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A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer

Open ArchivePublished:February 22, 2017DOI:https://doi.org/10.1016/j.jval.2017.01.006

      Abstract

      Background

      The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing.

      Objectives

      To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy.

      Methods

      We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network–defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in BRCA1 and BRCA2 and the seven-gene test strategy for variants in BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, and PALB2. Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance.

      Results

      The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the BRCA1/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort.

      Conclusions

      Testing seven breast cancer–associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.

      Keywords

      Introduction

      Breast cancer is the most commonly diagnosed noncutaneous cancer and the second leading cause of cancer death among women in the United States. An estimate for 2015 predicted 231,840 new cases of breast cancer and 40,290 breast cancer deaths [
      American Cancer Society
      Breast Cancer Facts and Figures 2015–2016.
      ]. Women with a family history of breast cancer are at increased risk, with about 13% of women with breast cancer having one or more first-degree relatives with the disease [
      Collaborative Group on Hormonal Factors in Breast Cancer
      Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease.
      ]. Pathogenic variants in the BRCA1 and BRCA2 genes explain approximately 15% of the breast cancer familial relative risk (i.e., the ratio of the risk of an individual with an affected relative to the risk of individuals in the general population), whereas pathogenic variants in other genes, including TP53, PTEN, CDH1, and PALB2, contribute further to the familial relative risk for breast cancer [
      • Couch F.J.
      • Nathanson K.L.
      • Offit K.
      Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
      ].
      Women with a pathogenic variant in BRCA1 have a 65% chance of developing breast cancer by age 70 years, whereas those with a BRCA2 pathogenic variant have a 45% chance [
      • Antoniou A.
      • Pharoah P.D.
      • 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.
      ]. In contrast, women in the general population have a 7% chance of developing breast cancer [
      American Cancer Society
      Breast Cancer Facts and Figures 2015–2016.
      ]. Pathogenic variants in other breast cancer–associated genes can also confer substantial risk. For example, a recent study reported that women with a pathogenic variant in PALB2 have a 33% to 58% chance of developing breast cancer by age 70 years, a risk similar to that of women with a pathogenic variant in BRCA2 [
      • Antoniou A.C.
      • Casadei S.
      • Heikkinen T.
      • et al.
      Breast-cancer risk in families with mutations in PALB2.
      ]. Pathogenic variants in breast cancer–associated genes also increase the risk of developing ovarian and other cancers [
      • Couch F.J.
      • Nathanson K.L.
      • Offit K.
      Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
      ].
      For women whose lifetime risk of breast cancer is greater than 20%, the National Comprehensive Cancer Network (NCCN) guidelines recommend enhanced breast cancer surveillance by magnetic resonance imaging (MRI). The NCCN guidelines also recommend risk-reducing oophorectomy for BRCA1/2 carriers, and the NCCN Breast Cancer Risk Reduction Panel supports “the use of RRM [risk-reducing mastectomy] in carefully selected women at high risk for breast cancer who desire this intervention (e.g. women with a BRCA1/2, TP53, PTEN, CDH1 or STK11 mutation …)” [
      • Bevers T.B.
      • Ward J.H.
      • Arun B.K.
      • et al.
      Breast cancer risk reduction, version 2.2015.
      ]. These recommended procedures have been shown to confer substantial survival benefits on at-risk individuals [
      • Hartmann L.C.
      • Schaid D.J.
      • Woods J.E.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
      ,
      • Meijers-Heijboer H.
      • van Geel B.
      • van Putten W.L.
      • et al.
      Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.
      ,
      • Rebbeck T.R.
      • Friebel T.
      • Lynch H.T.
      • et al.
      Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
      ,
      • Sigal B.M.
      • Munoz D.F.
      • Kurian A.W.
      • et al.
      A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers.
      ]. For example, clinical studies have found that risk-reducing mastectomy can decrease the risk of developing breast cancer by more than 90% for women with a family history of breast cancer or with a pathogenic variant in BRCA1 or BRCA2 [
      • Hartmann L.C.
      • Schaid D.J.
      • Woods J.E.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
      ,
      • Meijers-Heijboer H.
      • van Geel B.
      • van Putten W.L.
      • et al.
      Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.
      ,
      • Rebbeck T.R.
      • Friebel T.
      • Lynch H.T.
      • et al.
      Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
      ]. And decision-analytic modeling has predicted that enhanced surveillance could increase life expectancy by 1.4 years for 50-year-old women who carry a pathogenic variant in BRCA1 and by 1.0 year if they carry a pathogenic variant in BRCA2 [
      • Sigal B.M.
      • Munoz D.F.
      • Kurian A.W.
      • et al.
      A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers.
      ]. Similarly, risk-reducing mastectomy could increase life expectancy by 2.8 years for BRCA1 carriers and by 2.0 years for BRCA2 carriers; younger women would receive greater survival benefits [
      • Sigal B.M.
      • Munoz D.F.
      • Kurian A.W.
      • et al.
      A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers.
      ].
      Genetic analysis is recommended for individuals at risk of hereditary breast cancer [
      National Comprehensive Cancer Network
      NCCN clinical guidelines in oncology.
      ,
      • Moyer V.A.
      US Preventive Services Task Force
      Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
      ]. Basic genetic testing for breast cancer detects pathogenic germline variants in the BRCA1 and BRCA2 genes, and the test results are used to guide the assessment and management of breast cancer risk. Newer testing options allow for the simultaneous analysis of expanded panels of genes, which include BRCA1/2 as well as other genes whose pathogenic variants confer moderate to high risk for breast cancer [
      • Kurian A.W.
      • Kingham K.E.
      • Ford J.M.
      Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment.
      ,
      • Shiovitz S.
      • Korde L.A.
      Genetics of breast cancer: a topic in evolution.
      ]. Recent clinical studies have found that testing with expanded gene panels identifies substantially more individuals with pathogenic variants in breast cancer–associated genes than does BRCA1/2 testing alone, and that the detection of these pathogenic variants in these genes can lead to clinical action [
      • Desmond A.
      • Kurian A.W.
      • Gabree M.
      • et al.
      Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment.
      ,
      • Kurian A.W.
      • Hare E.E.
      • Mills M.A.
      • et al.
      Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.
      ].
      For women at high risk of breast or ovarian cancer, BRCA1/2 testing followed by prophylactic surgery when test-positive has been found to be cost-effective compared with no BRCA1/2 testing [
      • Holland M.L.
      • Huston A.
      • Noyes K.
      Cost-effectiveness of testing for breast cancer susceptibility genes.
      ,
      • Li Q.
      • Cardeiro D.
      • Kaldate R.
      • et al.
      Cost effectiveness analysis of genetic testing for breast and ovarian cancer susceptibility genes (BRCA1/BRCA2).
      ,
      • Goodman A.
      BRCA1/2 genetic testing found cost-effective in current era.
      ]. This raises the question of whether testing with an expanded panel of breast cancer–associated genes is cost-effective compared with BRCA1/2 testing alone. In this study, we used a decision-analytic model to compare the relative cost and effectiveness of a seven-gene panel test strategy with a BRCA1/2 test strategy for women at risk of hereditary breast cancer.

