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© 2002 American Society for Clinical Oncology Effect of Prevention Strategies on Survival and Quality-Adjusted Survival of Women With BRCA1/2 Mutations: An Updated Decision AnalysisByFrom the Herbert Irving Comprehensive Cancer Center, Department of Medicine, and Joseph L. Mailman School of Public Health, College of Physicians and Surgeons, Columbia University, New York, NY. Address reprint requests to Victor Grann, MD, MPH, FACP, Herbert Irving Comprehensive Cancer Center, Columbia University, PH18-201A, 630 W 168th St, New York, NY 10032; email: VRG2{at}columbia.edu
PURPOSE: This study updates findings regarding the effects of prophylactic surgery, chemoprevention, and surveillance on the survival and quality-adjusted survival of women who test positive for BRCA1/2 mutations. MATERIALS AND METHODS: Markov modeling of outcomes was performed in a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations. The model incorporated breast and ovarian cancer incidence rates from the literature and mortality rates from the Surveillance, Epidemiology, and End Results Program. Quality adjustment of survival estimates were obtained from a survey of women aged 33 to 50 years. Sensitivity analyses were performed of varied assumptions regarding timing and effects of preventive measures on cancer incidence and adverse effects. RESULTS: A 30-year-old woman could prolong her survival beyond that associated with surveillance alone by use of preventive measures: 1.8 years with tamoxifen, 2.6 years with prophylactic oophorectomy, 4.6 years with both tamoxifen and prophylactic oophorectomy, 3.5 years with prophylactic mastectomy, and 4.9 years with both surgeries. She could prolong her quality-adjusted survival by 2.8 years with tamoxifen, 4.4 years with prophylactic oophorectomy, 6.3 years with tamoxifen and oophorectomy, and 2.6 years with mastectomy, or with both surgeries. The benefits of all of these strategies would decrease if they were initiated at later ages. CONCLUSION: Women who test positive for BRCA1/2 mutations may derive greater survival and quality adjusted survival benefits than previously reported from chemoprevention, prophylactic surgery, or a combination. Observational studies and clinical trials are needed to verify the results of this analysis of the long-term benefits of preventive strategies among BRCA1/2-positive women.
The BRCA1/2 mutations were first identified 8 years ago.1,2 By use of decision analysis based on the available data about the efficacy of preventive measures, several investigators estimated that women who had BRCA1/2 mutations would live longer if they had prophylactic surgery than if they had intensive screening alone.3-6 More recent observational studies and clinical trials have demonstrated that high-risk women have a relative risk of 0.1 for breast cancer after prophylactic mastectomy; of 0.6 for breast cancer and 0.04 for ovarian cancer after prophylactic oophorectomy; and of 0.51 for breast cancer after tamoxifen therapy, compared with those who do not receive preventive treatment.7-9 Tests for BRCA1/2 mutations are now widely available and are increasingly performed on samples taken from women who have been diagnosed with breast or ovarian cancer at a young age or whose first-degree relatives have had these cancers. But the value of testing depends on what those who test positive can do to reduce their risk of death from cancer. In this study, we incorporated findings from recent studies into the mathematical model we previously used to assess the survival and quality-adjusted survival benefits of preventive strategies compared with those associated with surveillance alone. We have also conducted sensitivity analyses to explore the possible outcomes of the preventive strategies used in combination or under various assumptions regarding timing, treatment efficacy, cancer risk, and cancer mortality.
Our methods were updated versions of ones described in previous studies4,10 and used a Markov process11 and Data 3.57 (TreeAge Software, Williamstown, MA) to estimate the effects on survival and quality-adjusted survival of eight cancer prevention strategies: tamoxifen, oral contraceptives, prophylactic oophorectomy, prophylactic mastectomy, both prophylactic mastectomy and oophorectomy, prophylactic oophorectomy and tamoxifen, having children, and surveillance. Our base case was a hypothetical 30-year-old woman who has tested positive for a BRCA1/2 mutation at risk for eight health states: good health, breast cancer, ovarian cancer, breast and ovarian cancer, cataract, endometrial cancer, thrombophlebitis/pulmonary embolism, and death (Table 1).12-19 We observed her for 70 years (Markov cycles) starting at age 30. For each year, for each of the strategies, we calculated the age-dependent probabilities of developing breast cancer, developing ovarian cancer, developing side effects from tamoxifen, dying from breast or ovarian cancer, dying from any cause, or remaining well.
