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Originally published as JCO Early Release 10.1200/JCO.2004.06.090 on February 23 2004 © 2004 American Society of Clinical Oncology. Hormone Replacement Therapy and Life Expectancy After Prophylactic Oophorectomy in Women With BRCA1/2 Mutations: A Decision AnalysisFrom the Department of Medicine, Center for Clinical Epidemiology and Biostatistics, and Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine; Leonard Davis Institute of Health Economics, University of Pennsylvania; Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA. Address reprint requests to Katrina Armstrong, MD, MSCE, University of Pennsylvania, 423 Guardian Dr, 1204 Blockley Hall, Philadelphia PA 19104-6021; e-mail: karmstro{at}mail.med.upenn.edu
PURPOSE: The decision about prophylactic oophorectomy is difficult for many premenopausal women with BRCA1/2 mutations because of concerns and controversy about the use of hormone replacement therapy (HRT) after oophorectomy. PATIENTS AND METHODS: A Markov decision analytic model used the most current epidemiologic data to assess the expected outcomes of prophylactic oophorectomy with or without HRT (to age 50 years or for life) in cohorts of women with BRCA1/2 mutations. Sensitivity analyses were conducted to assess the impact of alternative assumptions about effects of HRT, effects of prophylactic oophorectomy, and risks of cancer associated with BRCA1/2 mutations. RESULTS: In our model, prophylactic oophorectomy lengthened life expectancy in women with BRCA1/2 mutations, irrespective of whether HRT was used after oophorectomy. This gain ranged from 3.34 to 4.65 years, depending on age at oophorectomy. Use of HRT after oophorectomy was associated with relatively small changes in life expectancy (+0.17 to -0.34 years) when HRT was stopped at age 50, but larger decrements in life expectancy if HRT was continued for life (-0.79 to -1.09 years). HRT was associated with a gain in life expectancy of between 0.39 and 0.79 years for mutation carriers undergoing both prophylactic mastectomy and oophorectomy. CONCLUSION: On the basis of the results of this decision analysis, we recommend that women with BRCA1/2 mutations undergo prophylactic oophorectomy after completion of childbearing, decide about short-term HRT after oophorectomy based largely on quality-of-life issues rather than life expectancy, and, if using HRT, consider discontinuing treatment at the time of expected natural menopause, approximately age 50 years.
Prophylactic oophorectomy reduces the risk of ovarian cancer in women with BRCA1/2 mutations by greater than 95% [1]. Premenopausal oophorectomy also reduces the risk of breast cancer in this high-risk population [2]. However, premenopausal women with BRCA1/2 mutations are often reluctant to undergo prophylactic oophorectomy because of concerns and confusion about hormone replacement therapy (HRT) after surgery. The use of HRT in women with BRCA1/2 mutations after prophylactic oophorectomy is controversial for several reasons. It is difficult to estimate the overall impact of HRT on life expectancy because of its many competing effects, particularly given the increased risk of breast cancer conferred by a BRCA1/2 mutation [3-6]. Recent data from the Women's Health Initiative (WHI) trial of HRT in healthy postmenopausal women have dramatically changed beliefs about the effect of HRT on the risk of coronary heart disease (CHD), resulting in considerable uncertainty about the use of HRT after menopause for any women [7-10]. Furthermore, it is unclear how the duration of HRT use after oophorectomy affects the balance of risks and benefits in women with BRCA1/2 mutations. Thus, some experts suggest that women with BRCA1/2 mutations use HRT only until age 50 years, the time they were likely to have experienced natural menopause, and others recommend against HRT use completely in these high-risk women [11]. Given these clinical uncertainties, new data on the effects of prophylactic oophorectomy and HRT, and the complexity of the many interrelated risks and benefits involved, we performed a decision analysis to assess the expected outcomes of prophylactic oophorectomy and subsequent HRT (either to age 50 years or for life) in women with BRCA1/2 mutations.
