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Identifying the optimal timing of HER2 testing in patients with breast cancer: a Canadian economic evaluation |
Dranitsaris G, Norris B, Hanna W, O'Malley F, Gelmon K |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology Testing for human epidermal growth factor receptor 2 (HER2) in patients with stages I - III breast cancer was examined. The testing procedure entailed an initial immunohistochemistry (IHC) test, followed by a fluorescent in situ hybridisation (FISH) test if the IHC test results were inconclusive.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised pre-menopausal and postmenopausal women diagnosed with stages I - III breast cancer. Stage IV breast cancer patients were not included in the study population, as the patients would automatically have been tested for HER2 status at diagnosis.
Setting The setting of the study was not explicitly stated, but the economic study was carried out in Canada.
Dates to which data relate The effectiveness data were obtained from studies published between 1990 and 2001. The dates to which the resource use data related were not reported. The price year was not reported.
Source of effectiveness data The effectiveness data were derived from a review of completed studies.
Modelling A decision analytic model was used to simulate and compare the economic outcome of HER2 testing at two different times, that is, diagnosis and recurrence.
Outcomes assessed in the review The outcomes assessed were:
the rates of conclusive HER2-positive or HER2-negative test results with IHC,
the incidence of definitive results with FISH following inconclusive IHC outcomes, and
the likelihood of disease recurrence at 5 years in patients with stages I - III disease.
The likelihood of disease recurrence was based on estimates derived from the Population Health Model (POHEM) from Statistics Canada (see Other Publications of Related Interest). The POHEM simulates the health status of various populations such as breast cancer patients.
Study designs and other criteria for inclusion in the review The types of studies included in the review were not reported. The search criteria were designed to identify human studies that evaluated the concurrence of IHC and FISH in patients with a diagnosis of breast cancer.
Sources searched to identify primary studies MEDLINE and the databases of the Cochrane Collaboration were searched for primary studies.
Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included It would appear that two primary studies were included in the review.
Methods of combining primary studies The results of the individual primary studies were not combined.
Investigation of differences between primary studies The authors did not investigate differences between the primary studies.
Results of the review The risk of recurrence was 32.8% for Stage I, 46.1% for Stage II and 70.6% for Stage III breast cancer.
The incidence rate was 16.4% (95% confidence interval, CI: 13.7 - 19.1) for an HER2-positive IHC result, 5.2% (95% CI: 3.6 - 6.8) for an inconclusive HER2 IHC result, and 35.9% (95% CI: 20.8 - 51.0) for an HER2-positive result from a FISH test (performed on inconclusive IHC samples only).
Methods used to derive estimates of effectiveness The authors made assumptions to derive other parameters used in the model.
Estimates of effectiveness and key assumptions The authors assumed that there was no difference in recurrence rates between the two testing strategies (i.e. testing at diagnosis or recurrence).
Measure of benefits used in the economic analysis No summary measure of benefits was reported. Therefore, a cost-minimisation analysis was performed.
Direct costs In the base-case, the costs were reported with and without discounting. The annual discount rate used was 3%. The quantities and the costs were not analysed separately. The costs included in the study were for the initial HER2 IHC test (plus FISH test for inconclusive cases) and for the retrieval of archived breast tissue. The costs of retrieving archived breast tissue entailed resources used for tissue identification, transportation, the preparation of haematoxylin and eosin stained sections by a laboratory technologist, and the time for a pathologist to review sections of the tumour and to select a representative block for HER2 testing. The costs for HER2 testing and tissue retrieval were obtained from the pathology departments of Sunnybrook and Women's College Health Sciences Centre and Mount Sinai Hospital in Toronto, and of the British Columbia Cancer Agency. The final retrieval cost used in the model was the pooled average of the estimates obtained from the three centres. The quantities were estimated from the model, while the costs were estimated from actual data. The price year and the dates for the resource use data were not reported.
Statistical analysis of costs No statistical analysis of the costs was performed.
Indirect Costs The indirect costs were not included.
Currency Canadian dollars (Can$). The authors reported that, as at October 2002, the conversion rate was Can$1 = US$0.65. However, the costs were reported in Canadian dollars.
Sensitivity analysis One-way sensitivity analyses were carried out on the choice of adjuvant chemotherapy and the incidence of inconclusive results. A threshold analysis was also performed on the cost of tissue retrieval and the risk of 5-year recurrence. The purpose of these analyses was to investigate variability in the data. The ranges of parameter values investigated in the one-way sensitivity analyses were selected from the upper and lower limit of the 95% CIs.
Estimated benefits used in the economic analysis See the 'Effectiveness Results' section.
Cost results For patients with Stage I breast cancer, the costs of testing at diagnosis amounted to Can$343,800 compared with Can$305,000 when testing at recurrence. Therefore, early HER2 testing for Stage I breast cancer resulted in additional costs of Can$38,800.
For patients with Stage II breast cancer, the costs of testing at diagnosis amounted to Can$343,800 compared with Can$428,500 when testing at recurrence. Therefore, early HER2 testing for Stage II breast cancer resulted in cost-savings of Can$84,700.
For patients with Stage III breast cancer, the costs of testing at diagnosis amounted to Can$75,500 compared with Can$144,000 when testing at recurrence. Therefore, early HER2 testing for Stage III breast cancer resulted in cost-savings of Can$68,500.