Health Parameters The model utilizes Struewing’s estimates of the cumulative incidence of breast cancer and ovarian cancer among BRCA1/2-positive women20 in each decade of age, up to age 100. We converted these 10-year risks to annual conditional probabilities of cancer by assuming constant instantaneous rates of disease per year. We assumed that the risks of developing the two cancers were independent; therefore, among BRCA1/2-positive women, those with breast cancer had the same conditional probability of developing ovarian cancer as those who were well. A group of clinical oncologists provided us with recommendations for modeling assumptions (Table 1). For patients who developed breast cancer, we calculated the annual risks of dying, developing ovarian cancer, or surviving with breast cancer. We took into account both the age at which the patient was diagnosed and the time from diagnosis. Because intensive surveillance may influence stage at diagnosis, we assumed that BRCA1/2-positive women, given a choice of preventive measures at age 30 years and subsequently diagnosed with breast cancer, would be similar in stage distribution to the participants in the Breast Cancer Prevention Trial, 70% of whom had localized (node-negative) and 30% regional (node-positive) disease.9 We assumed that BRCA1/2-positive women who developed cancer would have the same conditional probability of death as women with cancer in the general population.12 We therefore used the United States National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data for 1973 to 1998 (issued April 2001) to calculate probabilities of dying.12 We did not adjust for screening for ovarian cancer because it does not seem to alter the prognosis of this cancer. We assumed that patients with breast cancer who subsequently developed ovarian cancer would leave the breast cancer state and enter the ovarian cancer state in the next cycle. We based our estimates of the health effects of preventive strategies on recent studies. We therefore assumed that among BRCA1/2-positive women, prophylactic oophorectomy may reduce the risk of ovarian cancer by 96% and the risk of breast cancer by 40% (T.R. Rebbeck, personal communication, October, 2001),8 prophylactic mastectomy may reduce the risk of breast cancer by 90%,7,21 tamoxifen may reduce it by 49%,9,22 the combination of tamoxifen and prophylactic oophorectomy may reduce the risk of breast cancer by 84%,16 and oral contraceptives may reduce the risk of ovarian cancer by 54%.18 For our base case, the risk reduction associated with these strategies was assumed to last indefinitely. We assumed that women aged 30 who were given estrogen replacement therapy after prophylactic oophorectomy would not have an increased risk of breast cancer above that conferred by BRCA1/2 and would have the same risk of cardiovascular disease and osteoporosis as the general population.8,23 We calculated the incremental mean years of survival that each primary preventive measure would yield by subtracting from it the mean life expectancy associated with surveillance.
Quality-of-Life Adjustment
Discounting We examined differences in survival and quality-adjusted survival until death or age 100 with no discounting.
Special Complications of Tamoxifen
Other Studies
Sensitivity Analysis The duration of the risk reduction associated with tamoxifen use is unknown. We therefore conducted sensitivity analyses of the effects of tamoxifen on survival given 5, 10, and 15 years of breast cancer risk reduction.32 The efficacy of tamoxifen and newer selective estrogen receptor modulators among premenopausal BRCA1/2-positive women is also unknown. Many, although not all, breast cancer patients with BRCA1 mutations have hormone receptor-negative tumors.31,33-36 Most with BRCA2 mutations seem to have estrogen receptor-positive tumors.37 Because the Breast Cancer Prevention Trial found that tamoxifen prevented hormone receptor-positive but not hormone receptor-negative cancers, we performed additional sensitivity analyses assuming that the reduction in breast cancer risk among BRCA1/2-positive women who take tamoxifen is only 25% rather than 50%.9 The two studies of the effects of oral contraceptive agents on the risk of ovarian cancer among BRCA1/2-positive women have had conflicting results. The first suggested a relative risk of 0.464 for women who had used oral contraceptives for 6 years compared with those who had never used them; the second found no benefit. In response to a study indicating that oral contraceptives increased breast cancer risk in women with a family history of breast cancer, we also conducted an analysis assuming that oral contraceptives increase breast cancer risk by 20% while reducing ovarian cancer risk by 54%.18
Survival According to our model, among women with BRCA1/2 mutations, having prophylactic mastectomy with bilateral oophorectomy at age 30 years may extend survival by 4.9 years over surveillance alone (Table 3). The other preventive strategies also are estimated to extend survival by 0.6 to 4.6 years. For 30-year-old BRCA1/2-positive women, the major benefits in survival occur in the next 30 years (Fig 1). After 60 years, the survival curves begin to converge. Women who have a prophylactic mastectomy and oophorectomy or who take tamoxifen after an oophorectomy have a survival curve that is similar to that of noncarriers of the mutation.