A Markov decision analytic model was developed using DATA 4.0 (Treeage Software, Williamstown, MA) to represent the impact of prophylactic oophorectomy and HRT on five major diseases: breast cancer, ovarian cancer, CHD, osteoporosis, and venous thrombosis [12]. Stroke and colon cancer were not included in the model because of limited and inconsistent evidence about the effect of HRT on these outcomes. The health outcomes of a woman with a BRCA1/2 mutation adopting a particular management strategy were estimated by simulating the life span of a hypothetical cohort of women with BRCA1/2 mutations choosing that strategy. The simulated cohort moved among health states over time according to the probability of developing disease, dying from disease, or dying from other causes. Health state transition probabilities varied over time and by management strategy chosen. To calculate life expectancy, the proportion of the cohort remaining alive in each annual interval was summed from age at entry until all members died or reached age 100 years.
Patient Cohorts, Management Strategies, and Assumptions
Data and Health State Transition Probabilities
Breast and ovarian cancer. Published estimates of the risks of breast and ovarian cancer in women with BRCA1/2 mutations range from 45% to 85% for lifetime risk of breast cancer and 11% to 40% for lifetime risk of ovarian cancer [3,15,16,45,46]. Because the higher estimates were generally derived from highly selected research families, we used age-specific estimates from Struewing et al [16] (56% lifetime risk of breast cancer and 16% lifetime risk of ovarian cancer) in our base-case analysis and examined the higher estimates in sensitivity analyses. To calculate age-specific estimates, incidence estimates at age 50 and 70 years were converted into age-specific rates using established formulas [12]. Rates of second breast cancers were obtained from a cohort study of women with BRCA1/2 mutations [46]. Estimates of survival after a diagnosis of breast or ovarian cancer were obtained from Surveillance, Epidemiology and End Results [17]. To match the epidemiologic data as closely as possible while respecting the assumptions of a Markov model, cause-specific mortality after a diagnosis of breast cancer was assumed to be constant after the first year, whereas cause-specific mortality after a diagnosis of ovarian cancer was assumed to occur in the first 5 years after diagnosis. Sensitivity analyses examined variations in these assumptions and in case-fatality rates [18]. CHD. Age-dependent probabilities of developing CHD for women with various CHD risk profiles were calculated from the 30-year follow-up of the Framingham Heart Study [19-22]. The base-case analysis was conducted for a woman without major cardiac risk factors (ie, no history of cigarette smoking, diabetes, hypercholesterolemia, hypertension, or left ventricular hypertrophy). Mortality after a diagnosis of CHD (case-fatality) was obtained from a 1993 analysis of the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Survey adjusted for the significant decline in CHD case-fatality in the United States since 1990 [24]. Osteoporosis. Mortality from osteoporosis is largely attributable to hip fractures. Age-dependent risk of hip fracture was obtained from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Survey and adjusted for second hip fractures [25-28]. Mortality was attributed to hip fracture only in the first year after fracture [29-33]. Dying as a result of other causes. The probability of dying as a result of other causes was calculated from 2000 National Center for Health Statistics mortality data by adjusting age-dependent all-cause mortality for the probability of dying as a result of breast cancer, ovarian cancer, CHD, and hip fracture [47]. Prophylactic surgery. The effects of prophylactic oophorectomy and mastectomy on cancer risks were obtained from our recent analyses of a cohort of women with BRCA1/2 mutations [1,2]. On the basis of these analyses, prophylactic oophorectomy was assumed to reduce the risk of ovarian cancer by 96% and prophylactic mastectomy was assumed to reduce the risk of breast cancer by 85% [1,2]. In addition, these analyses demonstrated that mutation carriers who underwent prophylactic oophorectomy between ages 35 and 50 years experienced a 51% reduction in breast cancer risk that persisted up to age 80. On the basis of observational studies of average-risk women, prophylactic oophorectomy before age 50 without use of HRT was assumed to double the rate of developing CHD and osteoporosis up to age 60 years [41,42]. Although the rates of new diagnoses of CHD or osteoporosis were