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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 854-863 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.158 HER-2 Testing and Trastuzumab Therapy for Metastatic Breast Cancer: A Cost-Effectiveness AnalysisFrom the Harvard University Center for Risk Analysis and School of Public Health, Cambridge; the Department of Adult Oncology, Dana-Farber Cancer Institute; and the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA Address reprint requests to Elena B. Elkin, PhD, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 44, New York, NY 10021; e-mail: elkine{at}mskcc.org
PURPOSE: Trastuzumab therapy has been shown to benefit metastatic breast cancer patients whose tumors exhibit HER-2 protein overexpression or gene amplification. Several tests of varying accuracy and cost are available to identify candidates for trastuzumab. We estimated the cost-effectiveness of alternative HER-2 testing and trastuzumab treatment strategies. PATIENTS AND METHODS: We performed a decision analysis using a state-transition model to simulate clinical practice in a hypothetical cohort of 65-year-old metastatic breast cancer patients. Outcomes were quality-adjusted life-years (QALYs), lifetime cost, and incremental cost-effectiveness ratio (ICER). Interventions included testing with the HercepTest (DAKO, Carpinteria, CA) immunohistochemical assay alone, fluorescence in situ hybridization (FISH) alone, and both tests, followed by trastuzumab and chemotherapy for patients with positive test results and chemotherapy alone for patients with negative test results. RESULTS: In the base case, initial HercepTest with FISH confirmation of all positive results had an ICER of $125,000 per QALY gained. The incremental cost-effectiveness of initial FISH was $145,000 per QALY gained. Other strategies yielded the same or poorer effectiveness at a higher cost, or lower effectiveness at a lower cost, but with a less favorable ICER. These findings persisted under a range of assumptions, and only changes in test characteristics substantially altered results. CONCLUSION: It is more cost-effective to use FISH alone or as confirmation of all positive HercepTest results, rather than using FISH to confirm only weakly positive results or using HercepTest alone. When multiple tests are available to identify treatment candidates, test characteristics may have a substantial impact on the aggregate costs and effectiveness of treatment.
Trastuzumab (Herceptin; Genentech, San Francisco, CA), approved by the United States Food and Drug Administration (FDA) in 1998 for the treatment of metastatic breast cancer, preferentially targets tumor cells that overexpress the human epidermal growth factor receptor-2 protein (HER-2/neu), a product of the HER-2 oncogene. Among the estimated 20% to 30% of metastatic breast cancer patients whose tumors overexpress HER-2 [1,2], trastuzumab combined with chemotherapy significantly improves objective response rate, time until disease progression, and overall survival, compared with chemotherapy alone [3]. The effectiveness of a targeted intervention depends on the identification of potentially responsive patients. In clinical practice, HER-2 testing is limited to immunohistochemical assays (IHC) to detect protein overexpression and fluorescence in situ hybridization (FISH) to detect gene amplification. Currently two IHC assay kits (HercepTest; DAKO, Carpinteria, CA; and Pathway; Ventana Medical Systems, Tucson, AZ) and one FISH assay (PathVysion; Vysis, Downers Grove, IL) have FDA approval for the selection of trastuzumab recipients. Another FISH assay (INFORM; Ventana Medical Systems, Tuscon, AZ) is approved as a prognostic tool. IHC has been advocated as the primary test for identifying trastuzmab candidates because it is readily available and easily performed in most clinical pathology labs, it is relatively inexpensive, and it tests for overexpression of trastuzumab's therapeutic target, the HER-2 protein. In addition, patients in the randomized clinical trial of trastuzumab were selected by IHC. However, despite efforts to standardize assay protocol and interpretation, antibodies and methods vary across laboratories, and IHC scoring remains inherently subjective. A number of studies have cast doubt on interrater [4-8] and interlaboratory [9-14] reliability of IHC results. Compared with IHC, FISH is more expensive, time-consuming, and labor-intensive. Despite these constraints, FISH is appealing because of its objective and quantitative scoring system. More importantly, FISH is more predictive than IHC of response to trastuzumab [15-18]. Consequently, FISH has been advocated to confirm some or all positive IHC results [19-21]. The additional costs associated with using FISH must be weighed against the savings that result from avoiding treatment of women with false-positive IHC results. Test choice also affects aggregate effectiveness, which is maximized when all women likely to benefit from trastuzumab receive it. We performed a cost-effectiveness analysis of trastuzumab therapy by examining the costs and benefits of alternative HER-2 testing strategies, including the use of FISH either as the primary test or to confirm IHC results.
