|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.01.926 on February 23 2004 © 2004 American Society of Clinical Oncology.
Prophylactic Oophorectomy and Hormone Replacement Therapy: Protection at What Price?Dana Farber Cancer Institute, Boston, MA The publication of the Women's Health Initiative data within the last year has introduced more complexity into decisions faced by all women entering menopause who are trying to balance symptom management with increased risks of serious conditions, including breast cancer [1-4]. These decisions are perhaps more difficult for women with increased risk of breast and ovarian cancers based on mutations in the BRCA1 or BRCA2 breast and ovarian cancer susceptibility genes. Since prophylactic surgery reduces the risks of breast and ovarian cancers in these women, the question is no longer whether a carrier should undergo prophylactic bilateral salpingo-oophorectomy (BSO), but when to have surgery, whether or not to include the uterus, and whether to use hormone replacement therapy (HRT). The management of surgical menopause resulting from BSO requires strategies for mitigating frequently powerful menopausal symptoms, including hot flashes, loss of libido, potential cognitive effects, and changes in a woman's body image and self-image. One effective remedy, HRT, may further increase breast cancer risk above the excess risk conferred by the mutation. This situation, in which complete data on which to base recommendations are not yet available, is perfect for decision analysis. In this issue of the Journal of Clinical Oncology, Armstrong et al [4a] take on the challenge of helping women and their physicians deal with this dilemma, by reporting the results of a Markov decision analysis estimating gains in life expectancy for a cohort of women who carry a germline mutation in BRCA1 or BRCA2 after BSO, with and without HRT. The model uses data from both single-institution and multicenter studies of mutation carriers, in which BSO resulted in approximately 90% and 50% reductions in the dominant risks of ovarian and breast cancers, respectively [5,6]. The potential impact of HRT on five major diseases, including breast and ovarian cancers, osteoporosis, coronary heart disease, and venous thromboembolism was culled from recent large randomized studies in post menopausal women [1-4]. Using these figures in their model, the authors derive estimates for very small reductions in life expectancy gains from BSO with HRT. They conclude that caregivers should recommend BSO at completion of childbearing for women who carry germline mutations in BRCA1 and BRCA2, and that neither the physician nor the patient should be dissuaded from considering HRT use for symptom management for fear of increased breast cancer risk. The model is well constructed and is based on current data. However, the fundamental question that must be asked before the conclusion of the analysis can be applied in general practice is whether the data on postmenopausal hormone use from a cohort of women at average population risk of breast cancer apply to the women in the model, who have a markedly increased breast cancer risk based on their mutations. Armstrong et al [4a] use sensitivity analysis (shown in Table 2 of their article) to address this question and simulate a maximum 2.5-fold relative risk of breast cancer in this population of women taking HRT. However, recent studies of oral contraceptives and breast cancer risk in women with a family history of the disease in first-degree relatives or founder mutations in BRCA1 and BRCA2, though not always consistent, have demonstrated estimated relative risks of 3.3 and 7.8, respectively [7,8]. Breast cancer risk from exogenous hormone use among women with BRCA1 and BRCA2 mutations, therefore, may exceed those estimated in the current model. Furthermore, this model was not constructed to address potential scenarios in which hormone use alters the penetrance function to shift more breast cancer risk to earlier ages, or, perhaps more plausibly, to negate or substantively diminish the risk-reducing benefit of the BSO, at least for the duration of the hormone use. In addition, there are reasons to believe that the effects of estrogen or progesterone on breast tissue may differ between carriers of BRCA1 versus BRCA2 mutations, something that could not be examined in the Armstrong et al [4a] model. BRCA1 carriers are more likely to develop estrogen receptor-negative cancers [9]. These tumors have distinct genetic profiles and may have a specific cell of origin [10]. Conversely, women who carry a germline BRCA2 mutation are more likely to develop estrogen receptor–positive breast cancer and, therefore, may be more susceptible to the effects of HRT [9]. Yet, prophylactic BSO has been shown to substantially reduce the breast cancer risk in both BRCA1 and BRCA2 mutation carriers. The most likely mechanism of the risk reduction is the removal of the vast majority of endogenous hormonal influence, though loss of other ovarian products (eg, inhibin, Mullerian inhibitory factor) could contribute to the effect. This suggests that estrogen or progesterone may play a role in the development of BRCA1-associated tumors that is different from their action on sporadic, estrogen receptor–negative disease. These issues do not constitute direct evidence against the treatment