assumed to be independent of time at menopause after the age of 60, mutation carriers who had undergone premenopausal oophorectomy remained at higher absolute risk of CHD because of the increased incidence from the time of oophorectomy until age 60. Use of HRT after oophorectomy was assumed to negate this increase in risk. These assumptions were all tested in sensitivity analyses. Surgical mortality was assumed to be equivalent to that of general anesthesia (three of 10,000) [48,49]. HRT. We assumed that all mutation carriers had an intact uterus, which was not removed if they underwent oophorectomy, and used both estrogen and progestin if they chose to take HRT. Because specific data about the effects of HRT in women with BRCA1/2 mutations are not currently available and most studies suggest that the effects of HRT do not differ according to family history of breast cancer, we assumed that the effects of HRT were the same among women with BRCA1/2 mutations as women without BRCA1/2 mutations [35,36]. Thus, the effects of HRT on disease outcomes were obtained from the WHI randomized trial of estrogen plus progestin in healthy postmenopausal women [8]. In the WHI trial, HRT increased the risk of breast cancer by 26% overall, but this effect varied over time with no increase in risk for the first 4 years of therapy and an increase of 58% for subsequent years. This result is similar to a meta-analysis of observational studies that found a 35% increase in risk after 5 years [4]. Use of HRT was assumed to have no effect on the clinical course of breast cancer [37]. The effect of HRT on CHD is controversial. The WHI trial found that HRT increased the risk of CHD events by 29% (hazard ratio [HR] = 1.29) [8]. However, this effect was not significant after adjusting for multiple comparisons and did not meet the criteria for early stopping. Recent studies of HRT among women with known CHD, including the Heart and Estrogen/Progestin Replacement Study, have generally supported the hypothesis that HRT increases the risk of CHD in postmenopausal women [7,50]. Thus, we assumed that use of HRT after the age of 50 years increased the risk of CHD by 29% in our base-case analysis. The possibilities that HRT did not affect or reduced the risk of CHD were examined in sensitivity analyses [5,51]. On the basis of the results of the WHI, HRT was assumed to increase the risk of venous thromboembolism by two-fold and to reduce the risk of hip fracture by 47%. Both of these effect sizes are similar to those seen in prior cohort studies [5,34,51,52]. Routine surveillance. Because women with BRCA1/2 mutations are recommended to begin mammography screening before the age of 50 years and the effectiveness of mammography is less in women younger than 50 than in those older than 50, the relative risk reduction from mammography in women with BRCA1/2 mutations may be less than that in average-risk women older than age 50 [53,54]. However, increased frequency of screening, potentially higher compliance, and increased use of alternative modalities may improve effectiveness [55]. Magnetic resonance imaging (MRI) has been demonstrated to be more accurate than mammography in women with a hereditary risk of breast cancer, and trials of screening MRI in women with BRCA1/2 mutations are currently ongoing [56]. Thus, the overall benefit of more frequent breast cancer surveillance in this population was assumed to be equivalent to that of routine mammography in average-risk women older than 50 (relative risk, 0.74 for breast cancer mortality) [44].
Sensitivity Analyses
Our model suggests that women with BRCA1/2 mutations who undergo prophylactic oophorectomy between the ages of 30 and 40 years will experience a significant gain in life expectancy, irrespective of their decision about HRT after oophorectomy (Table 3). In this setting, the decreased risk of ovarian and breast cancer from oophorectomy more than offset the increased risk of coronary disease and osteoporosis from oophorectomy (in the absence of HRT) or the increased risk of breast cancer from HRT (if HRT is used). The gain in life expectancy from oophorectomy decreases as age at the time of oophorectomy increases, with a range from 4.65 years in a 30-year-old mutation carrier who chooses not to take HRT to 2.63 years for a 40-year-old mutation carrier who chooses to take HRT for life. The addition of prophylactic mastectomy to prophylactic oophorectomy is associated with an additional increase in life expectancy (2.98 years at age 30, 2.56 years at age 35, and 2.15 years at age 40), although these incremental gains are smaller than the comparison of prophylactic oophorectomy to no surgery.
