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Originally published as JCO Early Release 10.1200/JCO.2005.96.009 on September 12 2005 © 2005 American Society of Clinical Oncology.
Quality or Quantity in the Management of Hereditary Ovarian Cancer Risk: Is It Really a Trade-Off?Dana-Farber Cancer Institute, Boston, MA Women with increased probability of developing ovarian cancer face the dilemma of how best to manage their risk. Lifetime ovarian cancer risk is increased in women who carry germline mutations in the hereditary breast-ovarian cancer susceptibility genes BRCA1 (40% to 60%) and BRCA2 (15% to 20%),1 and in the hereditary nonpolyposis colon cancer–associated genes (10% to 12% risk),2 as well as in familial clusters not attributable to known genes. Current options for early detection of ovarian cancer include serial transvaginal ultrasound examinations and serum CA-125 determinations, but the sensitivity of these methods remains disappointing.3 Risk-reducing salpingo-oophorectomy (RRSO) has been shown to reduce the risk of ovarian and fallopian tube cancers in women with BRCA1/2 mutations by more than 90%.4,5 When performed in premenopausal BRCA1/2 mutation carriers, RRSO also reduces the risk of breast cancer by nearly 50%,4,5 consistent with older data documenting a substantial reduction in breast cancer risk in normal-risk women conferred by surgical menopause before age 40 years.6 Based on such data, RRSO is recommended by several groups for BRCA1/2 mutation carriers following completion of child-bearing after age 35 to 40 years.7,8 However, medical management strategies remain suboptimal for the consequences of premature menopause, including vasomotor symptoms, and sexual and skeletal health. Therefore, premenopausal women with high ovarian cancer risk must prepare to take on early menopause as the very significant price of effective risk reduction. In this issue of the Journal of Clinical Oncology, Madalinska et al9 present a snapshot of the quality of life (QOL) among high-risk women who have undergone RRSO, compared with those who are relying on surveillance to manage their increased ovarian cancer risk. In their cross-sectional study, the investigators used mailed surveys to collect data from women identified from gynecologic practices across the Netherlands who had increased ovarian cancer risk because of hereditary familial breast and ovarian cancer syndrome. The analysis was conducted on a large sample of 846 high-risk women, among whom 369 (44%) had undergone RRSO, while 477 (56%) were following surveillance programs (pelvic examination, transvaginal sonography, and serum CA-125 determination). A number of validated QOL measures were included in the instrument. The findings should be reassuring to women considering prophylactic surgery. Overall QOL measured using four of eight subscales of the SF36 Health Survey was not different between the two groups. Women who had undergone surgery had less cancer worry (P < .001), and in multivariate analysis, less specific worry about ovarian cancer risk (P < .001) for themselves and their family members (P < .0001) than did women who had chosen screening. However, women who had chosen surgery also reported significantly more endocrine symptoms and sexual dysfunction than women who had opted for gynecologic screening, despite similar levels of sexual activity, and also despite hormone therapy. Finally, 97% of women who had undergone RRSO reported satisfaction with surgery, while 33% of the women in the surveillance group reported their intention to have surgery in the future. The authors recommend that counseling for women about prophylactic ovarian surgery include both reassurance that most women report good QOL after surgery, with relief from cancer worry, and caution that menopause symptoms will often be problematic. The findings of Mandalinska et al are consistent with the existing literature10-12 and will resonate with providers caring for women facing these decisions. A significant strength of this study compared with prior reports is the direct data collection from a large control group of women who chose surveillance. The finding of QOL equivalence may be particularly reassuring given that the surgery group included more women with prior breast cancer (49.3% v 34%) and many more with BRCA1/2 mutations (72% v 21.6%). One puzzling finding is the lack of significant difference in worry about breast cancer between the groups, despite the marked preponderance of women with previous prophylactic mastectomy (45.5% v 13.2%) in the surgery group. These data capture the feelings and attitudes of women at increased ovarian cancer risk at one moment in time. The median time from surgery in that group was 2 years, so the data reflect life after adjustment, good overall QOL, but persistent menopausal and sexual complaints after surgery. How should these data be used? The efficacy of prophylactic surgery is undeniable, and, while not complete, is greater in magnitude than virtually anything else we have to offer patients facing cancer risk or cancer treatment. QOL data like these should not be misinterpreted to suggest that surveillance is equivalent to surgery as a real management option in the long-term. The fundamental challenge given the status of the data today is not in helping high-risk patients decide whether to have RRSO with or without hysterectomy (fallopian tube resection is not optional), but rather when to undergo the procedure. There is little controversy for women who are postmenopausal when they become aware of their increased ovarian cancer risk, as they accrue the near-complete reduction in remaining ovarian cancer risk without the threat of menopausal symptoms. For women age 35 to 50 years, the immediate reduction in ovarian and variable diminution in breast cancer risks with surgery are even more compelling given both the total risk remaining to a younger woman and the more dramatic consequences of cancer in women during their years of active parenting and employment. However, premenopausal women face the prospect of as much as 20 more years in menopause than they would have reasonably anticipated, as well as important concerns as to whether menopause symptoms will be even more intense with surgical as opposed to natural menopause.13 There are convincing data that bone loss, for example, is markedly accelerated with precipitous menopause from chemotherapy,14 but similar data after surgical oophorectomy are mostly