma in situ are also at high risk of developing invasive breast cancer (RR 6.0–12).(9)

Hormonal and reproductive risk factors

Early age at menarche, late age at menopause, late age at first birth and nulliparity are associated with an elevated risk of breast cancer.

Conversely, bilateral oophorectomy before the age of 40 years is protective against breast cancer.

The relationship between exogenous hormone use [oral contraceptive pill (OCP), hormone replacement therapy (HRT) and depot-medroxyprogesterone acetate (DMPA)] and risk of breast cancer is not conclusive. A recent meta-analysis of 54 studies relating OCP use to breast cancer found that women who are currently using combined OCP or have used them in the past 10 years are at a slightly increased risk (RR 1.07-1.24) compared to never users.(10) There is continuing debate about the relative effect of long-term HRT use on the risk of breast cancer with conflicting results being reported.(11,12)

Other risk factors

Several other factors implicated in the development of breast cancer include parity, length of menstrual cycle, breast feeding, diethylstilbestrol use during pregnancy, infertility, spontaneous and induced abortion, physical activity, stress, height, alcohol consumption and dietary factors. Current evidence suggests that breast cancer may also be affected by the intra-uterine environment and exposures during adolescence.(13) However, the evidence for these factors is not conclusive because of inconsistency in results or concern that unidentified confounding may explain the association.

Genetic and familial factors

A family history may be due to chance, to non-genetic risk factors shared by relatives, or may be due to the inheritance of a specific germline mutation from either maternal or paternal relatives. Between 5% to 10% of all breast cancers diagnosed in women aged 45 or younger are directly attributable to inherited factors. Inherited breast cancer may be distinguished clinically from sporadic breast cancer by a younger age of onset, a higher prevalence of bilateral breast cancer, and the presence of associated tumors in family members.

Mutations of BRCA1, BRCA2, and the p53 tumor-suppressor gene have been found to markedly increase the risk of breast and ovarian cancer and perhaps colon, rectum and prostate cancer.(14) These genes appear to be transmitted in an autosomal dominant manner.(6,8)

Mutations in BRCA1 are relatively uncommon, being carried by about 1 in 1000 women and explains only 1% or 2% of all breast cancer.(15)

Germline mutations of the BRCA1 gene, located on chromosome 17q21, were initially estimated to be associated with a 50% risk of breast cancer by about age 50 and an 85% lifetime risk in high-risk families.(14,16) A more broad-based survey among a group of Ashkenazi Jews in the Washington DC region showed a lifetime risk of about 50% for women with mutations in either BRCA1 or BRCA2.(17) In addition, the risk of a second primary in the contralateral breast for a woman with BRCA1 mutations appears to be similar to the risk of the first primary (65% for mutated BRCA1 gene carriers who live to age 70).(14)

Preliminary data suggest that the prognosis of patients with BRCA1 mutations may be slightly better than that of women with sporadic tumors (18,19) but this remains to be confirmed.

Over 80 distinct mutations in BRCA1 have been characterised in high-risk families.(20) It is not known whether all mutations on BRCA1 carry the same risk. The implication of mutations that occur in the absence of a strong family history of the disease is also uncertain.

BRCA2 has been located on chromosome 13 and is associated with early-onset breast cancer and breast cancer in males, and to a lesser degree with ovarian cancer.(21) The level of breast cancer risk with mutations of BRCA2 is similar to that of BRCA1.

Mutations in the tumor suppressor gene p53 are rare, found in about 1 in 10,000 women and contributing to an estimated 1% of breast cancer in women diagnosed before age 40.

More common genes, such as the AT gene for ataxia-telangiectasia and the HRAS1 gene have also been implicated in the contribution to familial breast cancer.(22,23) However, the evidence linking these genes with an increased risk of developing cancer is not conclusive.

Prepared by Anna Rangan

Westmead Breast Cancer Institute

References

1. Coates M, Armstrong B. Cancer in New South Wales. Incidence and mortality 1994. Sydney, NSW Cancer Council, 1997.

2. Feuer EJ, Wun LM, Boring CC et al: The lifetime risk of developing breast cancer. J Natl Cancer Inst 85:892, 1993

3. Parkin DM, Muir CS, Whelan SL et al: Cancer incidence in five continents. Comparability and quality of data. Publication no.120. IARC, 1992

4. Muir C, Waterhouse J, Mack T: Cancer incidence in five continents. Publication 88. IARC, Lyon, 1987

5. Aoki K, Kurihara M, Hayakawa N et al: Death rates for malignant neoplasms for selected sites by sex and five-year age group in 33 countries, 1953-57 to 1983-87. Nagoya University, Nagoya, 1992

6. Weber BL, Garber JE: Familial breast cancer: recent advances. In Harris JR, Lippman ME (ed): Diseases of the breast updates. Lippincott-Raven, 1997

7. Kliewer EV, Smith KR: Breast cancer mortality among immigrants in Australia and Canada. J Natl Cancer Inst 87:1154, 1995

8. Colditz GA, Willett WC, Hunter DJ et al: Family history, age, and risk of breast cancer. Prospective data from the Nurses Health Study. JAMA 270:338, 1993

9. Bodian CA: Benign breast diseases, carcinoma in situ, and breast cancer risk. Epidemiol Rev 15:177, 1993

10. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 347:1713, 1996

11. Colditz GA, Hankinson SE, Hunter DJ et al: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 332:1589, 1995

12. Stanford JL, Weiss NS, Voigt LF et al: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274:137, 1995

13. Kelsey JL: Breast cancer epidemiology: Summary and future directions. Epidemiol Rev 15:256, 1993

14. Ford D, Easton DF, Bishop DT et al: Risks of cancer in BRCA1-mutation carriers. Lancet 343:692, 1994

15. Easton DF, Ford D, Peto J et al: Inherited susceptibility to breast cancer. Cancer Surveys 18:95, 1993

16. Easton DF, Bishop DT, Ford D et al: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 52:678, 1993

17. Struewing JP, Hartge P, Wacholder S et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401, 1997

18. Lynch H, Marcus J, Watson P et al: Distinctive clinicopathologic features of BRCA1-linked hereditary breast cancer. Proc ASCO 13:56, 1994

19. Marcus JN, Watson P, Page DL et al: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77:697, 1996

20. Shattuck-Eidens D, McClure M, Simard J et al: A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. JAMA 273:535, 1995

21. Wooster R, Neuhausen SL, Mangion J et al: Localisation of a breast cancer susceptibility gene, BRCA2, to chromosome 13q 12-13. Science 265:2088, 1994

22. Krontiris TG, Devlin B, Karp DD et al: An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. N Engl J Med 329:517, 1993

23. Swift M, Reitnauer PJ, Morell D et al: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316:1289, 1987

Last Updated on Tuesday, 09 February 2010 12:30