Annals of Oncology Advance Access originally published online on December 6, 2007
Annals of Oncology 2008 19(3):487-495; doi:10.1093/annonc/mdm488
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breast cancer |
Cost-effectiveness of HER2 testing and 1-year adjuvant trastuzumab therapy for early breast cancer
1 Medical Management Centre, Karolinska Institutet, Stockholm
2 European Health Economics, Stockholm
3 Centre for Health Economics, Stockholm School of Economics, Stockholm
4 Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden
* Correspondence to: Dr M. Lidgren, European Health Economics, Vasagatan 38, 111 20, Stockholm, Sweden. Tel: +46-8-545-28-540; Fax: +46-8-545-28-549; E-mail: mathias.l{at}healtheconomics.se
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Abstract |
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Background: Clinical studies have demonstrated statistically significant reduction of breast cancer relapse and improved overall survival by adding trastuzumab for 1 year after adjuvant chemotherapy in human epidermal growth factor receptor-2 protein (HER2)/neu-positive breast cancer. The aim of this study was to analyze the cost-effectiveness of HER2/neu testing and the addition of 1-year adjuvant trastuzumab after adjuvant chemotherapy from a societal perspective in a Swedish setting.
Material and methods: We used a Markov state transition model to simulate HER2/neu testing and adjuvant trastuzumab treatment in a hypothetical cohort of early breast cancer patients.
Results: The cost per quality adjusted life year (QALY) gained for immunohistochemical (IHC) testing for all patients with FISH confirmation of IHC 2+ and 3+ and 1-year adjuvant trastuzumab for FISH-positive patients was estimated to 
36 000. The strategy of FISH testing for all patients, with 1-year adjuvant trastuzumab for FISH-positive patients was associated with the longest quality adjusted survival of all evaluated treatment strategies and the cost per QALY gained was estimated to 41 500. The remaining testing and treatment strategies were dominated.
Conclusion: FISH testing for all patients with 1-year adjuvant trastuzumab for FISH+ patients is a cost-effective treatment option from a societal perspective.
Key words: adjuvant, breast cancer, cost-effectiveness, cost-utility, QALY, trastuzumab
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introduction |
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TopAbstractintroductionmaterial and methodsresultsdiscussionconclusionfundingAcknowledgementsReferences |
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Breast cancer is the most common malignant cancer among women in Europe, with
370 000 patients being diagnosed each year. Breast cancer is also the most common cause for cancer death in Europe, with 130 000 deaths [1]. In Sweden, there is 7000 new breast cancer diagnosis [2] and 1500 women die of breast cancer each year [3], making it the most common type of female cancer in Sweden. About 10%–30% of breast cancers either overexpress the human epidermal growth factor receptor-2 protein (HER2/neu) or have an amplification of the HER2 oncogene, or both [4–6]. Trastuzumab (Herceptin, Roche, Basel, Switzerland) is a humanized monoclonal antibody against the HER2 protein. Trastuzumab has been shown to benefit patients with HER2-positive metastatic breast cancer when given as a monotherapy [7, 8] or in combination with chemotherapy [9, 10]. Due to the positive results of trastuzumab on metastatic breast cancer, studies evaluating trastuzumab in the adjuvant setting were initiated. These studies have shown a highly significant lower risk of recurrence and improved survival in women with HER2-positive early breast cancer treated with adjuvant trastuzumab [11–15] in addition to adjuvant chemotherapy therapy.
Due to scarce resources in the health care system, and the substantial cost of trastuzumab treatment, it is important to evaluate the cost-effectiveness of adjuvant treatment with trastuzumab. However, there are still relatively few economic evaluations of adjuvant trastuzumab available. The study by Kurian et al. [16] found that adding 1 year of adjuvant trastuzumab treatment to adjuvant chemotherapy had an incremental cost-effectiveness ratio (ICER) of about $ 40 000 ( 32 100) per quality adjusted life year (QALY) gained when compared with adjuvant chemotherapy without trastuzumab. The study by Liberato et al. [17] estimated the cost per QALY gained to 14 900 and $ 19 000 ( 15 200), for the Italian and USA setting, respectively, for adding 1 year of adjuvant trastuzumab to adjuvant chemotherapy compared with no additional adjuvant trastuzumab. A report by Kunnskapssenteret (Norwegian Knowledge Centre for the Health Services) estimated the cost per life year gained to 152 000 NOK ( 19 000) for adding 1 year of adjuvant trastuzumab compared with no additional adjuvant trastuzumab for women with early breast cancer that have received adjuvant chemotherapy [18].