The model indicates that the benefits of preventive strategies vary inversely with the age at which they were initiated and would virtually disappear after age 60 (Fig 2). The decrease in benefit would be greatest for women who delay the surgical treatments that, if undertaken early, may yield the greatest potential survival benefits. The survival benefits start to approach control levels when high-risk women delay treatment until age 60. Survival also depends on the duration of the risk reduction conferred by tamoxifen (Table 4).
Quality-Adjusted Survival In our model, quality adjustment increases the estimates for the benefits of both oophorectomy and chemoprevention dramatically compared with those of mastectomy. The greatest quality-adjusted survival benefits observed are 4.4 years for oophorectomy and 6.3 years for tamoxifen and oophorectomy (Table 3). Like the survival benefits estimated by the model, the quality-adjusted survival benefits of preventive strategies are estimated to vary inversely with age at initiation (Fig 2). The benefits of mastectomy with or without oophorectomy decline to zero for women older than 50 years. However, both oophorectomy and chemoprevention remain viable therapeutic choices even for women older than 60 years.
Sensitivity Analyses The second sensitivity analysis demonstrates that if mortality were 10% higher among breast cancer patients with BRCA1/2 mutations than among those without such mutations, as some recent data suggest, the survival benefits of preventive interventions would increase by up to 11% and the quality-adjusted survival benefits would increase somewhat more. The third, fourth, and fifth sensitivity analyses involve only quality-adjusted survival. The third and fourth demonstrate that if the preference ratings of life with breast cancer and ovarian cancer were 10% higher than those used for the base case analyses of quality-adjusted survival the quality-adjusted survival benefits associated with preventive measures would be up to 61% lower. The fifth sensitivity analysis demonstrates that if the preferences of average-risk women aged 20 to 32 years were operative, quality-adjusted survival would increase for all preventive interventions involving mastectomy and would decline slightly for the others. Table 4 lists the incremental survival and quality-adjusted survival benefits associated with initiating tamoxifen use at age 30 years under varying assumptions. If tamoxifen reduces breast cancer risk for only 15, 10, or 5 years instead of a lifetime, it will add only 1.3, 1.0, or 0.5 years, instead of 1.8 years, to survival; the effect on quality-adjusted survival seems smaller. If tamoxifen reduces breast cancer risk for only 15, 10, or 5 years, the survival and quality-adjusted survival benefits of tamoxifen with oophorectomy will be similarly diminished. Table 4 also lists the effects of varying assumptions regarding the reduction in risk of ovarian cancer associated with oophorectomy and the assumption that oophorectomy does not reduce breast cancer risk. Table 5 presents sensitivity analyses of the benefits of preventive interventions given different assumptions about mutation penetrance. In our model, the higher the penetrance of the mutation, the greater the benefit of preventive interventions was compared with surveillance alone.
