Clinical Practice Patterns and Cost-Effectiveness of HER2 Testing Strategies in Breast Cancer Patients

1. Percentage of eligible patients tested for HER2 and methods used

Although there is clinical consensus that all patients with invasive breast cancer should be tested, some patients may not receive testing. In some cases patients may be tested, but their test results may not be properly documented.

We examined available evidence addressing the following questions:

• Do all patients with invasive breast cancer receive HER2 testing?

• Does test utilization vary according to personal characteristics, such as insurance status, socioeconomic status, and race/ethnicity, or by physician, health plan, or geographic characteristics?

We considered that patients may be tested by using IHC, FISH, or both methods but did not examine CISH because it has only recently been an FDA-approved option for clinical practice. Although there is no consensus about whether IHC or FISH should be used for initial testing, there is agreement that patients with indeterminate IHC results (approximately 15% of patients ⁷) should have a FISH test. However, some patients with indeterminate IHC results may not get confirmatory testing and there is continuing debate over the cut-off used. We examined available evidence addressing the following questions:

• What percentage of patients receives IHC, FISH, or both tests?

• Do patients with indeterminate IHC results get confirmatory FISH testing?

• Does the use of IHC or FISH vary by personal characteristics, such as insurance status, socioeconomic status, and race/ethnicity, or by physician, health plan, or geographic characteristics?

2. Percentage of tests with concordant results between community and central or reference laboratories

Even if positivity criteria can be determined so that only patients defined as having positive HER2 results are those who will benefit from trastuzumab, HER2 test performance in actual practice will be influenced by variability in laboratory procedures. Because the purpose of this study is to examine actual testing practices, our literature review focused on laboratory concordance rather than predetermined thresholds for determining positive results. We examined available evidence addressing the following question:

• What is the concordance between HER2 tests performed in community laboratories as compared to central or reference laboratories?

3. Percentage of patients who receive trastuzumab

Although clinical guidelines state that only patients testing HER2 positive according to established algorithms should receive trastuzumab, patients who either are not tested or have negative results may still receive trastuzumab because of doubts about test accuracy, clinical factors, personal or healthcare system factors, or human error. Patients with positive HER2 test results may not receive trastuzumab because of the same factors. We examined available evidence addressing the following questions:

• What is the percentage of patients with positive, negative, or no test results who receive trastuzumab?

• Does the use of trastuzumab (conditional on test results) vary by personal characteristics such as insurance status, socioeconomic status, and race/ethnicity, or by physician, health plan, or geographic characteristics?

4. Cost-effectiveness of HER2 testing in clinical practice

Studies that have examined the cost-effectiveness of trastuzumab in a population of patients already identified as HER2 positive have found that adding it to chemotherapy is relatively cost-effective.^10–12. These studies, however, do not address the cost-effectiveness of different HER2 testing strategies in the adjuvant setting. For example, if patients who would benefit from treatment are not tested, if the most efficient testing algorithm is not used, if tests are inaccurate, or if patients receive treatment that is inappropriate based on their test results, then the cost-effectiveness of testing and treatment in actual practice will be lower than the estimated cost-effectiveness. We examined the available evidence on the following question:

• What is the cost-effectiveness of HER2 testing strategies?

Percentage of eligible patients tested for HER2

Stark et al (2004), in a study of patients with metastatic breast cancer in the Henry Ford Health Care System (MI) shortly after the FDA approval of trastuzumab for patients with metastatic breast cancer (1999–2000), found that 52% were tested for HER2.¹³ Women with an absence of estrogen receptors, those with physicians in the surgery specialties, and those who had capitated insurance were more likely to be tested. A study of a 5% sample of Medicare enrollees in 2005 (N=6588) – reported only in abstract form – showed that 32% of patients newly diagnosed with invasive breast cancer had documentation in claims data of having undergone a HER2 test.¹⁴ Of those with documentation of having received trastuzumab, 68% had documentation of having had a HER2 test. Among those receiving trastuzumab, older women and white women were more likely to have been tested.

