- Top of page
- MATERIALS AND METHODS
- FUNDING SOURCES
- CONFLICT OF INTEREST DISCLOSURES
Breast cancer, the second most common cause of cancer death in women, is responsible for approximately 15% of cancer deaths in the United States. It is estimated that in 2013 there will be 232,340 cases of invasive breast cancer in the United States and that 39,620 women will die from the disease.
Approximately 20% of patients with breast cancer have human epidermal growth factor 2(HER2)-positive disease, which is associated with a poor prognosis.[2-4] HER2-positive tumors are also responsive to treatment with trastuzumab (Herceptin; Genentech, South San Francisco, CA), a monoclonal antibody that targets HER2, reducing the risk of recurrence and improving survival.[5, 6]
Two pathological diagnostic tests are commonly used to test for HER2 status: immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). IHC measures HER2 overexpression and is simple to implement, available in most laboratories, and relatively inexpensive. However, tissue handling and fixation, including time to fixation and fixation time, as well as test sensitivity and specificity can affect accuracy. FISH measures HER2 gene amplification and is less susceptible to tissue handling and fixation problems, but it is more complicated, requires training and experience, and is more expensive. The IHC test is scored as follows: 0 and 1+, negative; 2+, equivocal; and 3+, positive. The FISH test can also be positive, equivocal, or negative depending on the gene/chromosome 17 ratio (ie, a ratio of <1.8 is negative, a ratio of 1.8-2.2 is equivocal, and a ratio of >2.2 is positive). Because of the poor correlation between weak positivity by IHC2+ and FISH positivity, it is currently recommended that patients who are IHC2+ are considered to be equivocal and are reflex-tested with FISH to determine HER2 status.
Tumors of approximately 80% of new invasive breast cancer patients are tested for HER2 using IHC and 20% are tested using FISH. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), the College of American Pathologists (CAP), and other groups recommend treating patients whose tumors test IHC3+ or FISH-positive with trastuzumab, treating patients whose tumors are IHC0 or 1+ or FISH-negative with standard chemotherapy and retesting tumors that test IHC2+. ASCO and CAP also recommend either using IHC assays for initial evaluation of HER2 status followed by reflex testing by FISH of some IHC categories or primary use of FISH in initial testing.[10, 11] While concordance (defined as the number of patients who test the same on both tests) between unequivocal IHC and FISH results can be as high as 96%, recent studies have suggested that significant discordance remains.[12, 13]
Intratumoral discordance between test results may lead to false-negative results for HER2 overexpression status. Patients with a false-negative tumor result would be denied the clinical benefits of treatment with trastuzumab, which could have serious morbidity and mortality consequences. An additional important finding is that 2 large randomized trials now suggest that IHC-positive, FISH-negative patients demonstrate clinical benefit when treated with trastuzumab with a hazard ratio similar to that seen in patients whose tumors are both IHC- and FISH-positive. Finally, because of a small rate of discordance between IHC and FISH, some tumors may be positive by 1 test and negative by the second test, and a tumor may be mistakenly classified as HER2-negative if it falls into this category. Expanded reflex testing, as depicted in Figure 1, would reduce the likelihood of this occurrence.
Expanded reflex testing, represented schematically in Figure 2, implies taking a “believe the positive” approach (supported by extensive data) in which patients testing positive by either test would receive treatment with trastuzumab and patients testing negative by either test (IHC0, IHC1+, or FISH-negative) would receive the opposite test for confirmation. This would expand the categories of patients receiving additional testing for HER2 status, and the result would be a substantial reduction in patients with false-negative results (who would have been denied the benefits of adjuvant anti-HER2 therapy), but accepting the risk of increasing the number of patients with false-positive results (who would incur the added costs and possible adverse effects of trastuzumab).
Figure 2. Schematic of a decision tree representing outcomes with expanded reflex testing and the standard testing algorithm. The square indicates the decision node, circles indicate chance nodes, and triangles indicate endpoints.
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The objective of this analysis was to estimate the potential cost-effectiveness of expanded reflex testing for HER2 status among patients with early stage breast cancer. We assessed whether substantially reducing false-negative results is a rational choice for both cost and effectiveness reasons.