The purpose of this updated analysis is to assist health care providers and women who are contemplating genetic testing for BRCA1/2 mutations to evaluate the choices of preventive strategies that are now available to those who test positive. The current options are as follows: (1) to follow surveillance guidelines as outlined by the American Society of Clinical Oncology, (2) to undergo prophylactic surgery, (3) to take a chemopreventive drug, or (4) to use a combination of these strategies, such as oophorectomy and therapy with tamoxifen.31,38,39 Our model estimates the potential survival benefits of these options. Two studies have found that prophylactic mastectomy reduces the risk of breast cancer by 90% in high-risk and BRCA1/2-positive populations.7,21 Prophylactic oophorectomy seems to reduce the risk of both ovarian cancer and breast cancer.8 These risk reductions translate into large survival benefits and even larger gains in quality-adjusted survival. Figure 1 illustrates that the major survival benefit occurs in the first 20 to 30 years after the preventive measure is taken, rather than in old age. The figure also demonstrates that the survival curve projected for women who have both prophylactic surgeries is similar to that for nonmutation carriers. The benefits of chemoprevention alone are more problematic. Tamoxifen was approved by the United States Food and Drug Administration for the reduction of breast cancer risk based on the results of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial.40 In that trial, tamoxifen reduced the risk of invasive breast cancer by 49% among high-risk women.9 Participants in the Breast Cancer Prevention Trial with two or more affected first-degree relatives who took tamoxifen had a 50% lower risk than those who did not, similar to all other study participants.9 In a decision analysis, this reduction in breast cancer risk translated into a survival advantage of more than 3 months.41 Likewise, a case control study has now demonstrated a benefit of tamoxifen for the prevention of contralateral breast cancer among women with a history of breast cancer who test positive for either BRCA1 or BRCA2 mutations.16 In a study of BRCA1/2 carriers in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial, the benefit of tamoxifen among the 11 BRCA2 mutation carriers was found to be similar to that observed for all study participants.33 Among the eight BRCA1 mutation carriers, tamoxifen seemed to have no benefit. The number of mutation carriers in this study was too small to serve as a basis for definitive conclusions; studies of larger numbers of carriers of specific mutations are needed to enhance our knowledge of breast cancer prevention, given genetic high risk. The duration of the risk reduction associated with tamoxifen is unknown. A meta-analysis of tamoxifen trials among women with a primary breast cancer tumor found that the drug reduced the risk of contralateral breast cancer for more than 10 years,32 and another study suggested that the effects of tamoxifen on breast cancer risk were independent of those of oophorectomy.16 In our analysis, the survival benefits of taking tamoxifen after having an oophorectomy were similar to those of having both surgeries and to the nonmutation-carrier state. Many cancer centers in the United States now recommend tamoxifen for BRCA1/2-positive women who have had a prophylactic oophorectomy.31 In our sensitivity analysis, we found that even if tamoxifen provides only a 25% risk reduction that lasts for only 5 years, its use may prolong survival and greatly improve quality-adjusted survival. This difference between survival and quality-adjusted survival contrasts with that for mastectomy (Fig 2). The effects of oral contraceptives are ambiguous. In one published study, the use of oral contraceptives for 6 years decreased the risk of ovarian cancer by 54% in BRCA1/2-positive women.18 In another study of BRCA1/2-positive women, those who took oral contraceptives did not have a lower risk of ovarian cancer than those who did not, but those who had children had a lower risk than those who did not.17 This risk reduction translated into a small increase in survival and quality-adjusted survival associated with each live birth to a BRCA1/2 carrier in our model. Some data suggest that among BRCA1/2-positive women, taking oral contraceptives may increase the risk of breast cancer. Our sensitivity analysis demonstrated that this increase in breast cancer risk would eliminate any survival benefit of taking oral contraceptives. According to our model, among women who test positive for BRCA1/2 mutations, those who have prophylactic surgery or chemoprevention will survive longer than those who do not. These results are even more encouraging than previous analyses because they are updated by recent observational studies.3,5,42 In our previous analysis, we assumed that oophorectomy would reduce the risk of ovarian cancer by only 45%, but studies have found that it may be 96% effective in preventing ovarian cancer and 40% effective in preventing breast cancer.8 The breast cancer risk reduction conferred