      Methods

      Model

      The objective of this study was to inform the risk-reduction decisions of women at risk of hereditary breast cancer by comparing the effectiveness and lifetime costs of the use of either BRCA1/2 testing or seven-gene testing from a payer perspective. To this end, a decision-analytic model with Markov nodes was developed for hypothetical cohorts of 50-year-old and 40-year-old asymptomatic women with a family history of breast or ovarian cancer or other hereditary syndromes such as Li-Fraumeni syndrome and Cowden syndrome that predispose to breast cancer (Fig. 1). The model compares two strategies for detecting pathogenic genetic variants and using the test results to select appropriate breast cancer risk reduction: the usual care strategy tests for variants in the BRCA1 and BRCA2 genes (BRCA1/2 testing) and the other strategy tests for variants in the BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, and PALB2 genes (seven-gene testing). Individuals who carry a pathogenic variant in any one of these genes are considered test-positive; otherwise, they are considered test-negative. Women who test positive were assumed to receive genetic counseling and recommendations to follow the NCCN breast cancer risk-reduction guidelines [
      National Comprehensive Cancer Network
      NCCN clinical guidelines in oncology.
      ]. Specifically, women who test positive were assumed to either undergo annual surveillance by mammography and MRI till age 75 years or immediately undergo prophylactic risk-reducing mastectomy. Individuals who test negative were assumed to undergo annual surveillance by mammography till age 75 years.
      Fig. 1
      Fig. 1Decision-analytic model with Markov nodes. (A) Women at increased risk of breast cancer enter one of two test strategies and receive clinical recommendations on the basis of the test results. (B) The Markov model shows the four health states: well (no breast or ovarian cancer), breast cancer, ovarian cancer, and death. The logic nodes indicate that if patients survive in the breast cancer or ovarian cancer state for 5 years, they will return to the well state. The circle with an M indicates the Markov node, and the circle with an L indicates the logic node. MRI, magnetic resonance imaging; RRM, risk-reducing mastectomy.
      Patient outcomes were evaluated using a Markov model with a lifetime time horizon (lifetime limited to age 100 years) with a cycle length of 1 year (Fig. 1). The patients enter the model in the well state (i.e., no breast or ovarian cancer) and can remain in the well state, progress to breast or ovarian cancer, or die. Patients who survive breast or ovarian cancer for 5 years return to the well state and were assumed to have the same probability of developing breast or ovarian cancer (recurrent cancer rate) as did those in the well state who never had cancer. This recurrent cancer rate affects the model outcome only for the five-gene test-positive subgroup (groups that are BRCA1/2 test-positive or test-negative for all seven genes cancel out between the two strategies; see Fig. 1). This recurrent cancer rate is consistent with the rate (5%) reported by Bosco et al. [
      • Bosco J.L.
      • Lash T.L.
      • Prout M.N.
      • et al.
      Breast cancer recurrence in older women five to ten years after diagnosis.
      ] for the period between 5 and 10 years after breast cancer diagnosis, a rate that is on an annual basis similar to the base-case assumption (0.01196) for the five-gene test-positive group. The model does not allow patients to develop both breast and ovarian cancer because we assumed that this is a rare event. In health economics literature for breast cancer (e.g., [
      • Manchanda R.
      • Legood R.
      • Burnell M.
      • et al.
      Cost-effectiveness of population screening for BRCA mutations in Ashkenazi Jewish women compared with family history-based testing.
      ]), co-occurrence of breast and ovarian cancer is often not included in the modeling. Other studies (e.g., [
      • Anderson K.
      • Jacobson J.S.
      • Heitjan D.F.
      • et al.
      Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation.
      ]) considered that the risk of developing the two types of cancer is independent and consequently co-occurrence of breast and ovarian cancer is rare.