The overall effect of HRT on life expectancy after premenopausal oophorectomy ranged from a gain of 0.79 years to a loss of 1.09 years. The size and direction of the effect depended on length of HRT use, age at oophorectomy, and presence or absence of concurrent mastectomy. For mutation carriers who did not undergo concurrent prophylactic mastectomy, use of HRT from the time of prophylactic oophorectomy until age 50 was associated with a relatively small decrement in life expectancy for a 30-year-old woman (-0.34 years), essentially no change in life expectancy for a 35-year-old woman (-0.08 years), and a relatively small increase in life expectancy for a 40-year-old woman (+0.17 years). These changes were much smaller than the overall gain in life expectancy seen with prophylactic oophorectomy (3.34 to 4.65 years). The difference in the direction of the overall effect of HRT between ages 30 and 40 can be attributed in part to the fact that surviving to age 40 years without cancer extends overall life expectancy (providing more years where the beneficial effect of HRT on risk of osteoporosis can be realized) and in part to the greater risk of breast cancer than CHD between the ages of 30 and 40 (making the use of HRT during that decade relatively detrimental). For mutation carriers who did not undergo prophylactic mastectomy, use of HRT for life was consistently associated with a decreased life expectancy, ranging from -1.09 years in a 30-year-old carrier to -0.76 years in a 40-year-old carrier. In contrast, women with BRCA1/2 mutations who underwent prophylactic mastectomy in addition to oophorectomy experienced a net gain in life expectancy from the use of HRT, ranging from a gain of 0.79 years for a 30-year-old woman who uses HRT to age 50 to a gain of 0.39 years for a 30-year-old woman who uses HRT for life.
Sensitivity Analyses
Breast cancer risk also affected the expected impact of HRT on life expectancy after oophorectomy (Fig 1). If a BRCA1/2 mutation results in a lifetime breast cancer risk of 85%, short-term HRT was associated with a decrement of life expectancy ranging from 0.8 years in a 30-year-old woman to 0.1 years in a 40-year-old woman, and long-term HRT was associated with a decrement in life expectancy ranging from 1.6 years in a 30-year-old woman to 1.1 years in a 40-year-old woman. Variation in the estimated lifetime risk of ovarian cancer had little effect on the outcomes of HRT. Effects of prophylactic oophorectomy. The increase in life-expectancy conferred by premenopausal oophorectomy declined as the estimated effects of oophorectomy on breast cancer risk and ovarian cancer risk declined (Figs. 2 and 3). However, if prophylactic oophorectomy was assumed either not to reduce the risk of breast cancer or not to reduce the risk of ovarian cancer, it remained associated with an overall increase in life expectancy (1.4 and 2.6 years, respectively, in a 35-year-old woman). In a worst-case analysis where the effect of prophylactic oophorectomy on both breast and ovarian cancer risk was taken from the upper limits of the 95% CIs of the most recent analysis of oophorectomy in mutation carriers (HR = 0.77 and HR = 0.16, respectively), prophylactic oophorectomy remained associated with an increase in life expectancy of 2.16 years [1,2].
Although the magnitude of ovarian cancer risk reduction from oophorectomy had little effect on the impact of HRT after oophorectomy, varying the effect of oophorectomy on breast cancer risk did affect the impact of HRT. For 35-year-old women who underwent prophylactic oophorectomy, use of HRT to age 50 was associated with a net decrement in life expectancy of greater than half a year if oophorectomy was assumed to reduce breast cancer risk by less than 25% (ie, HR > 0.75). Use of HRT for life was associated with a net decrement in life expectancy of greater than a year if oophorectomy was assumed to reduce breast cancer risk by less than 45% (ie, HR > 0.55). Effects of HRT. Figure 4 shows the relationship among the effects of HRT on the risks of breast cancer, CHD, and life expectancy after oophorectomy for a 35-year-old woman with a BRCA1/2 mutation. Although HRT was associated with a decrement in life expectancy across the majority of the analyses, HRT became associated with an increase in life expectancy when its effect on breast cancer risk was relatively small and its effect on CHD risk was relatively beneficial. These results were similar for 30- and 40-year-old women (data not shown).