Model We developed a Markov state-transition model to evaluate the long-term effectiveness and cost of seven strategies for identifying and treating metastatic breast cancer patients with HER-2-positive tumors (Table 1). Outcomes were quality-adjusted life expectancy and lifetime direct costs attributable to breast cancer.
The decision model simulated outcomes for each test-treat strategy in a hypothetical cohort of 65-year-old women newly diagnosed with metastatic breast cancer. As depicted in Figure 1, once on treatment, patients could transition to one of four health states: (1) response to therapy (complete or partial response); (2) stable disease; (3) progressive disease; or (4) dead. At the end of each 1-week cycle, women moved among these health states as determined by treatment- and HER-2–specific transition probabilities.
We assumed that any objective response to therapy (ie, complete or partial reduction of tumors) would occur within the first 18 weeks of treatment. First-line therapy was discontinued on disease progression, and we assumed that no patient received more than eight cycles of chemotherapy. Patients were expected to receive subsequent treatment regimens after disease progression, but mortality in the progressive disease state did not depend on initial treatment or HER-2 status. Death due to breast cancer was only possible among women with progressive disease, and death resulting from other causes was possible in any state. Incremental cost-effectiveness analysis was performed by ranking the seven strategies in order of increasing effectiveness. After eliminating strategies that were more or equally costly and less effective than a competing strategy (ie, ruled out by simple dominance), the incremental cost-effectiveness ratio (ICER) of each strategy was calculated as the additional cost of that strategy divided by its additional benefit, compared with the next most effective strategy. If a strategy was less effective and had a higher ICER than another strategy, it was ruled out by extended dominance [22]. Strategies exhibiting extended dominance were eliminated from the rank-ordered list, and ICERs of the remaining strategies were recalculated.
Data Many studies have compared IHC and FISH [20,21,24-45], but few have used an FDA-approved IHC kit with adherence to the standardized protocol described by the test's manufacturer. We identified 10 studies that compared HercepTest with FISH, used in accordance with the test manufacturers' instructions, on a series of unselected cases, and reported results in adequate detail for our analysis (Table 2) [5,14,19,46-52]. In the base case, we used the average test characteristics, with each study's estimate weighted by the respective sample size of FISH-positive and FISH-negative cases. We assumed that FISH was a gold standard for HER-2 status.
Prognosis of Metastatic Breast Cancer We derived transition probabilities (Table 3) primarily from the only randomized trial of trastuzumab plus chemotherapy versus chemotherapy alone in women with HER-2-overexpressing metastatic breast cancer [3]. HER-2 levels were measured with a research-use-only IHC assay, and eligibility was limited to patients with a weakly-positive or strongly-positive result. Although patients in the trial received either paclitaxel or an anthracycline-cyclophosphamide regimen, our model assumed that all patients received paclitaxel, given that anthracycline-based therapy is associated with a much greater risk of cardiac toxicity among patients receiving trastuzumab [3,54].
In the absence of treatment with trastuzumab, HER-2 overexpression and gene amplification are correlated with more aggressive disease, shorter time to relapse, and poorer overall survival [1,2,53,55,56]. We modeled the probabilities of response and disease progression as a function of treatment regimen and HER-2 status. In a subgroup analysis of the trastuzumab randomized trial, the benefit of trastuzumab in terms of response rate was greater among patients with a positive FISH result than found in the trial as a whole [15,16]. Response rates were nearly equivalent among patients with a negative FISH result. Thus we assumed that trastuzumab provided no additional benefit in the absence of HER-2 gene amplification. We verified our transition probabilities by calibration with end points of the trastuzumab randomized trial. We simulated the trial using a first-order Monte Carlo technique, assuming that 76% of patients in each treatment arm were HER-2 positive by FISH [16]. The entering cohorts in the calibration model were 54 years old, the median age in the clinical trial. We iteratively adjusted the transition probabilities until the calibration model produced results that approximated trial end points and were stable with repeated simulations. We did not calibrate our transition probabilities to the median survival end point for the chemotherapy alone arm of the trial, because two thirds of patients initially randomly assigned to this arm crossed over to trastuzumab after disease progression. The final transition probabilities derived from the calibration model were used in the cost-effectiveness model. All calculations were performed using DATA 4.0 software (TreeAge, Williamstown, MA).