      Model Parameters

      Model parameters were based on peer-reviewed literature, Medicare fee schedules, and government agency program databases, as presented in Table 1 for the cohort of 50-year-old women. The frequencies of BRCA1 and BRCA2 carriers among the high-risk women were taken from a cross-sectional study of 46,276 women in the United States [
      • Hall M.J.
      • Reid J.E.
      • Burbidge L.A.
      • et al.
      BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.
      ]; the seven-gene panel test (BRCAvantage Plus, Quest Diagnostics) and the BRCA1/2 test were assumed to have equal sensitivity and specificity for the detection of pathogenic variants. Among BRCA1/2 noncarriers, the frequency of pathogenic variants in the five genes in the panel that are not BRCA1/2 was assumed to be 2.4% (21 of 874) in the base case. LaDuca et al. [
      • LaDuca H.
      • Stuenkel A.J.
      • Dolinsky J.S.
      • et al.
      Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.
      ] reported that among 874 BRCA1/2 noncarrier patients with breast and/or ovarian cancer or with a family history of breast or ovarian cancer, 21 had a pathogenic variant in the genes on the seven-gene panel test (14 of whom had a pathogenic variant in PALB2).
      Table 1Model parameters
      ParameterBase caseRangeDistributionReference
      Rates and probabilities
      BRCA1 carriers7.2%±50%Beta
      • Hall M.J.
      • Reid J.E.
      • Burbidge L.A.
      • et al.
      BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.
      BRCA2 carriers5.3%±50%Beta
      • Hall M.J.
      • Reid J.E.
      • Burbidge L.A.
      • et al.
      BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.
       Carriers of the other five genes among BRCA1/2 noncarriers2.4%±50%Beta
      • LaDuca H.
      • Stuenkel A.J.
      • Dolinsky J.S.
      • et al.
      Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.
       1-y probability of breast cancer
        BRCA1 carriers0.02284Fixed
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
        BRCA2 carriers0.01910Fixed
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
        Carriers of the other five genes0.011960.00950–0.01504Beta
      • Antoniou A.C.
      • Casadei S.
      • Heikkinen T.
      • et al.
      Breast-cancer risk in families with mutations in PALB2.
       1-y probability of ovarian cancer
        BRCA1 carriers0.02056Fixed
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
        BRCA2 carriers0.00751Fixed
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
       Prophylactic mastectomy when test-positive42%±50%Beta
      • Singh K.
      • Lester J.
      • Karlan B.
      • et al.
      Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers.
       Breast cancer risk reduction by prophylactic mastectomy90%70%–95%Lognormal
      • Rebbeck T.R.
      • Friebel T.
      • Lynch H.T.
      • et al.
      Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
       1-y probability of death from cancer (excluding other causes)
      • Ries L.A.G.
      • Young J.L.
      • Keel G.E.
      • et al.
      SEER survival monograph: cancer survival among adults: U.S. SEER Program, 1988–2001, patient and tumor characteristics.
        Breast cancer: age (y)
         50540.02151Mortality modifier
         55–590.02103Mortality modifier
         60–640.01961Mortality modifier
         65–690.01729Mortality modifier
         70–740.01502Mortality modifier
         75–790.01451Mortality modifier
         80–840.01368Mortality modifier
         ≥850.01583Mortality modifier
        Ovarian cancer: all ages0.10170Mortality modifier
        Mortality modifier1±25%Lognormal
       Relative risk of breast cancer mortality: MRI vs. no MRI0.7300.530–1.000Lognormal
      • Kurian A.W.
      • Munoz D.F.
      • Rust P.
      • et al.
      Online tool to guide decisions for BRCA1/2 mutation carriers.
       Relative risk of breast cancer detection: MRI vs. no MRI1.0941.000–1.197Lognormal
      • Kurian A.W.
      • Munoz D.F.
      • Rust P.
      • et al.
      Online tool to guide decisions for BRCA1/2 mutation carriers.
      Costs (2015 US dollars)
      BRCA1/2 test2,178Fixed
      Center for Medicare & Medicaid
       Seven-gene test (incremental over BRCA1/2 test)2400–800GammaQuest
       Consultation for test-positive331±50%Gamma
      • Anderson K.
      • Jacobson J.S.
      • Heitjan D.F.
      • et al.
      Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation.
       Mammography per year135±50%Gamma
      Center for Medicare & Medicaid
       MRI per year535±50%Gamma
      Center for Medicare & Medicaid
       Prophylactic mastectomy10,618±50%Gamma
      • Covidien
       Cancer treatment (annual)
      • Mariotto A.B.
      • Yabroff K.R.
      • Shao Y.
      • et al.
      Projections of the cost of cancer care in the United States: 2010–2020.
        Age <65 y
         Breast cancer—initial31,868Cost modifier
         Breast cancer—continuing2,540Cost modifier
         Breast cancer—last year108,499Cost modifier
         Ovarian cancer—initial113,682Cost modifier
         Ovarian cancer—continuing9,547Cost modifier
         Ovarian cancer—last year172,124Cost modifier
        Age ≥65 y
         Breast cancer—initial26,557Cost modifier
         Breast cancer—continuing2,540Cost modifier
         Breast cancer—last year72,333Cost modifier
         Ovarian cancer—initial94,736Cost modifier
         Ovarian cancer—continuing9,547Cost modifier
         Ovarian cancer—last year114,749Cost modifier
        Cancer treatment cost modifier1±50%Gamma
      MRI, magnetic resonance imaging.
      The 1-year probabilities of developing breast or ovarian cancer among BRCA1 and BRCA2 carriers were estimated from the cumulative cancer risk from age 50 to 70 years reported in a meta-analysis [
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
      ] using the conversion formula ps=1(1pt)st, where pt is the probability over time interval t and ps is the transition probability with a cycle length of s. The 1-year probability of developing breast cancer among women who test positive for the other five genes was based on the cumulative cancer risk from age 50 to 70 years for women who test positive for PALB2 (0.01196; 95% confidence interval 0.00950–0.01504) [
      • Antoniou A.C.
      • Casadei S.
      • Heikkinen T.
      • et al.
      Breast-cancer risk in families with mutations in PALB2.