The National Institute for Health and Clinical Excellence (NICE) has also carried out a cost-effectiveness analysis of adding 1 year of adjuvant trastuzumab compared with no additional adjuvant trastuzumab for women with early breast cancer that have received adjuvant chemotherapy. The analysis by the NICE evidence review group estimated the cost per QALY gained to £ 18 000 ( 26 300) [19].
Due to the relatively small number of economic evaluations concerning adjuvant trastuzumab treatment and the substantial additional drug cost associated with this treatment, more knowledge about the cost-effectiveness of adjuvant trastuzumab is needed. Information on cost-effectiveness is important as a basis for developing guidelines for an optimal use of resources for patients with breast cancer. Present studies are limited in terms of the setting of the study (USA, Italy, and UK), the perspective of the study (only direct costs are used), and data used for assessing effectiveness, costs and outcome. The aim of the study is therefore to carry out a cost-effectiveness analysis of the addition of 1-year adjuvant trastuzumab after adjuvant chemotherapy for patients with early breast cancer, based on a societal perspective in a Swedish setting, using a new and updated set of data. Costs are expressed in 2005 Euro, converted from SEK using the average European Central Bank exchange rate for 2005. (1 = 9.282 SEK; 1 = 8.009 NOK; 1 = 0.684 £; and 1 = 1.244 $;)
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material and methods |
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cost-effectiveness analysis
In cost-effectiveness analysis the costs and effects of two or more interventions are compared. Effects are expressed in nonmonetary units, such as life years (LYs) gained or QALYs gained. In order for the results of a cost-effectiveness analysis to be useful for decisions about resource allocation in health care, the ICER of the different interventions should be calculated [20]. The ICER is defined as the ratio of the difference in cost to the difference in effect between two comparators: ICER = (Ca–Cb)/(Ea–Eb), where Ci is the cost and Ei is the effect of intervention i.
A treatment alternative can be dominated for two reasons. The first reason is usually referred to as ‘simple dominance’, and arises when a treatment is less effective and more costly compared with an alternative treatment. The second alternative is when a treatments ICER is higher than that of another treatment. This is usually referred to as ‘extended dominance’.
model
A model is useful when there is a need to combine data from various sources, such as clinical trials, epidemiological databases, and cost studies. Models are also useful when there is a need to extrapolate clinical trial results beyond the time frame of the clinical trials. In order to estimate lifetime costs, lifetime effects, and cost-effectiveness of different strategies of HER2 testing and adjuvant trastuzumab treatment for early breast cancer patients, we chose to construct a Markov state transition model. The model assumed that all patients had a completely excised breast cancer and already finished their adjuvant chemotherapy before the model started. Since the adjuvant chemotherapy was assumed to be identical for all patients and to have been finished before the model started, the cost of adjuvant chemotherapy was not included in the model. In total, five different strategies were evaluated using the model. Strategy 1 consisted of no HER2 testing and no additional adjuvant trastuzumab treatment. The strategy of adjuvant chemotherapy with no additional adjuvant trastuzumab will subsequently be referred to as ‘standard care’. The remaining four strategies consisted of different HER2 testing and adjuvant trastuzumab treatment strategies. The different strategies are presented in Table 1.
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The model uses yearly cycles and consists of five different states: ‘no recurrence’, ‘locoregional recurrence’, ‘contralateral recurrence’, ‘distant recurrence’, and ‘dead’. All patients start in the state ‘no recurrence’ where they either receive 1 year of adjuvant trastuzumab treatment or no additional adjuvant therapy (standard care). In the state ‘no recurrence’ patients can transition to anyone of the other states, or remain in ‘no recurrence’. Patients in the state ‘locoregional recurrence’ can remain in that state, or make a transition to ‘distant recurrence’ or ‘dead’. Similarly, patients in the state ‘contralateral recurrence’ can remain in that state, or make a transition to ‘distant recurrence’ or ‘dead’. The first year in either ‘locoregional recurrence’ or ‘contralateral recurrence’ is associated with a cost and utility that reflect the additional treatment patients undergo due to their recurrence. The second and following years in either ‘locoregional recurrence’ or ‘contralateral recurrence’ patients have an annual cost and utility similar to patients in ‘no recurrence’.
