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Benefits and Costs of Screening Ashkenazi Jewish Women for BRCA1 and BRCA2

From the Herbert Irving Comprehensive Cancer Center, School of Public Health, and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.

Address reprint requests to Victor Grann, MD, MPH, Director of Health Outcomes Research, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, PH18-201A, 630 West 168th St, New York, NY 10032; email vrg2{at}columbia.edu

	ABSTRACT

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PURPOSE: To determine the survival benefit and cost-effectiveness of screening Ashkenazi Jewish women for three specific BRCA1/2 gene mutations.

METHODS: We used a Markov model and Monte Carlo analysis to estimate the survival benefit and cost-effectiveness of screening for three specific mutations in a population in which their prevalence is 2.5% and the associated cancer risks are 56% for breast cancer and 16% for ovarian cancer. We assumed that the sensitivity and specificity of the test were 98% and 99%, respectively, that bilateral prophylactic oophorectomy would reduce ovarian cancer risk by 45%, and that bilateral prophylactic mastectomy would reduce breast cancer risk by 90%. We used Medicare payment data for treatment costs and Surveillance, Epidemiology, and End Results data for cancer survival.

RESULTS: Our model suggests that genetic screening of this population could prolong average nondiscounted survival by 38 days (95% probability interval, 22 to 57 days) for combined surgery, 33 days (95% probability interval, 18 to 43 days) for mastectomy, 11 days (95% probability interval, 4 to 25 days) for oophorectomy, and 6 days (95% probability interval, 3 to 8 days) for surveillance. The respective cost-effectiveness ratios per life-year saved, with a discount rate of 3%, are $20,717, $29,970, $72,780, and $134,273.

CONCLUSION: In this Ashkenazi Jewish population, with a high prevalence of BRCA1/2 mutations, genetic screening may significantly increase average survival and, depending on costs and screening/treatment strategies, may be cost-effective by the standards of accepted cancer screening tests. According to our model, screening is cost-effective only if all women who test positive undergo prophylactic surgery. These estimates require confirmation through prospective observational studies and clinical trials.

	INTRODUCTION

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THE PURPOSE OF CANCER screening is to prevent death from cancer at a reasonable cost.^1,2 Papanicolaou (Pap) smears for cervical cancer³ and mammography for breast cancer⁴ are believed to save lives at reasonable cost and have therefore been accepted by patients, health care providers, and most insurers. However, some screening procedures, such as mammography in women under the age of 50 years⁵ and the sixth stool guaiac examination for colon cancer,⁶ remain controversial because evidence that they reduce cancer mortality is weak.

Commercial tests for the BRCA1⁷ and BRCA2⁸ genes now provide specific information about risk for breast and ovarian cancer to patients who are generally free of cancer at the time of the test. The measures that positive screenees can take to prevent death from cancer are limited and invasive. Therefore, only patients who have a strong family history of breast and/or ovarian cancer are considered eligible for the tests for these genes. However, the finding that certain specific mutations are highly prevalent among Ashkenazi Jewish women and a better understanding of cancer risks⁹ have generated interest in more widespread use of genetic testing.

Recently, two independent groups^10,11 used decision analysis to demonstrate that prophylactic surgery could prolong survival among women who tested positive for three specific mutations, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. These mutations, reported to be associated with risks of 56% for breast cancer and 16% for ovarian cancer,⁷ appear to be present in 2.5% in the Ashkenazi Jewish population.¹² Many women in this population are now concerned about their genetic risk and options. Providers and insurers also confront the need to make choices while awaiting findings from prospective studies and clinical trials that have not yet begun. We have therefore used existing data on prevalence and risks to generate estimates of the effects on survival and the cost-effectiveness of screening for BRCA1 and BRCA2 in a population of Ashkenazi Jewish women unselected for a family history of breast or ovarian cancer. We have approached this question from a societal or public health perspective.

	METHODS

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We used a decision model of the health effects and costs associated with four alternative treatment strategies in BRCA1- or BRCA2-positive patients¹¹ to assess the costs and benefits of screening a large high-risk population, Ashkenazi Jewish women, from a public health perspective. We followed individuals from age 30 to age 80 years according to a Markov process.^13,14 For our reference case, we assumed that women were screened at age 30 and that the test was repeated for confirmation among women who tested positive. A patient was considered positive for one of the mutations only if both test results were positive; Myriad Genetics, which conducts most commercial BRCA1/2 testing, follows this procedure.