The authors estimated that the total costs in Canada of early HER2 testing in patients with stages I to III were Can$763,100, compared with Can$877,500 for testing at recurrence. Therefore, early testing resulted in cost-savings of Can$114,400 (equivalent to Can$98,700 if discounted at a rate of 3% over 5 years).
These costs were incurred over the time period from diagnosis to 5 years.
Synthesis of costs and benefits The sensitivity analysis indicated that the use of adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF), rather than cyclophosphamide/epirubicin/5-fluorouracil (CEF), for HER2-negative cases would be associated with a drug cost-saving of Can$4,000 per patient. This was a conservative estimate because it did not include the costs of treating secondary leukaemias and cardiac toxicities, which are more common with CEF.
The results of the sensitivity analysis that investigated the 95% CIs for the inconclusive rate indicated that the cost-savings were lower with the upper limit and higher with the lower limit.
In the threshold analysis, a cost of $88 for tissue retrieval would result in cost equivalence between testing at diagnosis and at recurrence for Stage I patients. The threshold cost was reduced to $50 for Stage II and $18 for Stage III patients.
Finally, the costs of both treatment strategies would be equated if the risk of recurrence was 37%. The authors considered that a patient whose primary tumour was greater than 2 cm in size, but less than 3 cm, and was Grade 3 with negative axillary nodes, would be a typical example of a tumour pathology with a 37% risk of recurrence within 10 years.
Authors' conclusions Testing the human epidermal growth factor receptor 2 (HER2) status of all newly diagnosed stages I - III breast cancer patients would result in cost-savings for the Canadian health care system compared with the current practice of testing at recurrence.
CRD COMMENTARY - Selection of comparators A justification was given for the comparator used. HER2 testing at recurrence was current practice. You should decide if this is a widely used health technology in your own setting.
Validity of estimate of measure of effectiveness The authors did not state that a systematic review of the literature had been undertaken. The authors only used data from two studies. Hence, it was not necessary to consider the impact of differences between the primary studies when estimating the effectiveness.
Validity of estimate of measure of benefit No summary measure of benefit was used.
Validity of estimate of costs All the categories of cost relevant to the perspective adopted were included in the analysis, although some relevant costs were omitted. In the base-case, the cost and clinical benefit of anticancer therapy was not included because the use of HER2 status for selecting treatment other than trastuzumab was considered to be controversial. Further, the costs of trastuzumab and paclitaxel were excluded from the analysis because they were common to both arms of the model. These omissions are unlikely to have affected the authors' conclusions. The costs associated with the loss or destruction of tissue blocks were not included in the study, even though these costs would be avoided under a strategy of early HER2 testing. Therefore, the inclusion of these costs would increase the cost-savings arising from HER2 testing at diagnosis. In the sensitivity analysis, the authors also excluded the costs of treating side effects arising from adjuvant CEF. This omission is likely to underestimate the cost-savings from using the alternative CMF. The costs and the quantities were not reported separately. A sensitivity analysis of the quantities was not conducted, which may limit the interpretation of the study findings. However, a sensitivity analysis of the prices was conducted.
Other issues The authors did not make appropriate comparisons of their findings with those from other studies. They did, however, address the issue of generalisability to other settings. In particular, the authors acknowledged that the use of cost data only from the provinces of Ontario and British Columbia might restrict the generalisability of the results to other provinces or countries. The authors do not appear to have presented their results selectively. The model incorporated patients with stages I - III breast cancer and this was reflected in the authors' conclusions. The authors did not include those patients with Stage IV disease because these patients automatically receive HER2 testing at diagnosis.
The authors reported a number of limitations of their study. First, they assumed that the distribution of HER2-positive results was the same among patients diagnosed with stages I, II and III of the disease. However, there was no evidence to support this assumption. Second, the study did not include survival data.
Implications of the study The authors postulated that the use of HER2 testing as a predictive tool could result in the selection of optimal anticancer therapy and, therefore, may result in further cost-savings and improved patient care. The authors identified the need for additional data on adjuvant CMF and CEF before the former could be used as a substitute for the latter. Also, the authors looked forward to the publication of the results of five major trials that are studying the use of adjuvant trastuzumab in patients with HER2-positive primary breast cancer.
Source of funding Funded by Roche Canada Inc.
Bibliographic details Dranitsaris G, Norris B, Hanna W, O'Malley F, Gelmon K. Identifying the optimal timing of HER2 testing in patients with breast cancer: a Canadian economic evaluation. Current Oncology 2003; 10(1): 36-44 Other publications of related interest Wolfson MC. POHEM - a framework for understanding and modeling the health of human populations. World Health Statistics Quarterly 1994;47:157-76.
Will BP, Berthelot JM, Nobrega KM, et al. Canada's Population Health Model (POHEM): a tool for performing economic evaluations of cancer control interventions. European Journal of Cancer 2001;37:1797-804.
Indexing Status Subject indexing assigned by CRD MeSH Biomarkers, Tumor; Breast Neoplasms; Cost-Benefit Analysis; Female; Gene Expression Regulation, Neoplastic; Monitoring, Physiologic; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Risk Assessment; Time Factors AccessionNumber 22003009408 Date bibliographic record published 30/11/2004 Date abstract record published 30/11/2004 |
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