of hormone replacement in the Armstrong et al model, but they do provide some reasons for caution in considering the model as a basis for recommendation of hormone use in mutation carriers. Another reason to consider BRCA1 and BRCA2 mutation carriers separately in future models is the emerging difference in the ovarian cancer penetrance curves between the two genes. There are much higher age-specific and lifetime risks of ovarian cancer for BRCA1 carriers (in which the ovarian cancer risk is 40%) than for BRCA2 carriers, who have a 10% lifetime risk [11]. Although the authors suggest that the lower risk of an individual for breast and ovarian cancer results in a smaller benefit of BSO in life expectancy gain, separate analyses for BRCA1 and BRCA2 carriers may ultimately prove useful in considering other complexities in estimating life-expectancy gains for these two groups. Strong, growing data support the ability of high-quality magnetic resonance imaging (MRI) to detect very early stage breast cancers, and this may also translate to a survival benefit [12-14]. Interventions, including tamoxifen and breast MRI screening, may significantly reduce the risk of both developing breast cancer and dying from it, perhaps permitting at least BRCA2 carriers to defer the difficult quality-of-life decisions for early BSO and HRT until they are older. The authors also indicate that the current data on the adverse effects of hormones on the risk of breast cancer and other potentially life-threatening conditions (coronary artery disease, thromboembolism) are confined to estrogen-progesterone combinations and raise the question as to whether estrogen alone may be a preferable option for women considering short-term hormone use for symptom management. For young BRCA1 and BRCA2 mutation carriers, this strategy currently requires the addition of hysterectomy to BSO, more extensive surgery with longer recovery and higher complication rates. In the absence of definitive data or a model specifically addressing these issues, medical oncologists must carefully weigh the results of the Armstrong et al [4a] model and other emerging data in their recommendations to the increasingly identified population of young BRCA1 and BRCA2 mutation carriers. Many experts consider the data for another hormonal manipulation, tamoxifen, to be at best preliminary in BRCA1 and BRCA2 mutation carriers. Yet a recent survey of medical oncologists interested in breast cancer found that many were more likely to prescribe tamoxifen to BRCA2 carriers than BRCA1 carriers [15]. We have not always served our patients well by relying on clinical judgment and speculation instead of data, as the recent experience with HRT and cardiovascular disease illustrates. The Armstrong et al model is a huge step forward in this process and should help ease some of our concerns over recommending short-term HRT for menopausal symptoms. However, many aspects of the effects of HRT on breast cancer risk in mutation carriers remain unclear. Therefore, advising caution in the widespread prescription of HRT after BSO in these women seems prudent. Better early detection tools and risk-reduction strategies should obviate the need for prophylactic surgeries and the associated decisions that compromise our patients' quality of life. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Shumaker SA, Legault C, Rapp SR, et al: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study—A randomized controlled trial. JAMA 289:2651-2662, 2003
2. Rapp SR, Espeland MA, Shumaker SA, et al: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study—A randomized controlled trial. JAMA 289:2663-2672, 2003
3. Chlebowski RT, Hendrix SL, Langer RD, et al: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA 289:3243-3253, 2003
4. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al: Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative—A randomized trial. JAMA 289:2673-2684, 2003
4. Armstrong K, Sanford Schwartz J, 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
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. 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
7. Sellers TA, Grabrick DM, Hartmann LC: Oral contraceptives and risk of breast cancer in women with a family history of breast cancer. JAMA 285:39-40, 2001
8. Ursin G, Henderson BE, Haile RW, et al: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women?. Cancer Res 57:3678-3681, 1997
9. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al: The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310-2318, 2002
10. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 11. Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003[CrossRef][Medline]
12. Warner E, Plewes DB, Shumak RS, et al: Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol 19:3524-3531, 2001 13. Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, et al: First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 63:53-60, 2000[CrossRef][Medline]
14. Kuhl CK, Schmutzler RK, Leutner CC, et al: Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: Preliminary results. Radiology 215:267-279, 2000
15. Peshkin BN, Isaacs C, Finch C, et al: Tamoxifen as chemoprevention in BRCA1 and BRCA2 mutation carriers with breast cancer: A pilot survey of physicians. J Clin Oncol 21:4322-4328, 2003 Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