Among women who tested positive for mutations in BRCA1 or BRCA2, we examined the outcomes of four different prophylactic strategies: oophorectomy, mastectomy, oophorectomy and mastectomy, and surveillance alone¹¹ (Table 1). We assumed that patients who tested negative would receive a modified form of surveillance consisting of annual Pap smears, a mammogram at age 35, and annual mammograms from age 40. We incorporated time-dependent risks of breast cancer, ovarian cancer, and death from all causes for patients who tested positive and negative.^9,15 Because having breast physical examinations and mammography may affect survival by influencing stage at diagnosis, we assumed that 80% of women who developed breast cancer would be diagnosed in stage I or stage II.^10,16 We did not adjust for ovarian cancer screening, because there is no evidence that it alters the prognosis of this cancer.

Health Parameters
Using the estimates reported by Struewing et al⁹ of the age-dependent cumulative probabilities of developing breast cancer and ovarian cancer in Ashkenazi Jewish women who tested positive for three specific mutations of BRCA1 and BRCA2, we assigned to the reference case a 56% risk of breast cancer by age 70 and a 16% risk of ovarian cancer by age 70.

Data regarding the efficacy of prophylactic surgery are scarce and derived from studies conducted before genetic testing was available. We assumed that prophylactic oophorectomy would reduce the risk of developing ovarian cancer by 45%¹⁷ and that prophylactic mastectomy would reduce the risk of developing breast cancer by 90%.¹⁸

We obtained data on the sensitivity and specificity of the screening test from Myriad Genetics (data on file, Myriad Genetic Laboratories, Inc, Salt Lake City, UT). For the reference case, we assumed that the sensitivity of a single test for one of the three most common mutations among Ashkenazi Jewish women was 98% and that the specificity was 99%. With a mutation prevalence of 2.5%, and a policy of considering the patient positive for this mutation only if two test results were positive, the positive predictive value of the screening strategy in the reference case was 99.6% and the negative predictive value was 99.9%.

We obtained age-dependent breast cancer–specific mortality estimates from the National Cancer Institute's Surveillance, Epidemiology, and End Results program for 1973 to 1992.¹⁵

Cost Parameters
We assumed that gene testing for the three specific mutations found in patients of Ashkenazi Jewish ancestry would cost $450 (data on file, Myriad Genetic Laboratories). The lowest cost of testing for these mutations was assumed to be $200 (data on file, Yale University Comprehensive Cancer Center, New Haven, CT). The cost of a full-sequence analysis of BRCA1 and BRCA2 was assumed to be $2,400; Myriad Genetics, which supplied the cost information we used, repeats the test without charge for patients who initially test positive (data on file, Myriad Genetic Laboratories). We included a charge of $300 for genetic counseling. We based our estimates of other medical costs, including screening, surgical procedures, and treatments, on Medicare payments for 1995 from the Health Care Financing Administration as a proxy for costs.¹⁹ Drug costs for chemotherapy were obtained from the 1996 Fundamental Reference.²⁰ These study costs were further refined by whether or not the patient had prophylactic surgery¹¹ (Table 2). All costs were expressed in 1995 dollars. Indirect costs related to loss of earnings or other medical conditions were excluded.²¹

Discounting
In comparing treatment strategies for their effects on duration of survival, we valued each year alive as 1 with no discounting. However, in calculating costs per life-year saved, we used a discount rate of 3%, equivalent to the price of capital.²¹ In our sensitivity analyses, we also varied the discount rate from 2% to 4%.