      ]; breast cancer risk for other genes appears to be similar to or higher than that for PALB2 [
      • Shiovitz S.
      • Korde L.A.
      Genetics of breast cancer: a topic in evolution.
      ,
      • Pilgrim S.M.
      • Pain S.J.
      • Tischkowitz M.D.
      Opportunities and challenges of next-generation DNA sequencing for breast units.
      ]. The 1-year probabilities of dying from breast or ovarian cancer were estimated from the 5-year relative survival rates of the patients with cancer in the Surveillance, Epidemiology, and End Results program [
      • Ries L.A.G.
      • Young J.L.
      • Keel G.E.
      • et al.
      SEER survival monograph: cancer survival among adults: U.S. SEER Program, 1988–2001, patient and tumor characteristics.
      ] and the expected survival or the age-specific mortality in the life tables for females [
      • Arias E.
      • Curtin L.R.
      • Wei R.
      • et al.
      United States Decennial Life Tables for 1999–2001, United States Life Tables.
      ]. For age-specific mortality applied to all patients, the 2011 life tables for females were used [
      • Arias E.
      United States Life Tables, 2011.
      ].
      We assumed that the probability of choosing prophylactic mastectomy was the same for women with a positive test result in any of the seven genes as for BRCA1/2 carriers in the United States [
      • Singh K.
      • Lester J.
      • Karlan B.
      • et al.
      Impact of family history on choosing risk-reducing surgery among BRCA mutation carriers.
      ]. Breast cancer risk reduction from prophylactic mastectomy was set at 90% in the base case [
      • Hartmann L.C.
      • Schaid D.J.
      • Woods J.E.
      • et al.
      Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
      ,
      • Meijers-Heijboer H.
      • van Geel B.
      • van Putten W.L.
      • et al.
      Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.
      ,
      • Rebbeck T.R.
      • Friebel T.
      • Lynch H.T.
      • et al.
      Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
      ]. Compared with routine surveillance with mammography alone, enhanced surveillance with MRI and mammography was assumed to result in increased detection of breast cancer and reduced mortality from breast cancer. The additional cases of breast cancer detected and the relative risk of breast cancer mortality for women undergoing enhanced surveillance compared with women undergoing routine surveillance were estimated using the decision tool for women with BRCA mutations (http://brcatool.stanford.edu/brca.html) [
      • Kurian A.W.
      • Munoz D.F.
      • Rust P.
      • et al.
      Online tool to guide decisions for BRCA1/2 mutation carriers.
      ]; we used this decision tool to derive the number of cases and death from breast cancer at age 70 years for BRCA2 carriers undergoing enhanced or routine surveillance starting from age 50 to 54 years.
      Costs were from a payer perspective and are presented in Table 1 in 2015 US dollars. Costs for the BRCA1/2 test, mammography, and MRI surveillance were based on the 2015 Medicare clinical laboratory fee schedule [
      Center for Medicare & Medicaid
      ]. Cost for the seven-gene test was provided by Quest Diagnostics. Cost for genetic consultation was based on Anderson et al. [
      • Anderson K.
      • Jacobson J.S.
      • Heitjan D.F.
      • et al.
      Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation.
      ]. Costs for mastectomy were based on 2014 mastectomy and breast reconstruction Medicare reimbursement coding and included physician fees for mastectomy (Current Procedural Terminology [CPT] code 19303) and breast construction (CPT code 19340) and the average of the costs for the hospital outpatient and ambulatory surgical center; the total cost was then further adjusted by a modifier of 150% for bilateral mastectomy [
      • Covidien
      ]. Costs for cancer treatment were from Mariotto et al. [
      • Mariotto A.B.
      • Yabroff K.R.
      • Shao Y.
      • et al.
      Projections of the cost of cancer care in the United States: 2010–2020.
      ]. All costs that were not in 2015 dollars were inflated to year 2015 dollars according to the consumer price index for medical care (https://research.stlouisfed.org/).
      Model parameters for the cohort of 40-year-old women were the same as for the cohort of 50-year-old women except the following. The 1-year probability of breast cancer was 0.02219 for BRCA1 carriers and 0.01799 for BRCA2 carriers, and the 1-year probability of ovarian cancer was 0.01581 for BRCA1 carriers and 0.00580 for BRCA2 carriers. These probabilities were based on the cumulative cancer risk from age 40 to 70 years reported in a meta-analysis [
      • Chen S.
      • Parmigiani G.
      Meta-analysis of BRCA1 and BRCA2 penetrance.
      ]. The 1-year probability of breast cancer for women who test positive for the other five genes was assumed to be the same as that for PALB2 carriers, which was 0.01231 (95% confidence interval 0.00934–0.01581) on the basis of the cumulative cancer risk from age 40 to 70 years [
      • Antoniou A.C.
      • Casadei S.
      • Heikkinen T.
      • et al.
      Breast-cancer risk in families with mutations in PALB2.
      ]. In addition, the 1-year probability of death from breast cancer (excluding other causes) was 0.02504 for women of age 40 to 44 years and 0.02166 for women of age 45 to 49 years [
      • Ries L.A.G.
      • Young J.L.
      • Keel G.E.
      • et al.
      SEER survival monograph: cancer survival among adults: U.S. SEER Program, 1988–2001, patient and tumor characteristics.
      ].
      For quality-of-life adjustment, the following health state utility scores were based on the health economics evaluation in the National Institute for Health and Care Excellence clinical guideline for familial breast cancer [
      National Collaborating Centre for Cancer
      Familial Breast Cancer: Full Cost Effectiveness Evidence Review and Reports (June 2013).
      ]: 0.9 for the well state, 0.68 for the breast cancer state, and a health state utility decrement of 0.03 for the year that risk-reducing mastectomy is performed and a decrement of 0.05 for the year that a positive gene panel test result is received. The ovarian cancer health state utility score of 0.65 was based on Anderson et al. [
      • Anderson K.
      • Jacobson J.S.
      • Heitjan D.F.
      • et al.
      Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation.
      ].