Quality of Life
In clinical trials and postmarketing studies, trastuzumab has been associated with an increase in severe cardiac dysfunction and a very small risk of fatal infusion-related allergic reaction [70]. We explored the impact of these adverse effects in sensitivity analysis.
Costs We obtained pharmaceutical costs from the 2002 Drug Topics Red Book [62]. In the base case, trastuzumab and paclitaxel were valued at 95% of their average wholesale price, reflecting the Medicare reimbursement rate for chemotherapy drugs infused in the outpatient setting [71,72]. Drug dosages corresponded to those administered in the trastuzumab clinical trial using the average height and weight of US adult women. Infusion services and physician visits were valued at their Medicare reimbursement amounts. We assumed that patients saw an oncologist once every 3 weeks during the course of treatment and that all patients received standard premedication before every paclitaxel infusion. The average cost of treating chemotherapy-related side effects was based on a published cost-effectiveness analysis of paclitaxel [58]. The cost of round-trip travel for each infusion was valued at $11 per visit, based on the standard mileage rate for calculating tax-deductible business travel, [64] and an assumption that patients traveled 30 miles per visit. Patient time spent in treatment was valued using average annual earnings data collected in the March supplement to the Current Population Survey [65]. We assumed that patients on trastuzumab received a multiple-gated acquisition scan or echocardiogram at baseline and 16 weeks later to monitor their cardiac function. These scans were valued at their Medicare reimbursement amounts. The cost of treating progressive disease was $390 per week, representing the cost of care averaged over initial, continuing, and terminal phases of treatment for metastatic disease [66]. Costs are expressed in 2002 US dollars. Medicare relative value units, geographic practice components, and laboratory fees were obtained from the 2002 National Physician Fee Schedule [60] and from the 2002 Clinical Laboratory Fee Schedule [61]. Medicare reimbursement amounts represent an average across geographic areas. In the base case, costs and QALYs were discounted by 3% annually.
The most effective strategies in the base-case analysis yielded 1.37 QALYs (Table 5). Compared with chemotherapy alone, this represents an average gain of approximately one quality-adjusted life-month (QALM). Of these strategies, FISH testing followed by trastuzumab for patients with a positive result cost $54,700 per patient and yielded 16.41 QALMs. HercepTest followed by trastuzumab for 2+ and 3+ results was less effective and more expensive than FISH, and no test with trastuzumab for all patients had identical effectiveness and higher cost than FISH. These two strategies were therefore ruled out by simple dominance. HercepTest with FISH confirmation of 2+ results was also ruled out by simple dominance because it was equally effective but more costly than HercepTest with FISH confirmation of 2+ and 3+ results. HercepTest with trastuzumab for 3+ results yielded 16.05 QALMs at a cost of $51,200. Since this strategy was less effective than HercepTest with FISH confirmation of 2+ and 3+ results, but had a higher ICER, it was eliminated by extended dominance.
Only two strategies were not ruled out by simple or extended dominance. Compared with no testing and treatment with chemotherapy alone, HercepTest with FISH confirmation of 2+ and 3+ results had an ICER of $125,000 per QALY gained. Compared with that strategy, FISH alone had an ICER of $145,000 per QALY gained.