older, before the era of more precise measurement techniques. What other information will be important to shift this paradigm away from surgery and toward a longer period of intensive surveillance? Sensitive and Reliable Early Detection The better early detection strategies become, the more comfortable women will be in opting for surveillance over surgery. This active area of research has targeted the identification of circulating biomarkers, presently often using proteomic approaches.15 Novel markers require validation, making them likely at least a decade from widespread clinical practice. In the meantime, women who are using surveillance should be encouraged to participate in the GOG199 study (Gynecologic Oncology Group) in the United States and Australia, FOCSS (Familial Ovarian Cancer Screening Study) in the United Kingdom, and similar studies elsewhere to optimize the performance of CA-125 and future markers in this high-risk group (http://www.ovariancancer.gog199.cancer.gov). More Precise Risk Assessment We anticipate that ongoing studies will provide more precise estimates of breast and ovarian cancer risk separately for BRCA1 and BRCA2 mutation carriers given their disparate age-specific penetrances.1 We need to be able to incorporate the effects of risk modification, both exogenous (such as oral contraceptive use) and genetic (such as BRCA1/2 mutation-specific risk or alleles of other risk-modifying genes under investigation), into validated models in formats than can be communicated clearly to women and providers. Conceivably, validated circulating biomarkers could help to identify women in whom malignant transformation has begun and for whom surgery should be more immediate. Effective Treatment and Risk-Reduction Strategies Obviously, if ovarian cancer were always curable, independent of stage, this issue would disappear. Awaiting that, additional approaches should be developed to reduce breast and ovarian cancer risk in high-risk women. Alternatives to surgery may include chemopreventive agents currently in trials, such as tamoxifen or aromatase inhibitors; nonhormonal agents; and more distant possibilities such as vaccines. A combination of surgical and nonsurgical approaches may permit women to at least defer oophorectomy until chronologically closer to physiologic menopause. Improved Menopause Symptom Management The price for RRSO while premenopausal is the occurrence of premature menopausal symptoms (Table 1). 16 Whether the use of hormone replacement therapy mitigates the protective approach of RRSO has a crucial role in the discussion. At least one sophisticated model suggests that short-term hormone replacement therapy may not negate the cancer-preventive effects of oophorectomy,17 but prospective data will be critical. The apparent differential effects of estrogen alone (compared with estrogen plus progesterone) on breast cancer risk in the Women's Health Initiative, and the potential role of tamoxifen, have added consideration of hysterectomy to the decisions to be made.18 There are remarkably few data measuring the effects of surgical menopause compared with natural menopause regarding intensity and duration of menopause symptoms, and long-term consequences such as bone health. There is a paucity of compounds and combinations that optimize skin changes, libido, sexual comfort, vasomotor symptoms, bone health, and sleep disturbances, without increasing breast and endometrial cancer risks. Their identification will be welcomed by all women.
Women facing hereditary ovarian cancer risk will make their decisions based on complex calculations of their own. In societies that prize youth and beauty, current QOL measures cannot assess the extent to which women still feel comfortable, desirable, youthful and fundamentally female after the particular prophylactic procedures hereditary breast/ovarian cancer syndrome management can entail. As providers, we can help these women to see the wisdom of avoiding cancer that is far too frequently fatal, and we can promise to listen to their symptoms and help them to find the resources they will need to deal with them. In those ways, at least, we can hope to contribute to their QOL. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. 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]
2. Shannon C, Kirk J, Barnetson R, et al: Incidence of microsatellite instability in synchronous tumors of the ovary and endometrium. Clin Cancer Res 9:1387-1392, 2003 3. Modugno F: Ovarian cancer and high-risk women-implications for prevention, screening, and early detection. Gynecol Oncol 91:15-31, 2003[CrossRef][Medline]
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. Trichopoulos D, MacMahon B, Cole P: Menopause and breast cancer risk. J Natl Cancer Inst 48:605-613, 1972 7. Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer, II: BRCA1 and BRCA2—Cancer Genetics Studies Consortium. JAMA 277:997-1003, 1997[Abstract] 8. Eisinger F, Burke W, Sobol H: Management of women at high genetic risk of ovarian cancer. Lancet 354:1648, 1999
9. Madalinska JB, Hollenstein J, Bleiker EMA, et al: The quality of life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 23:6890-6898, 2005 10. Hallowell N: "You don't want to lose your ovaries because you think ‘I might become a man’." Women's perceptions of prophylactic surgery as a cancer risk management option. Psychooncology 7:263-275, 1998[CrossRef][Medline] 11. Robson M, Hensley M, Barakat R, et al: Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol 89:281-287, 2003[CrossRef][Medline] 12. Tiller K, Meiser B, Butow P, et al: Psychological impact of prophylactic oophorectomy in women at increased risk of developing ovarian cancer: A prospective study. Gynecol Oncol 86:212-219, 2002[CrossRef][Medline] 13. Bachmann G: Physiologic aspects of natural and surgical menopause. J Reprod Med 46:307-315, 2001[Medline]
14. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306-3311, 2001
15. Mills GB, Bast RC Jr, Srivastava S: Future for ovarian cancer screening: Novel markers from emerging technologies of transcriptional profiling and proteomics. J Natl Cancer Inst 93:1437-1439, 2001
16. Voelker R: NIH panel tries to clear confusion, spur research on managing menopause. JAMA 293:2329-2331, 2005
17. 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
18. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 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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