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Choices for Young Women at Intermediate Risk of Breast Cancer

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Choices for Young Women at Intermediate Risk of Breast Cancer Curr Oncol, Vol. 19, pp. e112-114; doi: http://dx.doi.org/10.3747/co.19.925 CHOICESGUEST IN INTERMEDIATE-RISK BREASTEDITORIAL CANCER Choices for young women at intermediate risk of breast cancer J. Iqbal MD* and S.A. Narod MD* Women with an inherited mutation in BRCA1 or node-positive or larger than 2 cm in size. Duffy and BRCA2 have a lifetime risk of breast cancer that ap- colleagues estimated that, at 10 years, the breast- proaches 80% 1–3. At that level of risk, many women cancer-specific mortality was lower by 20% in the will entertain prevention options that are drastic (for experimental cohort than in the control subjects example, preventive mastectomy) or expensive (for (relative risk: 0.80; 95% confidence interval: 0.66 to example, a lifetime of annual screening by magnetic 0.96; p = 0.02). Even if the difference in the mortality resonance imaging). But what of women at interme- rate was in fact attributable to screening (and not to diate levels of risk ... 10%–25%, say? treatment differences), a 20% lowering of mortality The latter group of women includes those with a is modest, and other options must be entertained. strong family history of breast cancer but no BRCA In favour of the program, almost all women mutation 4, those with a mutation in CHEK2 5,6, those offered mammography were compliant with the in the highest category of mammographic density 7, recommendation. How does their compliance com- and those with a past history of lobular carcinoma pare with compliance to tamoxifen? Two large tri- in situ or atypical hyperplasia 8,9. At this level of als—National Surgical Adjuvant Breast and Bowel risk, surgical prevention is chosen by few. Dietary Project P-1 and IBIS-I (International Breast Cancer modification and exercise have not been shown to Intervention Study)—demonstrated a reduction be very helpful in premenopausal women. In 2012 of up to 43% in the incidence of breast cancer in (as in 2001), options come down to tamoxifen and high-risk women (most being women who did not mammography. Currently, tamoxifen is the sole drug carry a BRCA mutation) 13,14. The protective effect approved for chemoprevention in premenopausal of tamoxifen appeared to extend beyond the 5-year women (raloxifene and aromatase inhibitors are to period of active treatment. be avoided in ovulating women), and mammography Despite the established benefit of tamoxifen remains the cornerstone of screening. in the prevention of breast cancer, only a small In the United Kingdom, the Family History proportion of eligible women take that option 15. In Study was undertaken to estimate how much life our cohort of established BRCA carriers, fewer than expectancy might reasonably be gained by an offer of 5% under the age of 50 opted for tamoxifen chemo- annual mammography to women at moderate risk 10. prevention 16. Fear of side effects seems to be the Annual mammography was offered for 4 years to major deterrent 17,18. However, data from tamoxifen 6710 women with a family history of breast cancer prevention trials suggest that serious adverse events who were younger than 50 years of age, but who were (endometrial cancer and venous thromboembolism) negative for both BRCA mutations. Their mortality are rare in women younger than 50 19. The risks fall experience was compared with that of two historical off rapidly after the active phase of treatment. Side cohorts 11,12. During the study, 96 invasive cancers effects in women younger than 50 are generally be- were found, and the sensitivity of mammographic nign—notably, hot flashes, vaginal discharge, and screening was 72% for invasive cancers. Compared irregular vaginal bleeding 20—and don’t significantly with women in the control cohorts who developed affect quality of life 21,22. invasive breast cancer, women who received an an- Perhaps a combination of mammography and nual mammogram had smaller tumors (<2 cm: 70% tamoxifen is best. Tamoxifen causes a significant vs. 55%, p = 0.0094) that were more likely to be reduction in breast tissue density in young women, node-negative (68% vs. 53%, p = 0.0083) and grade I thereby increasing the sensitivity of mammogra- or II (54% vs. 51%, p = 0.0072). Nevertheless, 32% phy 23,24. In a subset of patients in the Breast Cancer of the cancers in the mammography cohort were Prevention Trial, chemoprevention with tamoxifen CURRENT ONCOLOGY—VOLUME 19, NUMBER 3, JUNE 2012 e112 Copyright © 2012 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC). IQBAL and NAROD (compared with placebo) resulted in a 