Sensitivity Analysis In additional sensitivity analyses, we altered the assumption that the benefits of trastuzumab cease on disease progression by reducing the mortality rate in the progressive disease state among HER-2 positive patients who initially received trastuzumab. We also evaluated the impact of trastuzumab-related adverse effects, including a 5% incidence of symptomatic congestive heart failure and a 0.04% risk of infusion-related allergic reaction. In these analyses the same strategies were eliminated by simple and extended dominance, and the ICERs of the two remaining strategies were similar to the base-case results. The cost of FISH did not substantially alter results within the range of values we initially specified (Table 4). However, when the cost of FISH was at least $1,680 greater than the cost of HercepTest, the strategy of HercepTest with no FISH confirmation and trastuzumab for patients with a 3+ result was no longer ruled out by extended dominance. This strategy was less effective than the other two nondominated strategies, and it had an ICER of $131,000 per QALY gained, compared with no testing and chemotherapy alone, when the difference in test costs was $1,680. The ICER for FISH alone was $272,000 per QALY gained, compared with HercepTest followed by FISH confirmation of 2+ and 3+ results. The cost-effectiveness ranking of strategies changed only when the diagnostic characteristics of HercepTest varied. To explore the effect of test characteristics on outcomes, we replaced HercepTest in the model with a hypothetical IHC the results of which were categorized as positive or negative. We assumed this IHC had the same cost as HercepTest, and FISH remained the gold standard. Testing strategies evaluated were no test, IHC alone, IHC with FISH confirmation of positive results, and FISH alone. We assumed trastuzumab was given to patients deemed HER-2 positive by each test system. We simultaneously varied IHC sensitivity and specificity in two-way sensitivity analysis. Figure 2 shows the relationship between the incremental cost-effectiveness of nondominated strategies and IHC sensitivity for three values of IHC specificity. With a specificity of 100% (Fig 2A), the incremental cost-effectiveness of IHC compared with no testing and chemotherapy alone was approximately $124,000 per QALY gained as IHC sensitivity varied between 50% and 100%. The ICER of FISH alone increased from $129,000 per QALY gained when IHC sensitivity was 50%, to more than $450,000 per QALY gained when IHC sensitivity was 99%. At all values of IHC specificity, FISH alone was dominated if IHC sensitivity was 100%.
IHC followed by FISH confirmation of positive results (IHC + FISH) dominated IHC alone if the specificity of IHC was less than 99.6%, regardless of IHC sensitivity. Below this specificity threshold, the ICER of IHC + FISH remained relatively constant for varying values of IHC sensitivity (Figs 2B and 2C). When IHC specificity was 60% (Fig 2C) and IHC sensitivity was less than 70%, IHC + FISH was ruled out by extended dominance. Although the ICER of FISH alone rose with increasing values of IHC sensitivity, at each value of IHC sensitivity, the ICER of FISH alone declined with decreasing values of IHC specificity. Assuming IHC was less expensive than FISH, test cost had no qualitative impact on these results.
We used a decision-analytic model to estimate the incremental cost-effectiveness of different strategies for identifying and treating women with HER-2–positive metastatic breast cancer. In our base case, the only nondominated testing strategies were HercepTest with FISH confirmation of 2+ and 3+ results and FISH alone, with ICERs of $125,000 and $145,000 per QALY gained, respectively. These ratios are higher than those of many standard breast cancer treatments [58,73-76]. However, if we are willing to pay for trastuzumab for metastatic breast cancer at all, we must be willing to pay for one of these testing strategies, because the alternative is no testing and trastuzumab for all patients—a clearly dominated option. Several widely accepted cancer therapies have ICERs similar to or higher than those found here. Pamidronate for metastatic breast cancer, axillary lymph node dissection in women with small breast tumors, erythropoietin for chemotherapy-associated anemia, and ondansetron for cisplatin-induced nausea and vomiting have ICERs from $120,000 to more than $500,000 (in 2002 dollars) [77-80]. Although we have no official threshold for decision-making, evidence suggests that in the United States, societal willingness to pay for health improvements is at least $100,000 per QALY gained and is probably even higher [81]. Recognizing the low specificity of HercepTest, especially for weakly positive results, and the high overall concordance between IHC and FISH, some have advocated the strategy of HercepTest with FISH confirmation only of weakly positive (2+) results [19-21]. We found that this strategy was dominated by HercepTest with FISH confirmation of all positive (2+ and 3+) results. Except for changes in test characteristics, reasonable variations in model parameters did not affect the ranking of strategies. Two-way sensitivity analysis on IHC test characteristics demonstrated that the higher the false-positive rate of IHC, the more cost-effective it is to use FISH alone to select trastuzumab candidates. Assuming IHC specificity is less than 100%, IHC alone is a dominated option, so FISH is worthwhile alone or as confirmation of positive IHC