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HER-2/neu assessment in breast cancer by immunohistochemistry and fluorescence in situ hybridization: comparison of results and correlation with survival |
Kakar S, Puangsuvan N, Stevens J M, Serenas R, Mangan G, Sahai S, Mihalov M L |
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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 The use of immunohistochemistry (IHC) versus fluorescence in situ hybridisation (FISH) to test for the HER-2/neu proto-oncogene in invasive breast cancer patients. IHC is a quick and cheap test, but relies on a subjective interpretation of the results, classified from 0 to 3+ according to how much staining occurs. FISH is much more time-consuming and expensive, but relies on calculating the ratio of stained to unstained nuclei, and is thus more objective.
Type of intervention Other (secondary diagnosis).
Economic study type Cost-effectiveness analysis.
Study population The study population comprised patients with treated invasive breast cancer.
Setting The setting was a hospital. The economic study was performed at the University of Illinois, Chicago.
Dates to which data relate All of the effectiveness data were collected retrospectively in July 1999. The date to which the costs related was not stated.
Source of effectiveness data The effectiveness data were derived from a single study.
Link between effectiveness and cost data The costing was carried out on the same sample as that used in the effectiveness analysis.
Study sample No power calculations to determine the sample size were carried out. The study was conducted on archived biopsy specimens from 117 consecutive, unselected, treated breast cancer patients. Due to the nature of the study, the sample was appropriate for the study question. Both tests were carried out on archived material from all patients, thus they acted as their own controls.
Study design This was a single-centred, retrospective, non-randomised study with patients acting as their own controls. The patients were followed for at least 50 months' post-treatment. The loss to follow-up was 44%. Follow-up data were only available for 65 patients on account of incomplete or missing data.
Analysis of effectiveness The test results were compared for all 117 samples. Patient survival to 50 months was assessed for the 65 patients for whom there were data. The primary outcomes were the numbers of positive results with each test, correlated with survival to 50 months and stratified by test result. The authors stated that statistical tests were used to ensure that there was no significant difference between the patients at baseline, but the results of this were not shown.
Effectiveness results For the IHC test, 28% (33 out of 117) were positive (graded 2+ or 3+). Seventeen of these were scored as 2+ and 16 as 3+. Prominent background staining was observed in 16 of the 117 cases (13.7%), and normal breast tissue was stained in 12 of the 117 cases.
For the FISH test, 19% (21 out of 112) were positive (5 cases were unreadable due to insufficient tissue). Prominent background staining was observed in 12 of the 112 cases (10.7%).
The two tests were in agreement in 98 of the 112 cases (88%). Eighty-eight per cent (14 of 16 cases) graded 3+ by IHC were classed as positive by FISH, 35% (6 of 17 cases) graded 2+ by IHC were classed as positive by FISH, and 99% (78 of 79 cases) graded 0 or 1+ by IHC were classed as negative by FISH.
Survival data were available for 65 patients. The IHC was positive in 29.2% (19 of 65) of the patients. Mean survival was 51.2 months for IHC score 0 or 1+ patients, 60.8 months for IHC 2+ patients and 37.1 months for IHC 3+ patients. There was a significant difference in mean survival time between IHC 3+ and IHC 0 or 1+ patients, (p=0.02).
FISH was positive in 16.9% (11 of 65) of the patients. Mean survival was 52.9 months for FISH-negative patients and 45.9 months for FISH-positive patients, (p=0.15). Using a higher threshold to define FISH-positive patients, there was a significant reduction in life expectancy for FISH-positive patients, (p=0.02).
Clinical conclusions The IHC and FISH tests had a concordance rate of 88%. This was in line with other estimates, which ranged from 76 to 98%. IHC should be recommended for routine use. However, FISH can be a useful adjunct where the IHC results are inconclusive (i.e. score a 2+).
Measure of benefits used in the economic analysis No summary measure of health benefit was used in this analysis. Therefore, the study is classified as a cost-consequences analysis.
Direct costs The average unit costs of the two tests were reported. These costs were relevant to a hospital setting. The costs included were for the IHC (including antibody and reagents) and FISH tests. The authors also reported the technician time required for each test, but did not value this. The source and date of the costs were not stated.
