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Originally published as JCO Early Release 10.1200/JCO.2005.07.906 on October 11 2005 © 2005 American Society of Clinical Oncology.
Surgical Management of BRCA1 and BRCA2 Carriers: Bitter Choices Slightly SweetenedEvanston Northwestern Healthcare Center for Medical Genetics, Evanston, IL; Feinberg School of Medicine, Northwestern University, Chicago, IL Carriers of BRCA1 and BRCA2 mutations face a cruel choice. Their best chance for long-term survival comes at the price of removing their female organs. It is a bitter antidote to the probabilistic predictions about their ill-fated futures. As reported in this issue of the Journal of Clinical Oncology, Rebbeck et al1 lessen the bitterness of bilateral prophylactic salpingo-oophorectomy (BSO) by demonstrating that the breast cancer risk reduction is not appreciably diminished by hormone replacement therapy (HRT). Not only does BSO decrease the risk of ovarian and fallopian tube cancers to almost negligible levels, but Rebbeck et al show that women who undergo BSO and take HRT have approximately a third of the breast cancer risk of women who neither have BSO nor undergo HRT. For many BRCA1 and BRCA2 carriers, management of breast and ovarian cancer risks by BSO, use of short-term HRT, plus intensive breast cancer surveillance is a more palatable approach than prophylactic breast and ovarian surgeries. Although bilateral prophylactic mastectomy (BPM) has an effectiveness of approximately 90% to 95%2 and reconstructive options remain open, few American women undertake this option in our manifestly breast-conscious society.3 Alternative ways to reduce breast cancer risk, albeit to a lesser extent, include BSO4-6 and possibly tamoxifen chemoprevention.6 Augmentation of surveillance using breast magnetic resonance imaging is also appealing,7,8 though it should be made clear to carriers that early detection and treatment, with the attendant risks of morbidity and mortality, is not equivalent to surgical prevention. While BPM is considered ideal from a medical standpoint, yet optional from a quality-of-life standpoint, BSO is a standard of care that is strongly recommended. No reliable early detection methods exist for ovarian cancer, which is usually diagnosed at stages III or IV, in which long-term disease-free survival is small. BSO is 96% effective and can be performed when a woman has completed childbearing potential.4 The ovaries and fallopian tubes must be removed and the specimens subjected to detailed pathological analysis, as occult cancer may be present in 2.5% to 17% of cases, necessitating further staging and treatment.9 Until now, evidence-based treatment guidelines have ended at these recommendations. Rebbeck et al build on their prior work, demonstrating that BSO reduces breast cancer risk,4 and now also provide statistical evidence that the 37% risk reduction is not appreciably diminished by HRT. The knowledge that HRT can be used to combat the symptoms of surgical menopause, and perhaps help reduce the long-term health effects such as osteoporosis, should make the choice for BSO easier. This is important because it is not easy to elect an operation based on probabilistic threats when one is otherwise healthy. BSO may be a particularly difficult choice for women with no personal experience of ovarian cancer among her relatives or friends, and for women whose overall perception of ovarian and other cancers is that they are generally survivable. If one accepts the evidence that BSO is an effective way to reduce ovarian and breast cancer risks, then a cascade of questions ensues regarding the formulation of HRT, length of treatment and possible need for total abdominal hysterectomy (TAH). Once women adjust to the initial surprise that post-BSO HRT does not apparently increase their risk of breast cancer, they are dismayed to learn that additional medical choices may barter one cancer risk for another. For example, while unopposed estrogen poses a substantial risk of uterine cancer, data from the Women's Health Initiative (WHI) and the Million Women Study show an increased risk of breast cancer in postmenopausal women using combined estrogen and progesterone therapy compared with estrogen alone. As pointed out by Rebbeck et al, the WHI data suggest that short-term HRT use after premenopausal BSO has little effect on life expectancy, whereas long-term HRT after age 50 years has an adverse effect on health. A decision analysis regarding BSO, with or without HRT, in BRCA carriers also supported the use of BSO after childbearing age, HRT use based on quality of life, and cessation of HRT at approximately age 50 years.10 Nonetheless, concerns about the health risks of combined progesterone-estrogen HRT on the breast will instigate a discussion of total abdominal hysterectomy since unopposed estrogen can then be used. The addition of TAH to BSO takes a step backward in terms of the ease of the decision, since the recovery time and surgical morbidity are thereby increased. The decision regarding BSO alone compared with TAH/BSO is further complicated by (1) possible intended use of tamoxifen chemoprevention, raising the risk of endometrial cancer, (2) uncertainty about the efficacy of tamoxifen in BRCA1/2 carriers, (3) uncertainty about the baseline risks of endometrial cancer in BRCA1/2 carriers, and (4) theoretical concerns about residual risks of fallopian tube cancer at the site of insertion into the uterus. While there is no definitive evidence that tamoxifen chemoprevention works in BRCA1/2 carriers, Metcalfe et al6 found that tamoxifen use was associated with a 40% reduction in the risk of contralateral breast cancer in BRCA carriers with a prior history of breast cancer. Although tamoxifen chemoprevention raises the risk of endometrial adenocarcinoma by about 2.5-fold, and increases the risks of deep venous thrombosis, pulmonary embolism, and stroke, the absolute risks are low for women in their 40s.11,12 Furthermore, tamoxifen has the benefit of diminishing the risk of osteoporosis, a major concern for women who undergo premenopausal BSO. Therefore, one strategy is to use short-term HRT after BSO, with subsequent tamoxifen