      Base-Case Analysis

      All analyses were carried out using TreeAge Pro software 2015 (TreeAge Software, Williamstown, MA). In the base case, we estimated health outcomes in life expectancy, quality-adjusted life-year (QALY), and health care costs projected over a patient’s lifetime. Because of the complexity and differing opinions in the literature on how to define the utility of the various health states [
      • Peasgood T.
      • Ward S.E.
      • Brazier J.
      Health-state utility values in breast cancer.
      ], we present both life expectancy and QALYs as outcome measures. We applied a 3% discount to QALYs but not life expectancy. Health care costs were from a payer perspective. Total costs were the sum of the costs for genetic testing, genetic consultation, prophylactic surgery, MRI surveillance, mammography, and treatment of breast cancer. The incremental cost of the seven-gene test strategy, compared with the BRCA1/2 test strategy, is due to the higher cost of the seven-gene test and the increased costs from prophylactic surgery and enhanced surveillance. These increased costs were partially offset by the cost savings due to the lower breast cancer incidence and lower mortality due to prophylactic mastectomy and enhanced surveillance. Future costs were discounted by 3% per year.

      Sensitivity Analysis

      The robustness of the outcomes to uncertainties in the parameter estimates was examined by sensitivity analyses. Table 1 presents the ranges of the parameters explored. The risk of pathogenic BRCA1/2 variants for breast and ovarian cancer was not varied in the sensitivity analysis because costs and outcomes would be the same in both test strategies and therefore would not affect the incremental cost-effectiveness ratio (ICER). Nevertheless, the risk for breast cancer among carriers of the five genes in the panel that are not BRCA1/2 was varied to assess how the risk affected the ICER. Breast cancer mortality differs by age, and so we explored the sensitivity of our outcomes to the breast cancer mortality parameter by exploring a range of mortalities for each age range (Table 1). This was done by multiplying the base-case mortality for each age range by a mortality modifier that ranged from 0.75 to 1.25. The same mortality modifier was used to explore the sensitivity of the outcomes to ovarian cancer mortality. Similarly, because cancer treatment cost differs by stage, we explored the sensitivity of the cost-effectiveness to the cancer treatment cost parameters by multiplying the base-case cost for each stage of cancer (Table 1) by a cost modifier that ranged from 0.5 to 1.5. For probabilistic sensitivity analysis in a Monte-Carlo simulation, all parameters were drawn from their probability distributions and were assumed to be uncorrelated. Beta distributions were used for probability inputs, gamma distributions were used for costs, and lognormal distributions were used for relative risk and mortality modifiers.