In the state, ‘distant recurrence’ patients can either make a transition to ‘dead’, or remain in that state. In the base case scenario, the reference patient was a 55-year-old woman with early breast cancer that had been completely excised and treated with at least four cycles of adjuvant chemotherapy. Costs and effects were discounted at 3%. The model was created using DATA Pro Suite 2006 (TreeAge, Williamstown, MA). The model is depicted in Figure 1.
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HER2 testing
In clinical practice, HER2 status of tumors is usually determined using either immunohistochemical (IHC) tests, or FISH tests, or both. IHC tests use antibodies to localize specific proteins in cells of a tissue section. Specimens are scored semiquantitatively as to the intensity of membrane immunostaining on a four-point scale, with 0 indicating absence of staining, 1+ indicating the lowest level of detectable staining and/or nonhomogeneous weak staining, 2+ indicating moderate homogeneous membrane staining, and 3+ indicating intense homogeneous membrane staining [21]. FISH is a technique that can be used to determine the number of gene copies, in this case the HER2 oncogene. If the average HER2 gene copy number in relation to chromosome 17 centromere copy number is
2, or if the average number of HER2 gene copies per tumor cell nucleus is 4, then the FISH test is considered positive for HER2 gene amplification [22]. Studies indicate that FISH is the best predictor of trastuzumab response [23–25]. Because of this, we assumed that any benefit from trastuzumab treatment was derived in the presence of HER2 gene amplification. We have used the overview found in the article by Elkin et al. [26] to estimate the IHC test results of FISH-positive and FISH-negative patients.
risk of recurrence and survival
The risk of recurrence and mortality in the model has been based on a sample of 20 624 Swedish breast cancer patients (data on file). We used a Weibull regression to estimate the risks and the mortality of locoregional recurrence, contralateral cancer and distant recurrence [27]. The Weibull survivor S(t) function is defined according to: 
, where p and 
are nonnegative parameters to be estimated. When p = 1, the Weibull distribution reduces to the exponential with a constant hazard rate and if p > 1 (p < 1) the hazard rate is monotonically increasing (decreasing) in t. To introduce covariates in the model, in the equations above is replaced by 
. In our model, we used age as a covariate. The estimated cumulative 5, 10, and 20 year risks are given in Table 2. HER2-positive patients are know to have an increased risk of recurrence. Based on the findings by Joensuu et al. [13], the risk of distant recurrence for HER2-positive patients was assumed to be twice as high compared with HER2-negative patients. The mortality risk for patients in the ‘no recurrence’ state was not based on a Weibull regression, but was instead estimated based on Swedish life-tables [28] and breast cancer mortality estimates [3].
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Our estimates of the effectiveness of 1 year of adjuvant trastuzumab were based on the Herceptin Adjuvant (HERA) trial (Breast International Group 0101) [11, 15]. The HERA trial found an improved disease-free survival (absences of breast cancer recurrence, contralateral breast cancer, breast cancer related death, and nonbreast cancer-related death) for HER2-positive patients receiving adjuvant trastuzumab for 1 year after adjuvant chemotherapy compared with chemotherapy alone. These findings are consistent with the result of similar studies [12–14]. Outcome in terms of survival and QALY was calculated from the effect of 1-year adjuvant trastuzumab on the risk of having a locoregional recurrence, a contralateral recurrence, or a distant recurrence, and the absolute risk in our observation cohort of patients was thus multiplied with the hazard ratio of 0.64 (95% confidence interval 0.54–0.76) reported in the HERA trial. This risk reduction was only applied for HER2-positive patients in the ‘No recurrence’ state receiving 1 year of adjuvant trastuzumab. In the base case scenario, the duration of treatment effect was assumed to persist throughout the entire lifetime of the patient. Different scenarios of duration of treatment effect were evaluated in one-way sensitivity analysis.