by tamoxifen has also been found to be independent of that conferred by oophorectomy.16 Our base case assumption was that women who had oophorectomy would use hormone replacement therapy. One study has found a slightly smaller breast cancer risk reduction among users of hormone replacement therapy than in the overall cohort of women who had had an oophorectomy; both groups derived a statistically significant risk reduction from oophorectomy.8 Our study assesses other factors that affect the outcomes of preventive strategies for individuals who test positive for cancer-specific mutations: the age when the preventive procedure is performed; the penetrance of the disease in a particular population; the quality of life associated with the procedure and the cancer, including side effects of the disease or the treatment; and mortality from the disease. Survival and quality-adjusted survival curves for the preventive measures demonstrate that the major benefits of prevention occur within the first 20 to 30 years of the intervention. So the 3.7 years of survival added by a strategy such as bilateral oophorectomy are not added in old age but during a woman’s most productive and active years. These benefits are highly dependent on the age at which the intervention is undertaken. The survival benefit of prophylactic mastectomy and oophorectomy declines from 4.9 years at age 30 to 2.3 years at age 40, but is only 0.2 years at age 60. Thus, the rewards of initiating prevention early seem to be considerable. Health care providers and patients may find Fig 2 a useful aid to decision-making about preventive strategies and their timing. Another important factor is penetrance. For women who have more than four first-degree relatives with breast or ovarian cancer, the penetrance may be 85% for breast cancer and 63% for ovarian cancer by age 70, and prophylactic mastectomy and oophorectomy may extend survival by 8.2 years beyond surveillance.14 In populations like that of Iceland, where the penetrance of BRCA2 mutations is 37% for breast cancer and 16% for ovarian cancer, the benefit is only 3.6 years.15 A third key factor is quality of life. Quality-adjusted survival differs from survival and takes into account the effects that women expect cancer states and preventive interventions to have on their day-to-day lives. Women who contemplate prophylactic surgery must take into account its long-term physical and psychological consequences relative to the physical, emotional, and economic effects of living with cancer. Women who undertake a preventive strategy must live with its effects whether or not it prevents them from developing cancer. In our previous study, women assigned similar preference ratings to breast cancer and to prophylactic mastectomy and higher ratings to chemoprevention.5 As a result, in our study, the quality-adjusted survival benefit for tamoxifen was higher than for mastectomy although the survival benefit of mastectomy was greater than that of tamoxifen. The highest quality-adjusted survival estimate was for women who had the combination of prophylactic oophorectomy and tamoxifen. Mortality also influences both survival and quality-adjusted survival. One of the limitations of our study is that we based our mortality estimates on data from SEER. The SEER database covers 14% of the United States population, but the population of the SEER counties has been found to be more affluent, more educated, and more rural than the overall population.43 Little is known about the mortality rate for women with breast or ovarian cancer secondary to BRCA1/2 mutations. We assumed that it would be the same as that reported by SEER for these cancers. However, we conducted a sensitivity analysis on the basis of the assumption that women with BRCA1/2 mutations would have a 10% higher mortality rate than those in the SEER database. This analysis found an even greater benefit for preventive strategies over surveillance alone (Table 3). Decision analysis in the absence of data requires assumptions. Our assumptions are based on the most recent relevant trials and observational studies and the advice of a group of academic oncologists. Additional observational studies and randomized trials are needed to assess the effectiveness of preventive strategies for women at risk for breast cancer, and a concerted effort needs to be undertaken to enroll BRCA1/2 carriers onto clinical trials, such as the Study of Tamoxifen and Raloxifene. Mutation carriers should also be encouraged to enroll onto registries that collect data on the outcomes of preventive interventions. As these research efforts bear fruit, we plan to continue incorporating the results into our model to help women with BRCA1/2 mutations evaluate preventive interventions and their timing.
Supported in part by grant no. CRTG-98-260-01 from the American Cancer Society, Atlanta, GA; Sindab African American Breast Cancer Project; the Avon Breast Cancer Research and Care Program; and the Breast Cancer Alliance. We thank Timothy Rebbeck, PhD, for sharing the results of his analysis with us.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