Sensitivity Analysis
We performed one-way sensitivity analyses to test the potential effects of each assumption on our model results (Table 3). In addition to estimating survival and cost-effectiveness for our reference case risks of 56% for breast cancer and 16% for ovarian cancer by the age of 70, we also modeled these outcomes for risks of 40% for breast cancer and 6% for ovarian cancer and with risks of 73% for breast cancer and 40% for ovarian cancer. These values were based on the upper and lower confidence limits from the analysis by Struewing et al.⁹

We also incorporated prior uncertainty in a Bayesian probabilistic sensitivity analysis by defining posterior distributions for the uncertain parameters in our model (Table 3). We developed probability distributions on model parameters that were derived from the literature^17,18 for Monte Carlo simulations. To define probability intervals, we executed a set of 250 simulations for each of the four treatment strategies and for both survival and cost-effectiveness models, for a total of 2,000 simulations. For our base model, we assumed that women would have prophylactic surgery at age 30, but we also modeled outcomes for women given prophylactic surgery at age 40.

Screening and Follow-Up Care
We based our screening and follow-up strategies (Table 1) on recommendations from the Cancer Genetics Studies Consortium and the American Society of Clinical Oncology.^22,23

	RESULTS

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Table 4 summarizes the incremental survival and incremental costs of the four strategies for the entire cohort, assuming genetic testing only for the three specific Ashkenazi mutations, a positive test prevalence of 2.5%, and associated risks of 56% for breast cancer and 16% for ovarian cancer. The incremental survival is estimated at 6 days (95% probability interval, 3 to 8 days) for surveillance, 11 days (95% probability interval, 4 to 25 days) for oophorectomy, 33 days (95% probability interval, 18 to 43 days) for mastectomy, and 38 days (95% probability interval, 22 to 57 days) for combined prophylactic mastectomy and oophorectomy. The median discounted incremental cost-effectiveness ratios range from $20,717 per life-year for combined surgery to $134,273 for surveillance. The cost-effectiveness ratio is less than $50,000 per life-year in 98% of the simulations for combined surgery, 92% of the simulations for mastectomy, 28% of the simulations for oophorectomy, and none of the simulations for surveillance. Thus, genetic screening followed by any of the three prophylactic surgical strategies for the 2.5% who tested positive would, in our model, improve cost-effectiveness compared with surveillance. This means that women who test negative and those who test positive and elect to be followed with surveillance alone derive little benefit from having been screened.

We also found that the incremental cost is most influenced by the initial cost of the genetic test ($450) and counseling ($300) (Table 5). As an example, the cost-effectiveness ratios of testing for those who tested positive and elected combined surgery would be $20,717 for the $450 test, $65,427 for the $2,400 test, and only $14,869 for the $200 test.

Table 6 shows the effects of changing the penetrance of the mutations on the cost-effectiveness ratios associated with different treatment strategies. If the risk of breast cancer for positive screenees is 73%, the cost-effectiveness ratio of prophylactic mastectomy and oophorectomy is $14,376; if their risk is 40%, the ratio is $28,879. Given a 28% risk of ovarian cancer, the cost-effectiveness ratio for the same procedures is $18,246; and with a 6% risk, it is $22,636 (Table 6).

The benefits of testing are also influenced by the efficacy of prophylactic surgery. If the efficacy of prophylactic oophorectomy were 90% instead of 45%, the cost-effectiveness of oophorectomy would be $42,609 instead of $72,780; and if that of prophylactic mastectomy were decreased to 80% from 90%, the cost-effectiveness of mastectomy would be $33,128 instead of $29,970.

Table 7 shows the decrease in mortality associated with testing. Among 10,000 Ashkenazi Jewish women, screening at age 30 would avert 79 deaths from breast and ovarian cancer before age 80 if those who tested positive received both prophylactic mastectomy and oophorectomy. If positive screenees underwent prophylactic mastectomy alone, a cohort of 10,000 would experience 67 fewer deaths, whereas the cohort would experience nine fewer deaths if positive screenees underwent prophylactic oophorectomy. If positive screenees refused surgery and underwent surveillance alone, the cohort would avert only two deaths.

If women who tested positive delayed surgery until age 40, oophorectomy added 10 (instead of 11) days, prophylactic mastectomy 19 (instead of 33) days, and the combined procedures 26 (instead of 38) days to average survival (Table 8). The cost-effectiveness of oophorectomy increased by about 15%, but that of mastectomy or combined surgery nearly doubled.