costs of adjuvant trastuzumab treatment
Based on the HERA study we assumed trastuzumab was administered using an 8 mg/kg loading dose followed by 6 mg/kg every third week, for a total of 17 cycles. We estimated the resulting drug cost using the average height (1.66 m) and weight (67 kg) of Swedish women [29] and drug prices obtained from the Swedish pharmaceutical reference book [30]. Each cycle of 6 mg/kg trastuzumab was estimated to cost 2055. This gave a total drug cost of trastuzumab of 36 298 for 1 year of adjuvant treatment (including a loading dose of 8 mg/kg). This may be an overestimation of the trastuzumab drug cost if effectiveness is estimated for intention-to-treat, and some patients do not follow the full treatment schedule. Since trastuzumab is administered as an IV infusion, we assumed that each cycle of trastuzumab treatment required an outpatient visit to an oncology clinic, resulting in an additional outpatient cost of 2899 during the year of adjuvant trastuzumab [31]. Patients receiving adjuvant trastuzumab were assumed to have additional cardiac monitoring in the form of eight Multiple-Gated Acquisition Scans. The total additional cost of cardiac monitoring was estimated to 1559. In the HERA trial, adjuvant trastuzumab was associated with an increased cardiotoxicity, with 2.1% of the patients in the trastuzumab arm suffering symptomatic congestive heart failure. We assumed that patients with symptomatic congestive heart failure would need to be investigated by a cardiologist. The additional cost of hospitalization used to reflect this increase in adverse events for adjuvant trastuzumab was based on diagnosis-related group 127 (heart failure and shock), which had a unit cost of 3453 [32, 33]. The additional cost of cardiac monitoring and treatment of adverse effects was thus estimated to 1633 per patient, which is added to the treatment cost of adjuvant trastuzumab. The unit cost for the IHC test and the FISH test were gathered from an official price list of a large university hospital [34].
direct costs of breast cancer
The annual direct costs associated with different breast cancer states included in the model were based on a naturalistic study that estimated inpatient costs, outpatient costs, and informal care costs for Swedish breast cancer patients [31]. Patients in the terminal phase of metastatic breast cancer are usually discharged from hospitals and receive palliative care either in their home or in a palliative care institution.
This care is not included in the estimate of inpatient and outpatient cost, since it is financed by the municipality and takes place outside the hospitals. We included the cost of palliative care in our model as a one-time cost for patients dying of breast cancer when in the state ‘Distant recurrence’. The additional cost of palliative care was estimated to 6813 [31, 35].
indirect costs of breast cancer and future costs
Indirect costs for different breast cancer disease states included in the model were also based on the naturalistic study by Lidgren et al. [31]. These indirect costs represent the loss of productivity due to breast cancer in the different disease states, and the value of the productivity loss was estimated using the human capital approach [36]. Indirect costs relates to morbidity of breast cancer at different stages. However, changes in survival may also change costs not related to breast cancer, which is usually referred to as future costs (or costs of added years in life), and represent the difference between consumption and production. Our estimates for future costs in different age categories for the general Swedish population have been derived from a study by Ekman et al. [37]. The impact of the inclusion of future costs in the model is explored in one-way sensitivity analysis.
quality of life
QALYs are estimated by multiplying the time spent in each health states with a weight reflecting the quality of life in that health state. The health related quality of life (HRQoL) in the different states in the model were based on Swedish population HRQoL data [38], adjusted for a reduction in HRQoL due to breast cancer disease derived from a study by Lidgren et al. [39]. The study by Lidgren et al. was used to estimate a percentage decline in HRQoL compared with the general age- and sex-matched population for each disease state. This reduction was then applied in the model to the general population values. The utility reductions used in the model are given in Table 3. For patients suffering from symptomatic congestive heart failure, we assumed that their utility was reduced by 50% for 6 months [40, 41].
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results |
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In the base case analysis, the least effective and the least costly strategy was standard care for all patients (strategy 1), which was associated with a cost of
115 200 and yielded 11.020 QALY. The strategies of using IHC testing for all patients with 1-year adjuvant trastuzumab for 3+ patients (strategy 2), was ruled out by extended dominance. IHC testing for all patients, with 1-year adjuvant trastuzumab for 2+ and 3+ patients (strategy 3), was ruled out by simple dominance. The strategy of IHC testing for all patients with FISH confirmation of 2+ and 3+ and 1-year adjuvant trastuzumab for FISH-positive patients (strategy 4) was associated with a cost of 124 600 and yielded 11.282 QALY, resulting in an ICER of 36 000/QALY when compared with strategy 1. This was the lowest ICER of the different strategies evaluated. The most effective strategy in the base case was FISH testing for all patients, with 1-year adjuvant trastuzumab for FISH-positive patients (strategy 5). This strategy was associated with a cost of 125 000 and yielded 11.304 QALY, giving it an ICER of 41 500/QALY when compared with strategy 4. Results are presented in Table 4.