The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 has made it possible to identify women at significantly increased risk of breast and ovarian cancer [57]. Premenopausal prophylactic oophorectomy has been shown to reduce substantially the risk of subsequent breast and ovarian cancer in BRCA1/2 mutation carriers [1,2]. However, the decision of whether and when to undergo oophorectomy is difficult for many women because of concern about the use of HRT after oophorectomy and the potential for a marked decrease in quality of life related to premature menopause. This problem has been exacerbated by the recent results of the WHI, which demonstrated a significant increase in breast cancer risk and no reduction in CHD risk with the use of HRT in healthy postmenopausal women [8]. This decision analysis provides several insights to help women and physicians with these difficult decisions. Most importantly, prophylactic oophorectomy was associated with substantial increased life expectancy irrespective of subsequent use of HRT. To put this benefit in perspective, Table 4 shows the gains in life expectancy seen with several commonly used medical interventions, few of which provide gains of the magnitude seen with prophylactic oophorectomy. The smallest gain in life expectancy (2.6 years) associated with oophorectomy was for a 40-year-old woman who took HRT for life, a gain four times larger than that seen with adjuvant chemotherapy for node-positive breast cancer and 10 times larger than that seen with annual Pap smears among low-risk women [60,61]. Thus, given recent data about the benefits of oophorectomy on breast and ovarian cancer risk, women with BRCA1/2 mutations should not hesitate to undergo oophorectomy because of concerns about HRT.
In our comparison of 30-, 35-, and 40-year-old women, the benefit of oophorectomy on life expectancy increases the earlier oophorectomy is performed. This occurs because of the significant risk of breast cancer among women with BRCA1/2 mutations in their fourth decade of life, with several studies suggesting that a woman with a BRCA1/2 mutation has approximately a 20% risk of developing breast cancer by the time she is age 40 years. Our analysis did not assume that the effect of oophorectomy on breast cancer risk varied according to time before menopause. However, if oophorectomy is associated with a greater relative reduction in breast cancer risk when it is performed at age 30 than at age 40 (as might be expected), then the relative difference in life expectancy from oophorectomy between ages 30 and 40 would be even greater. Despite the greater benefit of oophorectomy at younger ages, we do not encourage women to forego or limit childbearing for this reason, given that the timing of oophorectomy has considerably less impact on life expectancy than the decision to undergo oophorectomy itself. On the basis of data from the WHI, in the absence of prophylactic mastectomy, the use of HRT from the time of oophorectomy until age 50 was associated with relatively small overall changes in life expectancy that were sensitive to the assumptions of the model. This finding suggests that the decision about short-term HRT use after prophylactic oophorectomy should be based on quality-of-life issues, such as symptomatic relief and cancer-related anxiety, rather than the effect of HRT on life expectancy. In contrast, women who have undergone prophylactic mastectomy as well as oophorectomy have a breast cancer risk that is so low that short-term HRT consistently increased life expectancy and should be considered for this reason alone. However, irrespective of whether a woman has undergone prophylactic mastectomy as well as oophorectomy, continuation of HRT after age 50 is associated with consistent and more substantial decrements in life expectancy, suggesting that women who do begin HRT at the time of oophorectomy should strongly consider discontinuing treatment around age 50, the average age of natural menopause in the United States. These results were consistent across the range of estimated penetrance rates for women with BRCA1 or BRCA2 mutations, with the decrement in life expectancy from HRT in the absence of prophylactic mastectomy generally being lower for women with BRCA2 mutations given that the estimated breast cancer penetrance is lower. Several previous decision analyses have evaluated effects of surgical prophylaxis in women with BRCA1/2 mutations but none have evaluated the influence of HRT, a critical factor for women making decisions about prophylactic mastectomy and oophorectomy. Our results are similar to a recent decision analysis that found that prophylactic oophorectomy was associated with a gain of life expectancy of between 5.3 years in a 30-year-old woman and 2.9 years in a 40-year-old woman, assuming a 56% lifetime breast cancer risk and 16% lifetime ovarian cancer risk in mutation carriers (the same rates used in our baseline analysis) [63]. However, this analysis assumed all women would take HRT until age 50 and did not consider alternative decisions