Clinical Review

Is Your Patient at High Risk for Breast Cancer?

Clinician Reviews. 2008 October;18(10):19-20

References

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20. Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89.

21. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233-1238.

22. Schumacher V, Vogel T, Leube B, et al. STK11 genotyping and cancer risk in Peutz-Jeghers syndrome. J Med Genet. 2005;42(5):428-435.

23. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998;128(11):896-899.

24. Vasen HF. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol. 2000;18(21 Suppl):81S-92S.

25. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886.

26. Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst. 1999;91(18):1541-1548.

27. Rockhill B, Spiegelman D, Byrne C, et al. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst. 2001;93(5): 358-366.

28. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer: implications for risk prediction. Cancer. 1994;73(3):643-651.

29. Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer–predisposition genes. Am J Hum Genet. 2007;81(5):873-883.

30. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer–susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998;62(1):145-158.

31. Berry DA, Iversen ES Jr, Gudbjartsson DF, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002;20(11):2701-2712.

32. Evans DG, Eccles DM, Rahman N, et al. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41(6):474-480.

33. Evans DG, Lalloo F, Wallace A, Rahman N. Update on the Manchester Scoring System for BRCA1 and BRCA2 testing.
J Med Genet. 2005;42(7):e39.

34. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23(7):1111-1130.

35. Antoniou AC, Pharaoh PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91(8):1580-1590.

36. Antoniou AC, Hardy R, Walker L, et al. Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet. 2008;45(7):425-431.

37. Thirthagiri E, Lee SY, Kang P, et al. Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer. Breast Cancer Res. 2008;10(4):R59.

38. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.™ Breast Cancer Risk Reduction. V.I.2008. www.nccn.org/professionals/physician_gls/PDF/breast_risk.pdf. Accessed September 23, 2008.

39. Tehard B, Friedenreich CM, Oppert JM, Clavel-Chapelon F. Effect of physical activity on women at increased risk of breast cancer: results from the E3N cohort study. Cancer Epidemiol Biomarkers Prev. 2006;15(1):57-64.

40. Terry MB, Zhang FF, Kabat G, et al. Lifetime alcohol intake and breast cancer risk. Ann Epidemiol. 2006;16(3):230-240.

41. Eliassen AH, Colditz GA, Rosner B, et al. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296(2):193-201.

42. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295(6):629-642.

43. US Food and Drug Administration, Center for Drug Evaluation and Research. Tamoxifen information. www.fda.gov/cder/news/tamoxifen/default.htm. Accessed September 23, 2008.

44. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371-1388.

45. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial: Multiple Outcomes of Raloxifene Evaluation. Breast Cancer Res Treat. 2001;65(2):125-134.

46. Martino S, Cauley JA, Barrett-Connor E, et al; CORE In—vestigators. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96(23):1751-1761.

47. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial: Multiple Outcomes of Raloxifene Evaluation [erratum in: JAMA. 1999;282(22):2124]. JAMA. 1999;281(23):2189-2197.

48. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA approves new uses for Evista (raloxifene hydrochloride). www.fda.gov/cder/Offices/OODP/whatsnew/raloxifene.htm. Accessed September 23, 2008.

49. Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-2741.

50. Grady D, Cauley JA, Geiger MJ, et al; Raloxifene Use for the Heart Trial Investigators. Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst. 2008;100(12):854-861.

51. Kriege M, Brekelmans CT, Boetes C, et al; Magnetic Resonance Imaging Screening Study Group. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351(5):427-437.

52. Leach MO, Boggis CR, Dixon AK, et al; MARIBS Study Group. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet. 2005;365(9473):1769-1778.

53. Lehman CD, Blume JD, Weatherall P, et al; International Breast MRI Consortium Working Group. Screening women at high risk for breast cancer with mammography and magnetic resonance imaging. Cancer. 2005;103(9):1898-1905.