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Using the cost per life year gained as the unit of effect instead of QALYs in the base case scenario, the ICER for strategy 4 was estimated to
26 800/LY and the ICER for strategy 5 was estimated to 30 900/LY.
subgroup analysis
We carried out subgroup analysis of the cost-effectiveness of 1-year adjuvant trastuzumab based on the age at the start of adjuvant trastuzumab treatment. The analysis showed an increasing cost per QALY gained as the age increased. For patients aged 35 at the start of adjuvant trastuzumab treatment the cost per QALY gained for strategy 4 and strategy 5 was 26 700 and 30 100, respectively. The costs per QALY gained increased to 56 200 and 64 700 per for strategy 4 and strategy 5, respectively, when the age at start of adjuvant trastuzumab treatment was increased to 65. For patients aged 75 at the start of adjuvant trastuzumab treatment, the cost per QALY gained for strategy 4 and strategy 5 was 116 000 and 133 800, respectively.
sensitivity analysis
To estimate the impact of different parameters on the result, one-way sensitivity analyses were carried out. With the exception of changes in the risk reduction (hazard ratio) of an event arising from 1 year of adjuvant trastuzumab the result was robust to 30% changes of selected parameters. According to our sensitivity analysis, the risk reduction (hazard ratio) of an event arising from 1 year of adjuvant trastuzumab, duration of treatment effect, and the inclusion of future costs were the parameters with the largest impact on the ICER. None of the changes in the one-way analyses altered the rank order of the different strategies or their dominance status compared with the base case scenario. The results of the one-way sensitivity analyses are presented in Table 5.
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Two-way sensitivity analyses were carried out to estimate the impact of changes to sensitivity and specificity of the IHC test. Although changes in the IHC test sensitivity and specificity had limited impact on the ICER of strategy 4, changes in sensitivity of the IHC test had a substantial impact on the ICER of strategy 5. Assuming that the IHC test identified HER2-positive patients as 3+ in 95% of the cases and as 2+ in the remaining 5% of the cases, strategy 4 dominated strategy 5. The rank order and dominance status of the remaining strategies were not influenced by changes in the IHC test characteristics.
A probabilistic sensitivity analysis was carried out in order to estimate the uncertainty of the base case analysis. The distributions of costs, utilities, and effect of 1-year adjuvant trastuzumab were used. The result of the probabilistic sensitivity analysis is presented graphically in Figure 2.
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discussion |
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Our analysis indicates that 1 year of adjuvant trastuzumab after adjuvant chemotherapy is a cost-effective treatment option compared with chemotherapy alone. The incremental cost per QALY gained was estimated to
36 000 for the strategy of IHC testing for all patients with FISH confirmation of 2+ and 3+ and 1-year adjuvant trastuzumab for FISH-positive patients (strategy 4). The incremental cost per QALY gained was estimated to 41 500 for the strategy of FISH testing for all patients with 1-year adjuvant trastuzumab for FISH-positive patients (strategy 5). These estimates of the cost per QALY gained are well below a willingness to pay threshold of 70 600, which is commonly used in Sweden [42]. Our analysis also indicates that a majority of the total lifetime costs will arise from direct and indirect costs related to breast cancer. This indicates that even though intervention costs associated with 1 year of adjuvant trastuzumab are substantial, they are not the main cost driver of total lifetime costs. Although direct and indirect costs constitutes a majority of the total lifetime costs, our analysis estimated the difference in direct and indirect costs between the different testing and treatment strategies to be small. This was an expected result, and is due to the structure of the model. HER2-positive patients receiving adjuvant trastuzumab will incur lower direct and indirect costs from breast cancer recurrence compared with HER2-positive patient not receiving adjuvant trastuzumab. However, HER2-positive patients receiving adjuvant trastuzumab will incur higher direct and indirect cost due to their increased survival compared with HER2-positive patient not receiving adjuvant trastuzumab. Since these factors work in the opposite direction, the overall cost offset between the different testing and treatment strategies will tend to be limited.