- Top of page
- MATERIALS AND METHODS
- FUNDING SOURCES
- CONFLICT OF INTEREST DISCLOSURES
In this study, the projected potential lifetime cost per QALY for implementing expanded reflex testing was estimated to be $39,745, a level that is below commonly accepted thresholds for cost-effectiveness for health care interventions.[21, 22] This projected benefit is driven by the additional yield of patients who are eligible for trastuzumab therapy—a 2.27% increase in the proportion of invasive breast cancer patients receiving this treatment. This increase amounts to 4700 additional women in the United States who would receive trastuzumab therapy annually in the base case. Over their lifetimes, they would be projected to gain an additional 9016 life years and 8330 QALYs (both discounted to a present value basis). This magnitude of this benefit is uncertain and could range from 2000 to 17,000 women within the plausible range. Nonetheless, the benefits are substantial and imply that the potential additional yield that results in reducing false-negative cases at the expense of increasing false-positive cases is cost-effective and may justify a change in clinical policy.
A recent retesting study performed in the VIRGO observational cohort, which included a substudy of 499 patients whose tumors were HER2-negative when locally tested, showed that 22 (4%) patients were found to be HER2-positive according to central laboratory testing. Importantly, of these 22 patients, 15 (68%) were found to be positive using a test that was not performed locally. This finding suggests that the 2.27% base case projection is likely to be conservative.[23-25] At that false-negative probability, the lifetime cost per QALY would improve, falling by 7% to about $37,000.
Our analysis implicitly assumes that all of the additional patients identified by reflex testing would accrue the additional benefit due to trastuzumab: that is, they would have the same biological response to treatment as patients identified in the definitive trials, who were identified by the current testing algorithm. This assumption is supported by data from the adjuvant N9831 trial and the HERA trial.
The other assumption implicit in our modeling framework is that there is no differential uptake or acceptance of trastuzumab treatment between women identified by the current testing algorithm and the extra women identified as a result of expanded reflex testing. This assumption is plausible because the implementation of reflex testing is likely to be a decision that is moved from the patient to the physicians. The pathologist would most likely be the decision maker and would simply perform any revised testing protocol: they would test each negative sample with the opposite test, and they would recommend trastuzumab to patients testing positive, regardless of whether they tested positive on the index or the reflex test, unless there are contraindications.
Misclassification of HER2 results can arise due to quality of laboratory testing and from the test itself. Misclassification due to quality of laboratory testing may be remedied by standardizing laboratory test procedures or repeating tests with independent pathologists. However, misclassification due to the test itself requires the development of a perfect test, which may not be feasible. Such a test might also be prohibitively costly. Although a few authors have suggested that FISH is superior to IHC in reproducibility and precision, recent data contradict this assumption: other data also suggest that both tests are similar in terms of reproducibility. Because both IHC and FISH retain a level of subjectivity in their interpretation, reflex testing might offer a cost-effective compromise between allowing women with potential false-negative tumor results miss out on the benefits of trastuzumab and perfect sensitivity and specificity in which there are no false-positive or false-negative results. Another source of potential misclassification of HER2 results may arise due to intratumoral heterogeneity, and one might consider retesting excision specimens for HER2 status even if tumors tested HER2-negative at the initial biopsy.
The “believe the positive” approach, the argument behind expanded reflex testing, implies that patients who are incorrectly diagnosed as being HER2-positive in the face of imperfect tests are treated with trastuzumab, and data suggest that they benefit from this treatment. This is a testament to the difficulty of defining false-positivity for FISH and IHC in this early breast cancer context given that they are based on subjective interpretation of pathological samples and that a true gold standard may not exist. In theory, patients incorrectly diagnosed as being HER2-positive would receive trastuzumab inadvertently and would face both an unnecessary incremental cost (of medication and adverse events) and the disutility of adverse events. We find no evidence that this is the case, and it has been suggested that misclassification leading to missed HER2 cases has worse consequences than misclassification leading to HER2-negative cases getting treatment with trastuzumab because of recent advances in reducing trastuzumab-related level 3 and 4 cardiotoxicity.