44.4% reduc- 11. Moss S, Waller M, Anderson TJ, Cuckle H on behalf of the tion in mammographic density (15.2%, p = 0.01) 25. Trial Management Group. Randomised controlled trial of Also, a reduction in breast density appears to be a mammographic screening in women from age 40: predicted good surrogate marker for a reduction in cancer risk: mortality based on surrogate outcome measures. Br J Cancer the IBIS-I study 26 observed a reduction of 63% in the 2005;92:955–60. risk of breast cancer incidence in women who expe- 12. Brekelmans CT, Tilanus–Linthorst MM, Seynaeve C, et al. rienced a 10% or greater decline in mammographic Tumour characteristics, survival and prognostic factors of her- density with tamoxifen. editary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 Given the foregoing observations, the combina- families as compared to sporadic breast cancer cases. Eur J tion of tamoxifen with mammographic surveillance Cancer 2007;43:867–76. seems to us to be a much better option than relying 13. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for on mammography alone. If a 40% reduction in can- the prevention of breast cancer: current status of the National cer incidence with tamoxifen is coupled with a 20% Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl reduction in mortality from screening, perhaps a Cancer Inst 2005;97:1652–62. halving of the mortality rate is within reach. 14. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer—96-month CONFLICT OF INTEREST DISCLOSURES follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007;99:272–82. The authors have no financial conflicts of interest 15. Kaplan CP, Haas JS, Pérez–Stable EJ, et al. Breast cancer to declare. risk reduction options: awareness, discussion, and use among women from four ethnic groups. Cancer Epidemiol Biomarkers REFERENCES Prev 2006;15:162–6. 16. Metcalfe KA, Birenbaum–Carmeli D, Lubinski J, et al. 1. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast International variation in rates of uptake of preventive op- and ovarian cancer associated with BRCA1 or BRCA2 mutations tions in BRCA1 and BRCA2 mutation carriers. Int J Cancer detected in case series unselected for family history: a combined 2008;122:2017–22. analysis of 22 studies. Am J Hum Genet 2003;72:1117–30. 17. Yeomans–Kinney A, Vernon SW, Frankowski RF, Weber DM, 2. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The Bitsura JM, Vogel VG. Factors related to enrollment in the genetic attributable risk of breast and ovarian cancer. Cancer breast cancer prevention trial at a comprehensive cancer center 1996;77:2318–24. during the first year of recruitment.Cancer 1995;76:46–56. 3. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and 18. Taylor R, Taguchi K. Tamoxifen for breast cancer chemo- penetrance analysis of the BRCA1 and BRCA2 genes in breast prevention: low uptake by high-risk women after evaluation cancer families. The Breast Cancer Linkage Consortium. Am of a breast lump. Ann Fam Med 2005;3:242–7. J Hum Genet 1998;62:676–89. 19. Iqbal J, Ginsburg OM, Wijeratne TD, et al. Endometrial cancer 4. Metcalfe KA, Finch A, Poll A, et al. Breast cancer risks in and venous thromboembolism in women under age 50 who take women with a family history of breast or ovarian cancer who tamoxifen for prevention of breast cancer: a systematic review. have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer Treat Rev 2012;38:318–28. Cancer 2009;100:421–5. 20. Chalas E, Costantino JP, Wickerham DL, et al. Benign gyne- 5. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ cologic conditions among participants in the Breast Cancer line hCHK2 mutations in Li–Fraumeni syndrome. Science Prevention Trial. Am J Obstet Gynecol 2005;192:1230–7. 1999;286:2528–31. 21. Day R on behalf of the National Surgical Adjuvant Breast and 6. Schmidt MK, Tollenaar RA, de Kemp SR, et al. Breast cancer Bowel Project P-1 study (NSABP-1). Quality of life and tamoxi- survival and tumor characteristics in premenopausal women fen in a breast cancer prevention trial: a summary of findings carrying the CHEK2*1100delC germline mutation. J Clin from the NSABP P-1 study. National Surgical Adjuvant Breast Oncol 2007;25:64–9. and Bowel Project. Ann N Y Acad Sci 2001;949:143–50. 7. Boyd NF, Guo H, Martin LJ, et al. Mammographic density 22. Fallowfield L, Fleissig A, Edwards R,et al. Tamoxifen for the and the risk and detection of breast cancer. N Engl J Med prevention of breast cancer: psychosocial impact on women 2007;356:227–36. participating in two randomized controlled trials. J Clin Oncol 8. Dupont WD, Page DL. Risk factors for breast cancer in women 2001;19:1885–92. with proliferative breast disease. N Engl J Med 1985;312:146–51.
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