Inherited Breast Cancer (D. Gareth Evans MD FRCP, 2011/2017)

updated from the original ‘Breastless’ pamphlet

by D Gareth R Evans, Consultant in Genetic Medicine Regional Genetics Service, St Mary’s Hospital Manchester, UK

Introduction – Breast cancer is the most common form of cancer affecting women. One in eight to twelve women will develop the disease in their lifetime in the developed world. Every year 48,000 women develop the disease in the UK and as a result, 12,000 will die (Cancer Research UK Statistics).

Family history is the most important risk factor for the development of breast cancer. About 4-5% of breast cancer is thought to be due to inheritance of a high risk single cancer predisposing gene [2;3]. Whilst hereditary factors are virtually certain to play a part in a proportion of the rest, these are harder to evaluate. In evaluating family history, the important features are:

  • Age at onset
  • Bilateral disease (cancer in both breasts)
  • Multiple cases on one side of the family
  • Other related early onset tumours (especially ovarian cancer)
  • Number of unaffected individuals (large families are more informative)
  • Ethnic origin (especially Ashkenazi Jewish)

Hormonal and reproductive risk factors – The incidence of breast cancer within the general population is increasing, and this may in part be related to the increasing use of exogenous hormones. Hormonal and reproductive factors have long been recognised to be important in the development of breast cancer. Early start of the period cycle, as it prolongs exposure to oestrogens, increases the risk of breast cancer, as does late menopause.

The age at first pregnancy influences the relative risk of breast cancer as pregnancy transforms breast parenchymal cells into a more stable state, resulting in less proliferation in the second half of the menstrual cycle. As a result, early first pregnancy offers some protection. Women having their first child over the age of 30 have double the risk of women delivering their first child under the age of 20 years.

Risk estimation – Epidemiological studies have demonstrated that between 40-85% of mutation carriers in known predisposing genes (BRCA1 and BRCA2) develop breast cancer in their lifetime [9;10]. These genes are ‘dominantly’ inherited. As such if a person carries a faulty copy there is a 50% chance of passing it down to each child; male or female. Men are not usually at increased risk although faults in BRCA2 cause about 1 in 12 men to get breast cancer and 1 in 5 to get prostate cancer. Finding a fault in BRCA1 or BRCA2 usually starts with an affected individual with breast or ovarian cancer. Once a gene fault is identified each family member can then decide if they want to know if they are high risk by undertaking a gene test themselves. There are now thought to be over 50 genetic locations that are associated with an increased risk of breast cancer. At present only testing of the high risk genes is routinely carried out in genetics departments.

High risk: BRCA1, BRCA2, TP53, PALB2, PTEN, STK11, lifetime risk 40-90%
Moderate risk: CHEK2, ATM, NF1, lifetime risk 20-40%

Low risk: 92 common gene locations including FGFR2/ TOX3, risk 11-13%

Common variants and gene panels are now increasingly being offered privately.

Breast/Ovarian families – When considering a woman with a family history of breast cancer it is also important to be aware of any family history of ovarian cancer. Families with strong histories of both breast and ovarian cancer are likely to have mutations in BRCA1 or BRCA2.

Ethnic populations and risk assessment of breast cancer – The Ashkenazi Jewish population has an increased incidence of breast cancer and there are a number of issues specific to this population. This is due to the high frequency of founder mutations – 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. (Combined frequency 1 in 40 people [12,13]).

What can a woman do about being at risk? Women at high risk of breast cancer can access extra screening such as regular mammography and if very high risk MRI screening. For instance women who carry mutations in BRCA1, BRCA2 or TP53 can access MRI from the age of 30 years. Although MRI is very good at detecting breast cancer early it causes a lot of false alarms. With MRI screening it is likely that 80- 90% of breast cancers will be cured.

Even with MRI screening, women who face risks of up to 80-90% of breast cancer frequently choose to have risk-reducing mastectomy. In Manchester 50% of gene fault carriers opt to have surgery by 7 years of follow-up from testing (14). Although surgery is a radical choice and does not remove all of the risk of breast cancer (90% reduction [15]), expertise with oncoplastic surgeons means that cosmetic results are usually very acceptable, although there are exceptions. A small proportion of women choose not to have reconstruction (around 10%).

Women can also reduce their risks to some extent by lifestyle measures such as maintaining a healthy weight, exercising and eating a good diet. Drug prevention such as 5 years on Tamoxifen is also now becoming available.

Clare Best has written a sequence of poems that reflects her experience of living with breast cancer risks and her decision to have risk-reducing mastectomies. As well as forming a commentary on her personal journey, the poems document dilemmas that face many women who have a strong family history.

Reference List

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(2) Newman B, Austin M, Lee M, King M-C. Inheritance of human breast cancer: Evidence for autosomal dominant transmission in high risk families. Proc Natl Acad Sci USA 1988; 85:3044- 3048.
(3) Claus EB, Risch N, Thompson WD. Autosomal Dominant Inheritance of Early-Onset Breast Cancer; Implications for Risk Prediction. Ca 1994; 73:643- 651.
(4) Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362(9382):419-427.
(5) MacMahon B, Cole P, Brown J. Etiology of breast cancer: a review. J Natl Cancer Inst 1973; 50:21-42. (6) Evans DG, Lalloo F. Risk assessment and management of high risk familial breast cancer. J Med Genet 2002; 39(12):865-871.
(7) Jernstrom H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J et al. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 1999; 354(9193):1846-1850.
(8) Jacobs TW, Byrne C, Colditz GA, Connolly JL, Schnitt S. Radial scars in benign breast-biopsy specimens and the risk of breast cancer. New England Journal of Medicine 340, 430-436. 1999.
(9) Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Lancet 1994; 343:692-695. (10) Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998. (11) Cancer risks in BRCA2 mutation carriers.The Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999; 91(15):1310-1316.
(12) Lalloo F, Cochrane S, Bulman B, Varley J, Elles R, Howell A et al. An evaluation of common breast cancer gene mutations in a population of Ashkenazi Jews. J Med Genet 1998; 35:10-12.
(13) Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M et al. The risk of cancer associated with speci c mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997; 336:1401-1408.
(14) Evans DGR, Baildam AD, Anderson E, Brain A, Shenton A, Vasen HFA, Eccles D, Lucassen A, Pichert G, Hamed H, Moller P, Maehle L, Morrison PJ, Stoppat-Lyonnet D, Gregory H, Smyth E, Niederacher D, Nestle-Kramling C, Campbell J, Hopwood P, Lalloo F, Howell A. Risk reducing mastectomy: outcomes in 10 European Centres. J Med Genet 2009; 46(4):254-8
(15) Evans DG, Lalloo F, Ashcroft L, Shenton A, Clancy T, Baildam AD, Brain A, Hopwood P, Howell A. Uptake of risk reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age and time dependent. Cancer Epid Biomarkers Prev 2009;18(8):2318-24