      Results

      Base Case

      In the base-case scenario for a cohort of 50-year-old women at elevated risk of breast cancer, the seven-gene test strategy cost $282 more per woman tested and increased life expectancy by 0.007 year, compared with BRCA1/2 testing (Table 2). This translates into an ICER of $42,067 per life-year gained. For a cohort of 40-year-old women at high risk of breast cancer, the seven-gene test strategy cost $276 more per woman tested and increased life expectancy by 0.012 year, which translates into an ICER of $23,734 per life-year gained. When taking quality of life into consideration, the ICER for the seven-gene test strategy was $69,920 per QALY gained for the 50 year-old cohort and $48,328 per QALY gained for the 40-year-old cohort (Table 2).
      Table 2Base-case outcome
      Cohort (age)StrategyCost ($/patient)Life expectancyQALYs
      LY gainedICER ($/LY gained)QALYs gainedICER ($/QALY gained)
      40 yBRCA1/223,95441.375Reference20.622Reference
      Seven-gene24,23141.38723,73420.62848,328
      50 yBRCA1/222,87032.419Reference17.931Reference
      Seven-gene23,15232.42642,06717.93569,920
      ICER, incremental cost-effectiveness ratio; LY, life-year; QALY, quality-adjusted life-year.

      Sensitivity Analysis

      We explored how the uncertainty of the model parameters affected the ICER in a deterministic sensitivity analysis (Fig. 2). The parameter that had the largest effect on the ICER was the incremental cost of the seven-gene test over the BRCA1/2 test; for example, the ICER for the seven-gene test strategy compared with the BRCA1/2 test strategy would be $5666 per life-year gained if the seven-gene test cost the same as the BRCA1/2 test. When considering other cost parameters, the costs for cancer treatment, MRI, and prophylactic mastectomy had a larger effect on the cost-effectiveness outcome than did the costs for mammography and genetic consultation.
      Fig. 2
      Fig. 2Deterministic sensitivity analysis of model parameters for the 50-year-old cohort. The ICERs based on the upper and lower boundaries of the input parameters are represented by the red and blue bars, respectively. BC, breast cancer; ICER, incremental cost-effectiveness ratio; MRI, magnetic resonance imaging; OC, ovarian cancer; RRM, risk-reducing mastectomy.
      For noncost parameters, those with the largest effect on the ICER were the proportion of women who chose prophylactic mastectomy, the proportion of women who tested positive for a pathogenic variant in the five genes in the panel that are not BRCA1/2, the mortality rate of breast and ovarian cancer, and the risk of breast cancer in patients with a pathogenic variant in the five additional genes (Fig. 2). The higher the proportion of women who test positive for a pathogenic variant in the five additional genes, the lower the ICER (Fig. 2, Fig. 3). Similarly, the higher the risk conferred by pathogenic variants in the five additional genes, the lower the ICER (Fig. 2, Fig. 3). The ICER for the seven-gene test strategy compared with the BRCA1/2 test strategy for the 50-year-old cohort would be $101,026 per life-year gained if the risk of breast cancer for women who carry a pathogenic variant in the five genes was half of the base-case value and would be $21,564 per life-year gained if the risk of breast cancer for women who carry a pathogenic variant in the five genes was 50% higher than the base-case value. The relationship between breast cancer risk and test-positive rate for the five additional genes according to the willingness-to-pay threshold of $100,000 per life-year gained is shown in Figure 3C. And the higher the frequency of women who test positive for a pathogenic variant in the five additional genes, the lower the breast cancer risk of these pathogenic variants that would be required to meet the willingness-to-pay threshold (Fig. 3C).
      Fig. 3
      Fig. 3One-way and two-way sensitivity analyses for the 50-year-old cohort. (A) Effect of the frequency of pathogenic variants in the five genes among BRCA1/2 noncarriers on the ICER. (B) Effect of the average breast cancer risk in BRCA1/2 noncarriers with a pathogenic variant in the five genes on the ICER. (C) Two-way sensitivity analysis. At a willingness-to-pay threshold of $100,000/life-year gained, the seven-gene test strategy would be preferred if the values of the two parameters were in the blue-shaded area, whereas the BRCA1/2 test strategy would be preferred if the values of the two parameters were in the red-shaded area. ICER, incremental cost-effectiveness ratio.
      We next conducted a probabilistic sensitivity analysis using Monte-Carlo simulations. On the basis of 10,000 iterations, the seven-gene test strategy could cost from $6 less to $1115 more per woman tested and could result in an increase in life expectancy by 0.003 to 0.015 year compared with the BRCA1/2 test strategy (Fig. 4A). And in 95.7% of the Monte-Carlo iterations, the seven-gene test strategy had an ICER of less than $100,000 per life-year gained (Fig. 4B).
      Fig. 4
      Fig. 4Probabilistic sensitivity analysis for the seven-gene test strategy compared with the BRCA1/2 test strategy for the 50-year-old cohort. (A) The scatter plot shows the incremental life-years and the incremental cost in Monte-Carlo simulations (n = 10,000) in which model parameters were randomly sampled from their probability distributions. The base-case outcome is shown by a white cross. (B) The cost-effectiveness acceptability curve shows the probability of the seven-gene test strategy being cost-effective vs. the willingness-to-pay threshold.
      Finally, we examined the effect of adherence of the test-positive patients to the NCCN guidelines on cost-effectiveness outcomes. For this purpose, we modified the decision tree such that patients who test positive for a pathogenic variant in any of the seven genes either adhere to the NCCN guidelines (i.e., choose risk-reducing mastectomy or undergo enhanced breast cancer surveillance) or do not adhere to the guidelines but rather undergo mammography only. One-way sensitivity analysis revealed that the higher the adherence rate, the lower the ICER (see Appendix Figure 1 in Supplemental Materials found at doi:10.1016/j.jval.2017.01.006). The ICER would increase to $78,157 per life-year gained for the 50-year-old cohort if the adherence rate to the NCCN guidelines was 50% among those who test positive for a pathogenic variant in any of the seven genes.

