The single most important risk factor for breast cancer is age, and hormonally linked reproductive and anthropometric risk factors contribute to the etiology of the disease.[1-3] There is an increase in the risk of breast cancer among women who have benign breast disease, especially those with atypical ductal or lobular hyperplasia.[4,5] Lobular carcinoma in situ (LCIS) increases risk significantly, as do a history of breast cancer in first-degree relatives and the presence of BRCA1 or 2 mutations. Surprisingly, and perhaps counterintuitively, diet, exercise, and environmental factors play a very small role in overall risk. Mammographic breast density increases relative risk fivefold among women with the highest density, and breast cancer risk is two to three times greater in women with elevated serum levels of estradiol or testosterone. Multivariable risk models allow determination of composite relative risks along with cumulative lifetime risk, although improved models for African-American women are required.
As outlined in Figure 1, management of women at increased risk for breast cancer should include comprehensive quantitative risk assessment, counseling appropriate to the individual’s risk, the opportunity for genetic testing where appropriate, and a specific management prescription.[8-10] The latter should include discussion of the risks and benefits of screening, prophylactic surgery when indicated, and risk reduction using approved chemopreventive agents. Clinicians who counsel women about selective estrogen-receptor modulators (SERMs) in this context should strive to ensure that the patient makes a fully informed decision that incorporates her personal values and preferences. The counseling process should be interactive and sensitive to the patient’s educational level and cultural background.
Breast Cancer Risk Assessment
The model developed by Gail et al is an accurate method of quantifying a woman’s risk of developing breast cancer. Only six factors need to be used as significant predictors of the lifetime risk of breast cancer:
(1) Current age
(2) Age at menarche
(3) Number of breast biopsies
(4) Age at first live birth (or nulliparity)
(5) History of breast cancer in first-degree relatives
A previous diagnosis of atypical lobular or ductal hyperplasia with atypia nearly doubles the estimated risk. The model accurately estimates the 5-year probability of developing breast cancer but slightly overestimates the risk for women classified in the higher quintiles of predicted 5-year risk and underestimates the risk for those in the lower quintiles.[12,13]
The Gail model works well for women at high risk, but other models may be required for women at only slightly increased risk or for whom age is the most important determinant of their risk. Risk-prediction models for breast cancer could possibly be improved by the addition of recently identified risk factors, including breast density and use of hormone therapy. Strategies for estrogen receptor (ER)-positive breast cancer risk reduction in postmenopausal women require screening of large populations to identify those with potential benefit. Age and age at menopause are statistically significantly associated with ER-positive but not ER-negative cancers.
A simpler model that includes only age, breast cancer in first-degree relatives, and previous breast biopsy examination performs similarly for ER-positive breast cancer prediction. Importantly, postmenopausal women aged 55 years or older with either a previous breast biopsy examination or a family history of breast cancer show a 5-year breast cancer risk of 1.8% or higher, a widely accepted definition of being at “high risk” for breast cancer. This simplified model may be easier to use than the Gail model for identifying women who are at increased risk for breast cancer.
1. Vogel VG: Epidemiology of breast cancer, in Bland KI, Copeland EM (eds): The Breast: Comprehensive Management of Benign and Malignant Disease, 3rd ed, vol 1, pp 341-354. Philadelphia, WB Saunders, 2004.
2. Gierach G, Vogel V: Epidemiology of breast cancer, in Singletary SE, Robb GL, Hortobagyi GN (eds): Advanced Therapy of Breast Disease, 2nd ed, pp 58-83. Hamilton, Ontario, BC Decker, 2004.
3. Vogel VG: Epidemiology of breast cancer, in Winchester DJ, Winchester DP, Hudis CA, Norton L (eds): Breast Cancer, 2nd ed, pp 47-60. Hamilton, Ontario, BC Decker, 2006.
4. Hollingsworth AB, Singletary SE, Morrow M, et al: Current comprehensive assessment and management of women at increased risk for breast cancer. Am J Surg 187:349-362, 2004.
5. Vogel V: Atypia in the assessment of breast cancer risk: Implications for management. Diagnostic Cytopath 30:151-157, 2004.