Previously published studies estimated similar or lower costs per QALY gained for 1 year of adjuvant trastuzumab. The study by Kurian et al. [16] found that 1 year of adjuvant trastuzumab after anthracycline-based adjuvant chemotherapy had an ICER of $ 40 000/QALY ( 32 100/QALY) compared with anthracycline-based adjuvant chemotherapy alone. This result is consistent with our findings. However, there are some noticeable differences between our study and the study by Kurian et al. Our study included indirect costs that arise from productivity losses due to breast cancer as well as the cost and consequences of HER2 testing needed to identify patients eligible for trastuzumab treatment, whereas the study by Kurian et al. did not take these parameters into consideration. The study by Kurian et al. also used a different model structure compared with our study, and treatment effects were based on the combined analysis of the NSABP B-31 and NCCTG N9831 trials [12] instead of the HERA trial. Also, the utility of patients with breast cancer recurrence was lower than in our study.
Liberato et al. [17] found that 1 year of adjuvant trastuzumab after adjuvant chemotherapy was associated with a cost per QALY gained of 14 900 in an Italian setting and $ 19 000 ( 15 200) in a USA setting compared with adjuvant chemotherapy alone. This estimate cost per QALY gained is substantially lower than our estimated cost per QALY gained. Similar to the study by Kurian et al., Liberato et al. did neither include indirect costs associated with breast cancer nor the cost and consequences of HER2 testing needed to identify patients eligible for trastuzumab treatment. Liberato et al. used the combined analysis of the NSABP B-31 and NCCTG N9831 trials in their base case analysis, but also simulated a HERA-like scenario, which gave a slightly lower costs per QALY gained compared with their base case result. Utilities for disease free patients were higher than for comparable patients in our model, whereas utilities for patients in metastatic disease were assigned a lower utility compared with our study.
The report by Kunnskapssenteret [18] estimated the cost per life year gained to 152 000 NOK ( 19 000) for 1 year of adjuvant trastuzumab. Although this is lower than our estimated cost per life year gained of 26 800 for strategy 4, our results are still fairly consistent with the findings of Kunnskapssenteret.
In the analysis presented in the NICE technology appraisal guidance 107, the cost per QALY gained for 1 year of adjuvant trastuzumab was estimated to £ 18 000 ( 26 300) [19], which is lower than our estimated cost per QALY. However, the NICE technology appraisal guidance 107 reported a range in the cost per QALY gained between £ 16 000 ( 23 400) and £ 33 000 ( 48 300), which is consistent with our estimate cost per QALY gained for both strategy 4 and strategy 5. Neither Kunnskapssentere nor NICE have taken the cost and consequences of HER2 testing into consideration in their analysis. Also, indirect costs arising from breast cancer have been omitted in their analysis.
In the subgroup analysis, we analyzed cost per QALY gained for patients of different ages at the start of adjuvant trastuzumab treatment. We found the age and cost per QALY gained to be correlated, with the cost per QALY gained increasing as the age increased. Our analysis indicated that strategy 4 and strategy 5 could still be considered cost-effective treatment options even if adjuvant trastuzumab treatment was initiated at 65 years of age. However, for patients starting adjuvant trastuzumab at 75 years of age, the cost-effectiveness of both strategy 4 and strategy 5 becomes questionable.
Sensitivity analysis showed that the risk reduction (hazard ratio) of an event gained from 1 year of adjuvant trastuzumab, duration of treatment effect, and the inclusion of future costs were the most sensitive parameters in the analysis. However, none of the changes explored in the sensitivity analysis alter the rank order of the different strategies, and only changes in risk reduction of an event caused the ICER to exceed what is normally considered cost-effective. The impact of assuming that patients had no new breast cancer recurrences 10 years after their primary breast cancer was also explored in the one-way sensitivity analysis. This was done to take into consideration the increasing uncertainty of the Weibull estimates when extrapolating over long periods of time. Although the ICER was increased when we assumed no new breast cancer recurrences after 10 years, it did not exceed what is normally considered cost-effective.
There are currently no Swedish guidelines about trastuzumab treatment in the metastatic setting for patients that have already received adjuvant trastuzumab. In the base case scenario, we assumed that HER2-positive patients would not receive trastuzumab in the metastatic setting. Instead assuming that all HER2-positive patients would receive trastuzumab treatment in the metastatic setting ( 31 571 in outpatient drug costs in year 1 and 2733 the following years) resulted in an ICER of 33 100, 34 100, and 47 900 for strategy 2, strategy 4, and strategy 5, respectively. Assuming that only trastuzumab naive HER2-positive patients would receive trastuzumab treatment in the metastatic setting resulted in an ICER of 23 800, 29 800, and 41 500 for strategy 2, strategy 4, and strategy 5, respectively.