about HRT use. Earlier decision analyses found smaller increases in life expectancy associated with prophylactic oophorectomy but did not include recent data demonstrating the marked effectiveness of oophorectomy in breast and ovarian cancer risk reduction or alternative decisions about HRT [1,2,64,65]. Our results differ from prior decision analyses of HRT use after menopause, most of which found gains in life expectancy of between 0.5 and 3.5 years for women, varying by CHD risk factors [6,66,67]. However, these prior analyses were conducted before the recent data release from the WHI demonstrating the lack of benefit of HRT in prevention of coronary disease, and were not focused on women with BRCA1/2 mutation. The primary limitations of this analysis arise from inevitable uncertainty about many of the transition probabilities and the need to restrict the number of options included in the model. Because the ability to identify women with BRCA1/2 mutations is a relatively recent development, the risk of HRT, the clinical course of breast and ovarian cancer, and the benefit of routine surveillance and prophylactic surgery are not known precisely for women with mutations in these genes. On the basis of analyses of the effects of HRT among women with a family history of breast cancer, we assumed that the effect of HRT was the same among women with BRCA1 mutations, BRCA2 mutations, and women without mutations. However, several studies suggest that BRCA1-associated breast cancer is less likely to be positive for estrogen and progesterone receptors than BRCA2-associated breast cancer or sporadic breast cancer, raising the possibility that HRT may be less likely to increase breast cancer risk among women with BRCA1 mutations [68,69]. Although sufficient data are not yet available to allow the development of specific models on the basis of these early findings, potential differences in the effect of HRT on breast cancer risk were included in sensitivity analyses. Because we were unable to include other management alternatives for osteoporosis or CHD risk in the model, the impact of the availability of these alternatives on the decision about HRT was not determined, although they are unlikely to make HRT a more favorable option. We did not examine the use of hysterectomy at the time of oophorectomy, an option that allows women to use estrogen replacement without progesterone supplementation. Although many experts believe that the use of estrogen alone may be associated with fewer risks and greater benefits than the use of estrogen and progesterone, sufficient data are not yet available about this issue to enable a meaningful decision analysis. The completion of the corresponding WHI trial of postmenopausal estrogen supplementation will allow us to address this issue. Similarly, there currently are insufficient data about HRT to determine the optimal length of use after oophorectomy. We chose to examine the use of HRT until age 50 years because of the clear physiologic difference between replacing estrogen until the time of expected menopause and the extension of estrogen exposure after menopause. In addition, the impact of early menopause on the increase in risk of CHD and osteoporosis is fairly well understood. Although we do not yet have data to enable calculation of the association between shorter courses of HRT use and life expectancy, such courses may be reasonable for many women. Because the effect of HRT on quality of life may be quite variable across individual women and the most recent data suggest the effects at the population level are minimal, we did not to include an estimate of the mean effect of HRT on quality of life in our analyses [70]. However, we believe quality-of-life issues are an important part of individual decisions about short-term use of HRT. Despite the limitations inherent in modeling, this study provides important information for women with BRCA1/2 mutations [71]. For these women, premenopausal oophorectomy was associated with a substantial increase in life expectancy, irrespective of the decision about subsequent HRT. Furthermore, the risks and benefits of HRT until age 50 were closely balanced in these women, making the overall impact of HRT on life expectancy relatively small. However, on the basis of recent data from the WHI, long-term continuation of HRT beyond age 50 was associated with a significant decrement in life expectancy. Thus, we believe that all women with BRCA1/2 mutations should be strongly encouraged to undergo prophylactic oophorectomy after completion of childbearing, should decide about the use of short-term HRT after oophorectomy on the basis of quality-of-life issues and, if they choose to take HRT, should plan to discontinue its use at or before the expected age of natural menopause.
The authors indicated no potential conflicts of interest.
We thank Henry Glick, PhD, for assistance with regression models of coronary heart disease and Tim Rebbeck, PhD, for assistance with prophylactic surgery data.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