	DISCUSSION

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The results of this study suggest that genetic screening (Table 7) compares favorably to routine mammography for breast cancer^4,5 and Pap smears for cervical cancer,³ in terms of per person benefit in a screened cohort compared with an unscreened cohort. If screenees who test positive choose combined prophylactic mastectomy and oophorectomy, screened women will survive, on the average, 38 days longer than unscreened women. This average gain is comparable to 43 days for mammography and 95 days for Pap smears.^3,5 Genetic screening followed by the two surgical procedures for positive screenees in this population may avert 79 cancer deaths per 10,000 tested, again comparing favorably with mammography, which averts 52 cancer deaths in 50- to 69-year-olds and six cancer deaths in 40- to 49-year-olds per 10,000 tested,⁵ to age 80. In our model, screening extended the life of each of the 79 persons who would die with cancer by 13.2 years on average.

The cost-effectiveness ratio of genetic screening is $20,717 per life-year saved if it leads to both prophylactic oophorectomy and mastectomy for positive screenees, $29,970 if it leads to mastectomy alone, and $72,780 if it leads to oophorectomy alone. These figures again compare favorably to the $21,400 per life-year saved by routine mammographic screening (Table 7) among women aged 50 to 69 years, $105,000 per life-year saved⁵ among women aged 40 to 49, and $55,000 per life-year saved for genetic screening for hereditary nonpolyposis colon cancer.²⁵

Of course, screening Ashkenazi Jewish women with a family history of cancer will have a higher yield than screening Ashkenazi Jewish women irrespective of family history.²⁶ However, many Ashkenazi Jews lack information about their family history because of: small family size, the Holocaust, or the historical taboo surrounding discussion of cancer. The purpose of this paper was to estimate the costs and benefits of screening members of ethnic groups in which BRCA1/2 mutations are highly prevalent, such as Ashkenazi Jews,²⁷ in the absence of family history information. More information is needed about cancer risk and cancer mortality among Ashkenazi Jews with and without BRCA1/2 mutations who have no family history of cancer or no information about such a history.

The assumptions used in this model are conservative. We assumed 100% compliance with routine mammographic screening for women not tested for BRCA1 and BRCA2. However, a compliance rate of 50% or lower may be more realistic (Table 1). Likewise, if surveillance alone is used for gene-positive women, no mortality benefit would be expected from ovarian cancer screening. It is possible that the use of ovarian cancer screening in the women who tested positive for BRCA1 or BRCA2 might prove beneficial and lead to better survival and cost-effectiveness. In addition, prophylactic surgery may prove more efficacious than 90% for breast cancer and 45% for ovarian cancer. If so, the survival and cost-effectiveness benefits associated with prophylactic surgery will be higher than our projections.

Like other screening evaluations, this article deals with the capacity of the intervention to prevent cancer death; our measures are years of life saved and costs per year of life saved.^3,5,22 Of course, in a setting in which the condition addressed by screening does not require immediate medical attention but may be psychologically, socially, or economically stigmatizing, quality of life is also a critically important concern. A recent study showed that among high-risk subjects with cancer-related stress symptoms at baseline, at 1-month follow-up, subjects who had declined genetic testing for BRCA1/2 mutations were more likely to be depressed, and subjects who had tested negative for these mutations less so, than they had been before.²⁸ Subjects with high stress at baseline who tested positive and those with low to moderate stress symptoms at baseline were neither more or less depressed, regardless of testing status. Taking the prevalence of mutations into account, these results suggest that the information gained from genetic testing may benefit the majority of Ashkenazi Jewish women (about 97.5%) who are likely to test negative and may also allay their fears for their children.^29,30

In a previous study, we showed that among patients with BRCA1/2 mutations, prophylactic surgery may have a negative impact on quality-adjusted survival, depending on the surgical strategy chosen and the penetrance of the mutations.²⁴ In the present analysis, we assumed that the test would improve quality of life in the screened population, mainly because 97.5% of screenees would learn that they did not have a high-risk form of the gene; we further assumed that the 2.5% who tested positive would not be in worse condition emotionally than they were before. We are currently studying preferences associated with testing.