chemoprevention starting during the patients' late 40s or early 50s. Understandably, women find discussions about tamoxifen chemoprevention to be complex and perhaps also frightening.13 Whether to add TAH at the time of BSO remains an open question, but the overall long-term strategy is best discussed at the outset. The list of cancers for which BRCA carriers may face an increased risk is lengthy and much-debated. A study of Breast Cancer Linkage Consortium families found a 2.65-fold increased relative risk of cancer of the uterine body in BRCA1 carriers.14 However, this was based on only 11 cases in carriers and five cases in noncarriers, and loss of heterozygosity data are not available from these studies to confirm an etiologic role for BRCA1. Conversely, Levine et al15 did not find an excess BRCA1/2 carrier rate among 199 Ashkenazi Jewish women with endometrial carcinoma, though loss of the wild-type BRCA allele in two of three cases would be consistent with an etiologic role in these two cases. A unifying theory may be that BRCA1 is etiologically linked to endometrial carcinoma, but the penetrance is low, resulting in a low clinical impact. Case reports and small case series do suggest that BRCA carriers face increased risks of papillary serous carcinoma of the endometrium.16-18 Yet, analysis of 56 women with papillary serous carcinoma of the endometrium failed to reveal any BRCA1/2 mutations, even among the four patients with site-specific breast cancer.19 Furthermore, in the Levine et al series, none of the 17 women with papillary serous carcinoma of the endometrium had BRCA1/2 founder mutations.15 If the relative risk is nonetheless elevated, papillary serous carcinoma of the endometrium appears to be rare both in the general population and within BRCA families; furthermore, it is not classified as a hormonally influenced tumor and would not be expected to be seen in excess with tamoxifen treatment. Finally, although the intramural portion of the fallopian tube cannot be surgically resected in its entirety, there are no reports of fallopian tube carcinoma following BSO. Therefore prophylactic hysterectomy does not seem to be warranted based on cancer risks, which, if real, are quantitatively small. For now, it appears that it is safe to manage the symptoms of surgical menopause in BRCA carriers who undergo premenopausal BSO by using short-term HRT. Further studies will be required to address questions about specific HRT formulations, the optimal timing of BSO, and the best duration of HRT use for BRCA carriers. It is also important to determine the magnitude of breast cancer risk reduction with respect to age at BSO and menopausal status: is earlier BSO more worthwhile and how much risk reduction can be expected for postmenopausal BSO? Following a decade of experience in BRCA1/2 testing, we can practice evidence-based medicine for carriers only because high-quality studies such as the one reported herein by Rebbeck et al1 have been accomplished. We now have the means to study targeted chemotherapy in BRCA120 and BRCA221,22 carriers and to discern the influence of other genes and environmental factors on cancer penetrance. Without referral to centers that enroll carriers onto research studies,23 the treatment of these patients simply will not move forward. Authors' Disclosures of Potential Conflicts of Interest The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Rebbeck TR, Friebel T, Wagner T, et al: Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 23:7804-7810, 2005
2. Rebbeck TR, Friebel T, Lynch HT, et al: Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol 22:1055-1062, 2004
3. Wainberg S, Husted J: Utilization of screening and preventive surgery among unaffected carriers of a BRCA1 or BRCA2 gene mutation. Cancer Epidemiol Biomarkers Prev 13:1989-1995, 2004
4. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002
5. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002
6. Metcalfe K, Lynch HT, Ghadirian P, et al: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328-2335, 2004
7. Kriege M, Brekelmans CT, Boetes C, et al: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427-437, 2004
8. Warner E, Plewes DB, Hill KA, et al: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 292:1317-1325, 2004
9. Powell CB, Kenley E, Chen LM, et al: Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: Role of serial sectioning in the detection of occult malignancy. J Clin Oncol 23:127-132, 2005
10. Armstrong K, Schwartz JS, Randall T, et al: Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: A decision analysis. J Clin Oncol 22:1045-1054, 2004
11. 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
12. 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 13. Metcalfe KA, Snyder C, Seidel J, et al: The use of preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation. Fam Cancer 4:97-103, 2005[Medline]
14. Thompson D, Easton DF: Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358-1365, 2002 15. Levine DA, Lin O, Barakat RR, et al: Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol 80:395-398, 2001[CrossRef][Medline] 16. Hornreich G, Beller U, Lavie O, et al: Is uterine serous papillary carcinoma a BRCA1-related disease? Case report and review of the literature. Gynecol Oncol 75:300-304, 1999[CrossRef][Medline] 17. Moslehi R, Chu W, Karlan B, et al: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66:1259-1272, 2000[CrossRef][Medline]
18. Lavie O, Hornreich G, Ben Arie A, et al: BRCA1 germline mutations in women with uterine serous papillary carcinoma. Obstet Gynecol 96:28-32, 2000 19. Goshen R, Chu W, Elit L, et al: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 79:477-481, 2000[CrossRef][Medline]
20. Kennedy RD, Quinn JE, Mullan PB, et al: The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659-1668, 2004 21. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921, 2005[CrossRef][Medline] 22. Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005[CrossRef][Medline] 23. NCI Cancer Genetics Services Directory Accessed: 6-27-2005. http://www.nci.nih.gov/search/genetics_services/ Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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