Percentage of patients tested using IHC and/or FISH methods

The study noted above in the Medicare population also showed that 93% of the women tested received only IHC, 0.3% received only FISH, and 6% received both tests – although it is not known whether FISH was used for initial or confirmatory testing.¹⁴

Percentage of tests with concordant results between community and central or reference laboratories

We found no studies of laboratory concordance in routine practice, although several studies have examined concordance in conjunction with enrollment into clinical trials and they can be presumed to reflect routine practice in general.^15–18 The ASCO/CAP guidelines reviewed such studies and found that approximately 20% of IHC tests done by local, community-based laboratories are inaccurate when compared to central or reference laboratory results.⁷

Percentage of patients testing positive or negative who received trastuzumab

One study of patients with early-stage or metastatic breast cancer in a privately insured population was conducted by using 2005 United HealthCare data (personal communication, Lee Newcomer, 7/18/08).^{19, 20} They found that at least 12% and “probably” 20% of women receiving trastuzumab either did not have a HER2 test or had a test that showed no conclusive evidence of HER2 overexpression. More specifically, it was estimated that 8% were underexpressed, 4% had not been tested, and 8% were unknown because the physician did not provide the record. Details of this study have not been published in the peer-reviewed literature.

Cost-effectiveness of HER2 testing in clinical practice

Of 621 studies screened, we found four cost-effectiveness analyses of HER2 testing or trastuzumab treatment in US populations.^{10–12, 21} Two of these studies did not consider HER2 testing and examined only treatment strategies, assuming that the patients had already been tested.^{11, 12} Another study included testing in their model but did not compare different testing strategies.¹⁰ One study examined HER2 testing strategies in a US population by analyzing seven possible test-treat strategies for patients with metastatic breast cancer.²¹ We did not find any analyses that examined testing strategies in the adjuvant setting.

Summary and Implications for HER2 Testing

There is little evidence about the use of HER2 testing in routine clinical practice that can inform the current debate about selection of patients for treatment or the relative advantages and disadvantages of alternative testing strategies. The limited evidence available suggests that there are important variations in testing practices and key gaps in knowledge about those practices.

This study illustrates the gaps in what is known and the weaknesses in available evidence. Studies are generally of selected populations, use outdated data, and often are not published in peer-reviewed journals.

Understanding the use of HER2 testing in cancer care is important because of its critical role in targeting therapy. Withholding trastuzumab from a patient with HER2-positive breast cancer (underuse) or giving trastuzumab to a patient with HER2-negative breast cancer (overuse) will result in suboptimal outcomes. In the former situation, patients may not benefit from the substantial reduction in the risk of death from breast cancer conferred by trastuzumab.²² In the latter situation, patients who will not benefit from treatment are exposed to an unnecessary risk of heart failure and the healthcare system incurs unnecessary costs of about $100,000 annually for trastuzumab.⁷

Our results do not challenge the efficacy of HER2 testing and trastuzumab treatment – rather, they suggest a need to collect data on the utilization of tests and treatment, and incorporate this information into rigorous analyses of best testing practices. It appears that some clinicians and payers assume that all eligible patients are being tested, that tests are accurate, and only patients with positive test results are receiving trastuzumab. Our review suggests that gaps in the literature are substantial, and that these important assumptions cannot yet be verified. Although it is likely that testing has improved over time, this study demonstrates that even if one assumes that these problems are no longer issues, the paradigm outlined by HER2 and trastuzumab is likely to be repeated over and over as new targeted therapies are developed. If we don’t understand the mistakes that were made as this test/treatment combination were introduced then we are likely to repeat them.

Testing is now recommended for all invasive breast cancers, but no studies examine how utilization has changed since 2005, when testing indications were expanded to include women with early-stage breast cancers. It is particularly concerning that there are no studies of testing among typically underserved patients, including the uninsured, Medicaid insured, and minorities.

Little is known about how many patients receive one or both of the tests currently recommended and to what extent those patients are retested to confirm the results. As guidelines recommend using either IHC or FISH, it is important to know which method is used and how that usage varies by patient, provider, and healthcare system factors. In addition, considering the substantial percentage of patients who have indeterminate IHC results that require FISH testing for confirmation, it is important to know whether those patients actually get confirmatory testing. It is not known how the introduction of a third FDA-approved test (CISH) will improve or further widen the gap of evidence on tests used.