Women of Ashkenazi Jewish ancestry who test positive may benefit from clarification of their personal risk-benefit and the cost-effectiveness of the attendant treatment options.^11,31 Genetic testing may help them to choose between increased surveillance and prophylactic mastectomy and oophorectomy for themselves and inform them about the appropriateness of genetic testing for their first-degree relatives. A majority (97.5%) of this cohort would test negative; we therefore expect testing to remain cost-effective when quality of life is incorporated.

For women who are screened, delaying oophorectomy until age 40 has little effect on survival days. Those who delay bilateral mastectomy or both surgical procedures until age 40 do not fare as well, although they still have better survival than an unscreened group. The delay reduces the benefits of these procedures because the risk of breast cancer is higher than that of ovarian cancer for women aged 30 to 40 who test positive.

The cost-effectiveness of genetic testing is determined by the prevalence of the gene mutations, the cost of the genetic testing, and the benefits of the treatment strategy chosen, but it is only slightly influenced by the unit cost of the diagnostic work-up or cancer treatment strategy.²⁵ The risks of cancer among those with the gene mutations also strongly influences the cost-effectiveness of screening in our model.

Treatment choices on the part of positive screenees have a profound effect on outcomes (Table 7). Among women who test positive for BRCA1 and BRCA2 mutations and elect to have prophylactic mastectomy and oophorectomy, mean survival may be extended by up to 6.0 years.¹¹ The corresponding number of women who need to be screened to save one life is 132, which compares to screening 192 women aged 50 to 69 and more than 1,500 women aged 40 to 49 with mammography.⁵

Our results show that the benefits and cost-effectiveness of prophylactic mastectomy are almost as great as those of combined prophylactic mastectomy and oophorectomy and more than double those of prophylactic oophorectomy alone (Table 7). The effects of these procedures differ in part because positive screenees have a 56% risk of developing breast cancer but only a 16% risk of developing ovarian cancer and because prophylactic mastectomy is assumed to reduce breast cancer risk by 90% (10% of 56% = 5.6%), but oophorectomy is assumed to reduce ovarian cancer risk by only 45% (55% of 16% = 9%). The effect of having both procedures is greater than that of having only mastectomy.

We are aware that women who have BRCA1 or BRCA2 inherited mutations may be at higher risk from other cancers if, because of testing and prophylactic surgery, they do not die of breast or ovarian cancer. The BRCA1 and BRCA2 mutations may also be associated with higher risks for colon and pancreatic cancers.¹² As women with these mutations age, they may be found to develop other as yet unknown disease states that may reduce the survival benefits of test-related treatment.

Ashkenazi Jewish women who do not have the Ashkenazi-specific mutations may still have a family history of breast cancer and/or another as yet unknown high-risk mutation. A variety of environmental factors (eg, smoking, physical activity) may also affect breast cancer risk in this population. Because we do not know the distribution of these factors in this population, we have assumed that women who test negative for the Ashkenazi-specific mutations have average risk—that of the general population—for breast cancer.

Our approach to analyzing the benefits of genetic breast/ovarian cancer screening for Ashkenazi Jewish women may help women in this population to make personal decisions with regard to genetic testing and subsequent therapy. It should also enable policy makers to compare screening with other health care interventions. Potential primary prevention medications such as tamoxifen³² and raloxifene³³ have been found to reduce breast cancer risk. However, their specific effects on breast cancer risk in BRCA1/2-positive women are as yet unknown, as are their costs and side effects. These agents or as yet undeveloped gene therapies may soon be available to women who test positive. New studies may better define the efficacy of surveillance and prophylactic surgeries. In the meantime, our model addresses the potential benefits and costs of genetic screening for this high-risk population and suggests reasonable gains in survival at a reasonable cost, depending on treatment strategies chosen, commensurate with the survival benefits and costs of currently accepted cancer screening strategies.

Depending on current knowledge and the treatment strategies chosen, our analyses suggest that it may be reasonable and cost-effective to screen average-risk Ashkenazi Jewish women for BRCA1 and BRCA2 mutations.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. CRTG-98-260-01 from the American Cancer Society, Atlanta, GA, and grant no. CA-66224 from the National Cancer Institute, Bethesda, MD.

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Submitted June 1, 1998; accepted October 23, 1998.

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