Future costs are sometimes referred to as cost of added years of life, and represents the difference in consumption and production. It has been argued that this difference between consumption and production during life years gained should be included as a cost in economic evaluations when using a societal perspective [43, 44]. The difference in consumption and production becomes greater with increasing age and since our model predicts an increased survival for patients receiving 1 year of adjuvant trastuzumab, the total costs for these patients increases when future costs are included. This in turn increases the cost per QALY gained from 1 year of adjuvant trastuzumab. However, even when future costs were included in the analysis, 1 year of adjuvant trastuzumab was still considered a cost-effective treatment option.
In the base case scenario, we assumed that in the absence of HER2 gene amplification, the patient received no additional benefit from trastuzumab therapy [23–25]. Instead of assuming that benefit from trastuzumab treatment is only derived if patients have 3+ by IHC test, we can compare the strategy of using IHC testing for all patients with 1 year-adjuvant trastuzumab for 3+ patients (strategy 2), with the strategy of standard care for all patients (strategy 1). In this analysis, we estimated the cost per QALY gained for strategy 2 to 35 200. This result is consistent with our base case analysis where we assumed that only patients with HER2 gene amplification received benefit from trastuzumab therapy. This corroborates our findings that 1 year of adjuvant trastuzumab seems to be a cost-effective treatment option for patients with HER2 overexpression/gene amplification.
One limitation of this study is the lack of long-term follow-up in the HERA trial. Since a substantial part of the costs and effects are incurred after the end of the trial, and extrapolation of the clinical trial results becomes necessary to accurately analyze the total costs and effects of the treatment. In order to extrapolate costs and effects beyond the clinical trial period we used a simulation model. Although the risk of recurrence and mortality estimates used in our model were based on a very large sample of Swedish breast cancer patients (n = 20 624), it should be noted that extrapolation of data introduces uncertainties in the analysis.
As shown by various clinical trials adjuvant trastuzumab provides substantial benefits in the form of decreased risk of breast cancer recurrence and an increase in overall survival. However, due to its high price, trastuzumab as an adjuvant therapy is likely to have a noticeable financial impact on the Swedish health care system. In Sweden, sales of trastuzumab have steadily increased and reached 7 million in 2004 [45]. In 2006, the sales of trastuzumab reached 21 millions, a three-fold increase in 2 years [46]. This increase in sales is most likely due to the positive results of the adjuvant trials presented in 2005, prompting some oncologist to use trastuzumab in the adjuvant setting. As more and more oncologists adopt this new treatment, sales of trastuzumab are likely to increase even further. Even though our study, as well as pervious studies, has found adjuvant trastuzumab to be cost-effective, further discussion about the budget impact of adjuvant trastuzumab is needed. Since the health care system have limited resources at its disposal, additional money spent on trastuzumab requires either less money spent on other forms of health care or more funds allocated to the health care system.
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conclusion |
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According to our analysis, 1-year adjuvant trastuzumab is a cost-effective treatment option compared with no additional adjuvant trastuzumab for patients with early breast cancer that have received adjuvant chemotherapy.
IHC testing for all patients, with FISH confirmation of 2+ and 3+, and 1-year adjuvant trastuzumab for FISH+ patients is not dominated by any treatment strategies. However, according to our analysis, this strategy is only preferable to the strategy of FISH testing for all patients with 1-year adjuvant trastuzumab for FISH+ patients if our willingness to pay for a QALY is in the range of 36 000– 41 500. FISH testing for all patients with 1-year adjuvant trastuzumab for FISH+ patients is the treatment strategy associated with the longest quality adjusted survival in our analysis. FISH testing for all patients with 1-year adjuvant trastuzumab for FISH+ patients has an ICER well below commonly used willingness to pay thresholds, indicating that it is a cost-effective treatment strategy. This makes FISH testing for all patients with 1-year adjuvant trastuzumab for FISH+ patients the preferable treatment strategy from a societal perspective.
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Roche to M. L., B. J., and N. W.
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We are grateful to the Stockholm Oncology Centre at Karoliniska University Hospital for their help in gathering epidemiological data used to estimate risk of recurrence and mortality in different breast cancer disease states. Helpful comments on the manuscript by Henrik Lindman is acknowledged. JB has received research support from Roche and has taken part in advisory boards for Roche.
Received for publication March 5, 2007. Revision received September 18, 2007. Accepted for publication September 18, 2007.
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References |
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