In contrast to the lack of evidence for our other research questions, there is more solid evidence to suggest that a substantial percentage of HER2 tests performed by community laboratories are inaccurate, based on comparisons with higher-volume central or reference laboratories. The available studies may not be representative of routine practice, however, because they were conducted as a part of clinical trials and may therefore underestimate the extent of problems with test accuracy. Although there may be times when community labs have more accurate results, e.g. if the lesional tissue is small it may no longer be present on samples submitted to the reference lab or if the reference lab mistake DCIS for invasive carcinoma. However, we do not know of any studies that suggest the likelihood a patient will respond to the drug is more consistent with data from community vs. central labs.

Reasons for discordance between laboratory results are complex and include differences in how laboratories perform and interpret tests as well as the lack of consensus about accepted procedures. Several initiatives are being pursued to resolve these issues and standardize laboratory performance and there is increasing scrutiny of in house laboratory (“home brew”) tests; for example, recently developed guidelines recommend that HER2 testing be done in a CAP-accredited laboratory.⁷ Considering the serious implications of inaccurate tests for patients’ lives and the impact on the healthcare system, it is essential to have more data on test quality and interpretation. As one industry observer noted, “We need more rigorous validation processes. It has been like the wild, wild West out there.” ²³

It is also important to note that one study found that up to 20% of women receiving trastuzumab have no documentation of a positive HER2 test and one study found that up to 66% of eligible patients had no documentation of testing in claims records. However, these findings have not been published in detail, are not based on recent data, and do not distinguish between women who were not tested and those who had been tested but were missing documentation of testing or results in claims records. We found similar results in a pilot study of one health plan, and we have a larger and more recent study underway. ²⁴ These findings argue for more standardized test reporting practices, with requirements such as the inclusion of both quantitative and qualitative assessments from pathology reports.

Actual practice patterns may have a substantial impact on the costs and effectiveness of testing and treatment in the adjuvant setting, yet such analyses have not been conducted. Analyses examining the costs and effectiveness of current testing guidelines and how they might vary in actual practice are sorely needed.

Implications

Our findings regarding HER2 testing illustrate both the challenges and opportunities in building an evidence base to support effective and efficient decision-making about emerging testing technologies in cancer care. HER2 testing provides an example of a test that is clinically beneficial but that faces quality and implementation challenges – and such challenges will increasingly become relevant as more new testing technologies and targeted therapies emerge.^{25, 26} The underlying science and associated guidelines for testing technologies are evolving quickly, and the different new technologies make it harder to ensure that testing is done correctly and the results are interpreted appropriately. HER2 testing, as with many diagnostic tests, does not provide a black and white answer about treatment decisions.

With complex testing scenarios, there is ample room for mistakes and misinterpretation along the entire testing sequence.²³ Thus, one solution is greater standardization of test procedures and processes. Communication between the laboratory and the clinician may be of particular importance; for example, in the case of HER2 testing, the speculation is that patients with indeterminate scores are being treated as positive results.²³ Decision analytic tools for clinicians could facilitate improved interpretations and communications.

Another solution is increasing the amount of data available on testing technologies. Historically, there have been less data available on diagnostics than on other interventions, such as pharmaceuticals or surgical procedures – a gap that has taken on greater significance as the use of diagnostics to target therapies has accelerated. One major gap is the lack of administrative databases linking testing, test results, treatment, and outcomes. In the case of HER2 testing, claims databases do not typically include information on test results. Moreover, it is often impossible to identify the use of testing in administrative databases because of a lack of billing codes specific to each test or type of test received by a patient. In health insurance claims, the use of IHC and FISH tests for HER2 detection cannot be reliably distinguished from the same types of assays performed for other indications. Although Current Procedural Terminology code modifiers have been developed by the American Medical Association to differentiate specific tests, these modifiers are not commonly used in clinical practice. In addition, test codes may be bundled into a common pathology code that does not permit the identification of individual tests.