      Discussion

      This analysis suggests that genetic testing using next-generation sequencing of a seven-gene panel followed by risk-reduction procedures recommended by the NCCN guidelines could extend life expectancy of women at risk of hereditary breast cancer at an acceptable cost compared with genetic testing of the BRCA1 and BRCA2 genes alone. In the base-case scenario for 50-year-old and 40-year-old women undergoing genetic testing, the ICERs for the seven-gene test strategy compared with the BRCA1/2 test strategy were $42,067 and $23,734 per life-year gained or $69,920 and $48,328 per QALY gained, respectively. At these ICER levels, the seven-gene test strategy would be considered cost-effective according to the World Health Organization guidelines [
      • Anderson J.L.
      • Heidenreich P.A.
      • Barnett P.G.
      • et al.
      ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines.
      ,

      World Health Organization. Cost effectiveness and strategic planning (WHO-CHOICE). Available from: http://www.who.int/choice/costs/CER_levels/en/#. [Accessed December 17, 2015].

      ]. This approach would compare favorably with, for example, annual MRI for high-risk women, which was estimated to have an ICER of $179,600 per QALY gained [
      • Moore S.G.
      • Shenoy P.J.
      • Fanucchi L.
      • et al.
      Cost-effectiveness of MRI compared to mammography for breast cancer screening in a high risk population.
      ].
      Multigene panel testing can cost-effectively improve the outcome of cancer treatment compared with testing of a single gene or variant [
      • Li Y.
      • Bare L.A.
      • Bender R.A.
      • et al.
      Cost effectiveness of sequencing 34 cancer-associated genes as an aid for treatment selection in patients with metastatic melanoma.
      ,
      • Gallego C.J.
      • Shirts B.H.
      • Bennette C.S.
      • et al.
      Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis.
      ] and can cost-effectively help to identify at-risk patients for early health interventions [
      • Dinh T.A.
      • Rosner B.I.
      • Atwood J.C.
      • et al.
      Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population.
      ,
      • Kilambi V.
      • Johnson F.R.
      • Gonzalez J.M.
      • et al.
      Valuations of genetic test information for treatable conditions: the case of colorectal cancer screening.
      ]. Although BRCA1 and BRCA2 tests are the most commonly recommended genetic tests for breast cancer risk, pathogenic variants in other genes have been increasingly recognized as important contributors to the development of breast cancer [
      National Comprehensive Cancer Network
      NCCN clinical guidelines in oncology.
      ]. Our deterministic sensitivity analysis indicates that the more frequently the other pathogenic variants are detected, the more cost-effective multigene panel testing would become (Fig. 3A). Consequently, expanding the test panel to include additional breast cancer–associated genes would be desirable, assuming that the identification of a pathogenic variant in these additional genes could support effective risk-reducing recommendations. And as many as 11.4% of BRCA1/2 noncarriers were found to carry a pathogenic variant in other genes by multigene panels [
      • Kurian A.W.
      • Hare E.E.
      • Mills M.A.
      • et al.
      Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.
      ,
      • LaDuca H.
      • Stuenkel A.J.
      • Dolinsky J.S.
      • et al.
      Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.
      ,
      • Kapoor N.S.
      • Curcio L.D.
      • Blakemore C.A.
      • et al.
      Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer.
      ,
      • Tung N.
      • Battelli C.
      • Allen B.
      • et al.
      Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.
      ].
      A limitation of this analysis is that the risk for breast cancer is less well established for carriers of pathogenic variants in the five genes in the panel that are not BRCA1/2 (TP53, PTEN, CDH1, STK11, and PALB2) than it is for BRCA1/2 carriers. In the base case we assumed that carriers of a pathogenic variant in these five genes had the same risk for breast cancer as did the PALB2 carriers [
      • Pilgrim S.M.
      • Pain S.J.
      • Tischkowitz M.D.
      Opportunities and challenges of next-generation DNA sequencing for breast units.
      ]. Similarly, another limitation of this study is that the risk of dying from cancer may differ according to the pathogenic variants carried. For example, the risk of death among women with breast cancer was reported to be 2 times higher for those with certain pathogenic variants in PALB2 (509_510delGA or 172_175delTTGT) than for those without these variants [
      • Cybulski C.
      • Kluzniak W.
      • Huzarski T.
      • et al.
      Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis.