We found no economic evaluations of expanded reflex testing in the literature. Other economic evaluations of HER2 testing have attempted to identify the most cost-effective combination of FISH and IHC to minimize both false-positive and false-negative results. Dendukuri et al compared the cost-effectiveness of the following strategies for identification of early stage breast cancer patients for treatment with trastuzumab in Ontario: 1) IHC followed by FISH for IHC2+ patients; 2) IHC only with IHC2+ and 3+ receiving trastuzumab; 3) IHC only with IHC3+ receiving trastuzumab; 4) IHC followed by confirmation of IHC1+ and IHC2+ by FISH; 5) IHC followed by confirmation of IHC2+ and IHC3+ by FISH; 6) IHC followed by confirmation of IHC1+, IHC2+, and IHC3+ by FISH; and 7) FISH only. Each was compared with strategy 1 (IHC followed by FISH for IHC2+ patients) in terms of incremental cost per accurate diagnosis. The investigators found that confirmation of HER2 status by FISH in IHC3+ patients was optimal, reducing the false-positive results to 0% and increasing the percentage accurately determined to 97.6% at an ICER of $6175 per case of HER2 status accurately determined. This study differs from our study because expanded reflex testing does not seek to maximize accuracy but to maximize yield of HER2 cases (ie, minimize false-negative results). This is the reason that our modeling framework allows for the treatment of patient with initially false-positive results. Additionally, their study considered only testing costs and disregarded costs of treatment, measuring cost per accurate test as their outcomes compare to our study, which used cost per QALY.
Blank et al. used a life-long Markov model to assess the cost-effectiveness of HER-2 tumor testing strategies comparing IHC, FISH, the combination of the two, or FISH confirmation of IHC2 in the Swiss healthcare system. They found that FISH alone is the most cost-effective at €12,245 per QALY. Their optimal strategy would also differ from expanded reflex testing because with up to 5%-8% false-negative tests (ie, tumors that are FISH-negative and IHC-positive) patients would not receive trastuzumab if FISH alone is used. The advantage of expanded reflex testing is that it further reduces the chance of false-negative results, albeit at the cost of treating some false-positive results with trastuzumab.
One limitation of this analysis is that in taking the US payer perspective, we do not consider indirect time or productivity costs. In our previous analysis of trastuzumab in adjuvant therapy, we estimated that the time and travel costs associated with trastuzumab would be about $2000 over a lifetime, raising lifetime costs and the cost-effectiveness ratio only slightly (by 4.6%) to about $28,000 per QALY. This would still be considered cost-effective, but it also ignores any indirect benefits in terms of improved productivity or labor force attachment over the remainder of the patient's working life, which could be very substantial.
Several factors will affect the potential implementation of expanded reflex testing. In practice, many laboratories only have the capacity to perform IHC, given the additional equipment and expertise requirements for implementing FISH. Implementing expanded reflex testing will require improvements in capacity and investment in equipment, which may be costly. However, this would be less expensive than implementing FISH as the index test for HER2 status, as has been suggested, because the percentage of patients receiving the FISH test rises from 26.6% under the current testing algorithm to 86.9% under expanded reflex testing (compared with 100% if FISH were the index test). This would require increased capacity and reimbursement for extra tests. Furthermore, there remains uncertainty about whether particular payers will be willing to accept these changes. The US Food and Drug Administration has approved additional HER2 tests, such as silver in situ hybridization, chromogenic in situ hybridization (CISH), and dual in situ hybridization. These new tests may reduce analytic burden (eg, CISH requires widely available light microscopes instead of expensive fluorescent microscopes), thereby potentially reducing the costs of expanded reflex testing.
In addition to identifying patients for treatment with trastuzumab, HER2 testing is already being used to identify patients for treatment with the tyrosine kinase small molecule inhibitor lapatinib (Tykerb; GlaxoSmithKline, Philadelphia, PA), which has been approved recently in adjuvant and neoadjuvant metastatic disease settings. The emergence of newer therapies for adjuvant and metastatic treatment of breast cancer that target HER2 may impact the potential clinical utility and cost-effectiveness of expanded reflex testing, particularly if these drugs lead to additional gains in survival or QALYs, implying that the potential impact of false-negative results on patients is further amplified in LY or QALY terms.
HER2 testing is a cornerstone of treatment of patients with breast cancer. While accuracy in testing is important, a balance between having false-negative HER2 results and treating false-positive patients with trastuzumab is an important clinical and policy decision. Expanded reflex testing is projected to be cost-effective at $39,745 per QALY gained, and would affect approximately 4700 women annually in the United States. The estimated benefit would be even greater in younger patients. This base case projects a false-negative probability of 2.27%, but this may be a conservative figure given recent empirical evidence. Expanded reflex testing allows for a second opportunity to measure HER2 status accurately, correcting both handling errors and testing inconsistency.