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Li-Fraumeni syndrome is a highly penetrant, autosomal dominant disorder caused by a mutation in the TP53 gene.^4,6,19,20 Affected women’s overall cancer risk is 50% by age 35 and 90% lifelong. Breast cancer risk is estimated at 50% by age 50.³ Multiple primary cancers, including early-onset breast cancer (ie, before age 40), sarcoma, leukemia, childhood brain tumors, and adrenocortical carcinoma, are all associated with Li-Fraumeni.^6,10,19,21

Peutz-Jeghers syndrome is also an autosomal dominant condition, caused by a mutation in the STK11 gene.^3,22,23 The mean age of breast cancer diagnosis in affected women is 44. Hallmark features of Peutz-Jeghers include gastrointestinal hamartomas (often discovered during childhood²⁴) and cancers of the colon, small bowel, pancreas, uterus, thyroid, lung, and breast. The most commonly reported malignancies in patients with Peutz-Jeghers syndrome are breast cancer and colon cancer. Associated phenotypic features include pigmented spots on the lips, buccal mucosa, and skin.^10,24

Risk Assessment Tools
Women with any of the identified high-risk factors should be referred to a provider experienced in high-risk breast cancer assessment and management. Many comprehensive breast centers are adding high-risk programs to their array of services. Researching those programs in your area will facilitate the process of referral for women in your practice who are identified as high risk.

In efforts to identify patients at high risk for breast cancer, the importance of thorough history taking cannot be overstated. It is imperative that both the maternal and paternal sides of the family be assessed, as genetic mutations can be acquired through the patient’s mother or father.¹⁰

A variety of tools to assess breast cancer risk are available. The one most commonly used is the Gail risk assessment model,²⁵ which was developed at the National Cancer Institute. A modified version, validated during the Breast Cancer Prevention Trial,²⁶ calculates five-year and lifetime risk based on the following criteria:

• Current age

• Age at menarche

• Age at first live birth

• Race

• Number of first-degree relatives with a history of breast cancer

• Number of previous breast biopsies

• History of atypical cells on previous breast biopsy.

The Gail model has certain limitations. It cannot be used to assess women younger than 35²⁷ or older than 85. Also, age at breast cancer diagnosis, non–first-degree relatives with breast cancer, paternal cancer history, ovarian cancer history, and ethnicity are not included among its considerations.³

The Claus model²⁸ assesses risk in women with a family history of breast cancer more accurately than the Gail model, but it does not incorporate male breast cancer, ovarian cancer, or ethnicity.⁹

Several models are available to predict the risk for carrying a BRCA1 or BRCA2 mutation. The Myriad Genetic Laboratories database,²⁹ the BRCAPRO model,^30,31 the Manchester scoring system,^32,33 the Tyrer-Duffy-Cuzick (IBIS) model,³⁴ and the BOADICEA model³⁵ all provide probability data, but each has its limitations. Breast specialists who provide high-risk assessment services calculate risk using a variety of models and choosing the most appropriate model(s) for each patient.^36,37 Women with a high probability of carrying a mutation, based on history and findings from the risk assessment model, are referred for genetics counseling and testing.

Reducing the Risk
Risk reduction is an integral component of high-risk breast cancer management, and several strategies are currently recommended, including these:

• Exercise for 45 to 60 minutes at least five times per week.^2,38 In women who engage in at least five hours of vigorous exercise each week, a 0.62 relative risk for breast cancer has been reported.^38,39

• Limit alcohol intake to fewer than one to two drinks per day. A number of studies have documented a 30% to 50% increase in the incidence of breast cancer among women who consume alcohol in greater quantities.^38,40

• Avoid obesity. Compared with women who have maintained their weight since age 18, those who gain 55 lb or more by menopause onset have a 1.45 relative risk for breast cancer.^38,41

• Breastfeed infants. Lactation for two years or longer decreases the lifetime risk for breast cancer by 50%.³

• Follow a low-fat, high-fiber diet, rich in fresh fruits and vegetables. Increasing fruit and vegetable intake by even one serving per day has been associated with a 9% decrease in breast cancer incidence.^38,42

Chemoprevention for At-Risk Women
Another risk reduction strategy for women at particularly high risk for breast cancer is chemoprevention. Currently, two medications, tamoxifen and raloxifene, are FDA approved for breast cancer risk reduction in women at high risk. These agents are offered to women with specific high-risk factors, including:

• Findings of LCIS, ADH, or ALH on previous breast biopsy