Statistical analysis of costs Estimated benefits used in the economic analysis See the 'Effectiveness Results' section.
Cost results The cost of IHC (including antibody and reagents) was $14.90 per case. The cost of FISH was $122.00.
The technician time required for IHC was 105 minutes, plus 3 minutes for interpretation. For FISH, the technician time was 173 minutes over two days plus 15 to 20 minutes for interpretation.
Synthesis of costs and benefits Authors' conclusions It may be imprudent to advocate a more expensive test, that is, fluorescence in situ hybridisation (FISH) over immunohistochemistry (IHC). However, failing to use a more accurate test may incur greater costs later on, both medically and psychologically. The authors recommend the routine use of IHC, and the use of FISH where IHC proves inconclusive (or scores a 2+).
CRD COMMENTARY - Selection of comparators A justification for the comparators was given. IHC is a commonly used, cheap, quick test while FISH is more expensive, but potentially more accurate. You should decide whether these are widely used technologies in your setting.
Validity of estimate of measure of effectiveness The analysis used retrospective non-randomised trial with patients acting as their own controls. This is an appropriate study design for comparing two diagnostic tests. There was insufficient information to determine whether the sample was appropriate to the study population. However, the selection method, and the relatively large number of patients, would indicate that the sample would probably be representative. The authors stated that statistical tests were performed to compare the patients in terms of demographic characteristics, but the results of these were not reported.
Validity of estimate of measure of benefit In the cases of both IHC and FISH, there appears to be a decreasing survival trend with a more positive test result. It would have been appropriate to have performed a regression analysis of test result against survival. This way, it may have been possible to state which test was the better predictor of survival. Since this was not done, it is unclear how the authors arrived at the conclusion that FISH was superior from the results of this study.
Validity of estimate of costs The study contained a very limited exploration of the costs, with only the cost for the tests included. It is unclear whether this was the manufacturer's price or if it included any overhead for laboratory equipment and other costs. The authors calculated the time input required for each test, but did not value this. Nevertheless, it is clear that the FISH test is substantially more expensive than the IHC test. No sensitivity analysis of the costs was performed, and the price year and sources were not stated.
Other issues The authors made appropriate comparisons of their results with those from other studies, but did not address the issue of generalisability to other settings. The authors do not appear to have presented their results selectively. However, the conclusions of the study possibly do not support the scope of study. It is unclear how the superiority of FISH over IHC has been established, other than by reference to other publications.
The authors reported the small sample size in the survival analysis as a possible limitation to their study.
This is a useful background study comparing IHC and FISH to detect the HER-2/neu proto-oncogene. It is also apparent that FISH is more expensive than IHC. The true cost and cost-effectiveness of the tests (in terms of survival or quality-adjusted life-years) cannot be established from this study. A more thorough economic evaluation is required to confirm this.
Implications of the study The authors recommend a larger survival analysis, possibly modelled using Kaplan-Meier curves and multivariate analysis, to confirm the indications of this study.
Bibliographic details Kakar S, Puangsuvan N, Stevens J M, Serenas R, Mangan G, Sahai S, Mihalov M L. HER-2/neu assessment in breast cancer by immunohistochemistry and fluorescence in situ hybridization: comparison of results and correlation with survival. Molecular Diagnosis 2000; 5(3): 199-207 Other publications of related interest Comment: Molecular Diagnosis 2000;5:191-2.
Indexing Status Subject indexing assigned by NLM MeSH Breast Neoplasms /diagnosis /genetics /metabolism /mortality; Carcinoma /diagnosis /genetics /metabolism /mortality; Cell Nucleus /ultrastructure; DNA, Neoplasm /analysis; Female; Gene Amplification; Humans; Immunohistochemistry /economics /standards; In Situ Hybridization, Fluorescence /economics /standards; Prognosis; Reagent Kits, Diagnostic; Receptor, ErbB-2 /genetics /immunology /metabolism; Survival Rate AccessionNumber 22000001614 Date bibliographic record published 31/08/2003 Date abstract record published 31/08/2003 |
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