6. Thull D, Vogel VG: Recognition and management of hereditary breast cancer syndromes. Oncologist 9:13-24, 2004.
7. Eliassen AH, Missmer SA, Tworoger SS, et al: Endogenous steroid hormone concentrations and risk of breast cancer: Does the association vary by a woman’s predicted breast cancer risk? J Clin Oncol 24:1823-1830, 2006.
8. Vogel VG: Management of the high-risk patient. Surg Clin North Am 83:733-751, 2003.
9. Vogel VG: Reducing the risk of breast cancer with tamoxifen in women at increased risk. J Clin Oncol 19(18s):87s-92s, 2001.
10. Vogel VG: Chemoprevention strategies 2006. Curr Treat Options Oncol 8:74-88, 2007.
11. 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 81:1879-1886, 1989.
12. 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 91:1541-1548, 1999.
13. 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 93:358-366, 2001.
14. Chlebowski RT, Anderson GL, Lane DS, et al: Predicting risk of breast cancer in postmenopausal women by hormone receptor status. J Natl Cancer Inst 99:1695-1705, 2007.
15. 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 90:1371-1388, 1998.
16. Day R, Ganz PA, Costantino JP, et al: Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17:2659-2669, 1999.
17. Day R, Ganz PA, Costantino JP: Tamoxifen and depression: More evidence from the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention (P-1) randomized study. J Natl Cancer Inst 93:1615-1623, 2001.
18. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 97:1652-1662, 2005.
19. IBIS Investigators: First results from the International Breast Cancer Intervention Study (IBIS-I): A randomised prevention trial. Lancet 360:817-824, 2002.
20. Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23:1111-1130, 2004.
21. Cuzick J, Forbes JF, Sestak I, et al: Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99:272-282, 2007.
22. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296-300, 2003.
23. Veronesi U, Maisonneuve P, Sacchini V, et al: Tamoxifen for breast cancer among hysterectomised women. Lancet 359:1122-1124, 2002.
24. Veronesi U, Maisonneuve P, Rotmensz N, et al: Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 95:160-165, 2003.
25. Vogel VG: Raloxifene: A second-generation selective estrogen receptor modulator for reducing the risk of invasive breast cancer in postmenopausal women. Women’s Health 3:139-153, 2007.
26. 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. JAMA 281:2189-2197, 1999.
27. Martino S, Cauley JA, Barrett-Connor E, et al: Continuing Outcomes Relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 96:1751-1761, 2004.
28. Barrett-Connor E, Mosca L, Collins P, et al: Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125-137, 2006.
29. Vogel VG, Costantino, JP, Wickerham, DL, et al: 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 295 :2727-2741, 2006.
30. Land SR, Wickerham DL, Costantino JP, et al: Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2742-2751, 2006.
31. Freedman AN, Graubard BI, Rao SR, et al: Estimates of the number of U.S. women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst 95:526-532, 2003.
32. Gail MH, Costantino JP, Bryant J, et al: Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 91:1829-1846, 1999.
33. Schrag D, Kuntz KM, Garber JE, et al: Life expectancy gains from cancer prevention strategies for women with breast cancer and BRCA1 or BRCA2 mutations. JAMA 283:617-624, 2000.
34. Grann VR, Sundararajan V, Jacobson JS, et al: Decision analysis of tamoxifen for the prevention of invasive breast cancer. Cancer J 6:169-178, 2000.
35. Grann VR, Jacobson JS, Thomason D, et al: Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: An updated decision analysis. J Clin Oncol 20:2520-2529, 2002.
36. Hershman D, Sundararajan V, Jacobson JS, et al: Outcomes of tamoxifen chemoprevention for breast cancer in very high-risk women: A cost-effectiveness analysis. J Clin Oncol 20:9-16, 2002.
37. Ingle JN: Endocrine therapy trials of aromatase inhibitors for breast cancer in the adjuvant and prevention settings. Clin Cancer Res 11:900s-905s, 2005.
38. Goss PE, Strasser-Weippl K: Aromatase inhibitors for chemoprevention. Best Pract Res Clin Endocrinol Metab 18:113-130, 2004.
39. Kinsinger LS, Harris R, Woolf SH, et al: Chemoprevention of breast cancer: A summary of the evidence for the U.S. Preventative Services Task Force. Ann Intern Med 137:59-69, 2002.
40. Chlebowski RT, Col N, Winer EP, et al: American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol. In press.