results. Moreover, if we are willing to pay for IHC with FISH confirmation, we should be willing to pay for FISH alone unless IHC sensitivity exceeds approximately 96%, given that these two strategies have similar ICERs below this threshold. Among the 10 studies that compared HercepTest and FISH (Table 2), only one had a specificity of 100% using a 2+ positivity criterion, and this study had a sample size less than 70 [51]. With a 3+ positivity criterion, three additional studies found a HercepTest specificity of 100% [19,48,49]. However, the 95% CI on the weighted average of the false-positive rate (ie, the probability of a 3+ HercepTest result conditional on a negative FISH result) did not include zero, suggesting that 100% specificity is unlikely. There is also a trade-off between specificity and sensitivity. The four studies that found perfect specificity using a 3+ cutoff generally found low sensitivity (41%, 58%, 61%, and 82%). Of the nine studies with imperfect specificity using a 2+ cutoff, the one with the highest specificity (98%) found the lowest sensitivity (70%) [46]. Several limitations of our analysis warrant mention. We assumed that the response rates for FISH-positive and FISH-negative patients estimated from the trastuzumab randomized trial were independent of IHC result, even though all trial participants were HER-2–positive by IHC. The potential bias caused by this assumption is ambiguous, although it is unlikely to substantially alter our conclusions, in that evidence suggests FISH is a better predictor than IHC of response to trastuzumab [15-18]. We assumed that FISH is a gold standard for HER-2 amplification. Although other molecular diagnostic techniques have been used as gold standards [42], they require frozen tissue and are therefore poorly suited for routine clinical use. Both FISH and IHC can be performed on formalin-fixed, paraffin-embedded archival material. More importantly, only FISH and IHC have been linked to outcomes of the trastuzumab randomized trial. Our analysis excludes the possibility that single-gene copy HER-2 overexpressers benefit from trastuzumab. In studies using frozen tissue, single-gene HER-2 overexpression has been identified in 3% to 8% of breast tumors [24,82,83]. Pauletti et al [32] found that the prognosis of single-gene overexpressers was statistically indistinguishable from patients who were HER-2–negative by both IHC and FISH. Although the HER-2 protein is trastuzumab's putative target, the likelihood that single-gene overexpressers will respond to trastuzumab is unknown. We used average Medicare reimbursements as a proxy for test costs, although true costs may vary widely among pathology laboratories. In a separate analysis, we estimated the costs of FISH and HercepTest by summing the individual costs of materials, technician time, and pathologist time, using published values, national occupational earnings data, and an institutional cost-accounting system. The resulting estimates were similar to the Medicare reimbursement amounts. We did not consider recent technological and policy developments that may alter the current HER-2 testing debate. Computerized image analysis and quantitative interpretation of IHC assays [56,84,85], chromogenic in situ hybridization [86,87], and central laboratory processing of FISH and IHC [11,13] could affect both the costs and accuracy of these tests, requiring reanalysis of the cost-effectiveness of alternative testing strategies. Our analysis demonstrates the importance of considering both testing and treatment when estimating the cost-effectiveness of a biologically targeted intervention. From a societal perspective, the diagnostic performance of the test used to identify trastuzumab candidates has considerable influence on cost-effectiveness, independent of test cost, due to the high cost of treating patients with false-positive test results and the missed opportunity for patients with false-negative results to benefit from trastuzumab. As the development of pharmacogenomic and biologically targeted therapies accelerates, it will be increasingly important to weigh the costs and benefits of these interventions [88,67]. Cost-effectiveness information may be particular useful given the current lack of consensus regarding HER-2 testing. Among nations with HER-2 testing guidelines, most advocate IHC, and only the Danish guidelines specifically stipulate the use of HercepTest [89]. The American Society of Clinical Oncology recommends HER-2 evaluation of all primary breast cancers at the time of diagnosis or recurrence, but a specific method is not suggested [90]. The College of American Pathologists has also refrained from endorsing a particular assay [91]. Our base-case analysis suggests that a policy of IHC with FISH confirmation of all positive results is not dominated by any alternative. From a societal perspective, this strategy would only be preferable to FISH alone if our willingness to pay for a 1-year gain in quality-adjusted survival is in the narrow range of $125,000 to $145,000. Otherwise, if treatment with trastuzumab is considered worth the cost, then initial testing with FISH should be as well.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Eric Winer, Genentech; Stuart Schnitt, Genentech.
Supported by a grant (T15LMO7092) from the National Library of Medicine Research Training Program in Medical Informatics. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
4 or if the average ratio of HER-2 signals to chromosome 17 centromere signals is 