      ]. In the base case we have assumed that patients with breast cancer with a pathogenic variant in the genes tested are at the same risk of dying as are patients with breast cancer in general. We have not modeled a higher mortality rate for certain PALB2 variants (which would decrease the ICER for the seven-gene test strategy compared with BRCA1/2 test strategy) because the relative risk of death is unknown for those who carry other pathogenic variants in PALB2 or variants in the other four non-BRCA1/2 genes. Nevertheless, results from base-case and sensitivity analyses provide a health economic rationale for including testing of these other pathogenic variants in the management of breast cancer risk for women at high risk. This conclusion is consistent with the assertion by Long and Ganz [
      • Long E.F.
      • Ganz P.A.
      Cost-effectiveness of universal BRCA1/2 screening: evidence-based decision making.
      ] that “… bundling BRCA testing with other cancer-associated genes, such as p53 or PALB2, could further improve cost-effectiveness estimates, although more information is needed about the long-term risks of cancer associated with such rare mutations.”
      Several other limitations of this analysis should be noted. First, we have focused on the health outcome in life expectancy, an objective measurement that has been used in a number of decision modeling and health economics analyses for breast cancer [
      • Sigal B.M.
      • Munoz D.F.
      • Kurian A.W.
      • et al.
      A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers.
      ,
      • Kerlikowske K.
      • Salzmann P.
      • Phillips K.A.
      • et al.
      Continuing screening mammography in women aged 70 to 79 years: impact on life expectancy and cost-effectiveness.
      ,
      • Grann V.R.
      • Whang W.
      • Jacobson J.S.
      • et al.
      Benefits and costs of screening Ashkenazi Jewish women for BRCA1 and BRCA2.
      ,
      • Schrag D.
      • Kuntz K.M.
      • Garber J.E.
      • et al.
      Decision analysis—effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations.
      ]. Nevertheless, to facilitate comparison of our findings to other health economics analyses that report QALY-based outcomes for breast cancer, we have also adjusted the life-year gains by health state utilities. Such comparisons, however, should be interpreted with caution given the large variations in breast cancer–related health utility scores in the literature [
      • Peasgood T.
      • Ward S.E.
      • Brazier J.
      Health-state utility values in breast cancer.
      ]. Second, given that analytic sensitivity and specificity of the next-generation sequencing tests are very high [
      • Strom C.M.
      • Rivera S.
      • Elzinga C.
      • et al.
      Development and validation of a next-generation sequencing assay for BRCA1 and BRCA2 variants for the clinical laboratory.
      ], we did not consider false positives and false negatives resulting from genetic testing itself. Third, we did not model the uncertainty arising from the identification of variants of uncertain significance (VUS) in the five additional genes [
      • Lerner-Ellis J.
      • Khalouei S.
      • Sopik V.
      • et al.
      Genetic risk assessment and prevention: the role of genetic testing panels in breast cancer.
      ]. Nevertheless, although detection of VUS in these genes could create some anxiety, future reclassification of any of these VUS to pathogenic variants [
      • Balmana J.
      • Digiovanni L.
      • Gaddam P.
      • et al.
      Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing.
      ] could increase the test-positive rate for the five additional genes and consequently decrease the ICER for the seven-gene test strategy compared with the BRCA1/2 test strategy. Fourth, because the women had opted for genetic testing, we assumed in the base case that those who test positive for a pathogenic variant would adhere to the current NCCN guidelines and, when opting for prophylactic surgery, would do so immediately after the genetic test. In practice, some women who test positive may choose not to undergo prophylactic surgery or enhanced surveillance and may choose to receive delayed prophylactic surgery. Sensitivity analysis, however, shows that the seven-gene test strategy remained cost-effective at a willingness-to-pay threshold of $100,000 per life-year gained even when only half of the patients who test positive for a pathogenic variant in any of the seven genes adhere to the NCCN guidelines. Fifth, we did not consider other types of cancers that might be caused by pathogenic variants in the expanded panel of genes in our modeling. Identification of these pathogenic variants from testing an expanded panel of genes (but not from the BRCA1/2 testing) could lead to clinical action and likely increased life expectancy. For example, women with a pathogenic variant in CDH1 could reduce their risk of colon cancer by periodic colonoscopy.

      Conclusions

      Compared with genetic testing of BRCA1/2 alone, testing seven breast cancer–associated genes, followed by risk-reduction management plans, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.

      Acknowledgments

      Source of financial support: This study was supported by Quest Diagnostics.

      Supplemental Materials

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