Clinical and Health Economic Outcomes of Alternative HER2 Test Strategies for Guiding Adjuvant Trastuzumab Therapy

James A Lee; Megan Shaheen; Thomas Walke; Matt Daly

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(3):325-341. 

In This Article

Abstract and Introduction

Abstract

Aim: To evaluate the clinical outcomes and cost–effectiveness of human epidermal growth factor receptor 2 (HER2) testing strategies to guide adjuvant trastuzumab (AT) therapy in women with HER2-positive breast cancer.
Methods: A literature review produced 72 studies comparing HER2 test methods, and we computed concordance (assuming fluorescence in situ hybridization [FISH] as a reference assay) to assess performance relative to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. An economic analysis provided cost–effectiveness of alternative strategies, including a Monte Carlo simulation to vary key assumptions such as test price and performance.
Results: Of 46 studies comparing immunohistochemistry (IHC) and FISH, only seven met the ASCO/CAP guideline of 95% or better concordance. A total of 14 out of 21 studies comparing chromogenic in situ hybridization and three out of five studies comparing silver-enhanced in situ hybridization met the guideline. Confirmation of IHC 2+ and 3+ and primary FISH strategies are likely to reduce costs and improve quality of life relative to confirmation of IHC 2+ only. Initial testing with a gene amplification-based assay is probably a cost-effective alternative to confirmation of IHC 2+ and 3+. The results are not sensitive to varying test price but are sensitive to test accuracy below 98%.
Conclusion: Using a primary gene amplification-based assay to guide AT therapy for HER2-positive breast cancer probably results in lower US medical costs, increased life-years and increased quality of life compared with confirmation of IHC 2+ with a gene amplification-based assay. We recommend the ASCO/CAP guidelines reflect 98% or greater concordance relative to a reference assay. Additional research regarding therapy response is required to further differentiate between gene amplification-based assays.

Introduction

Breast cancer is the second leading cause of cancer death among women in the USA.[1] Overexpression of the human epidermal growth receptor 2 (HER2) is associated with increased tumor growth rates, increased disease recurrence, decreased survival and poor response to chemotherapy in women with breast cancer.[2–4] Overexpression of HER2 occurs in 20–30% of cases of breast cancer, although some suggest this may be an overestimate.[5,6]

Trastuzumab (Herceptin®, Genentech, Inc., CA, USA) is a humanized monoclonal antibody that has anti-tumor activity against HER2-overexpressing breast tumor cells.[7,8] Concurrent trastuzumab treatment with chemotherapy in HER2-positive women has been shown to dramatically reduce recurrence and mortality.[9] However, treatment with trastuzumab is costly[10] and may be associated with cardiotoxicity.[11] It is therefore important that only women who may potentially benefit from the treatment (those who are HER2-positive) receive it, and that those with little to no chance of benefit are not subjected to its possible side effects.

There is an ongoing debate regarding alternative HER2 testing strategies for adjuvant trastuzumab (AT) therapy. Current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines propose an algorithm for either primary immunohistochemistry (IHC) or primary fluorescence in situ hybridization (FISH).[12] Furthermore, according to the guidelines, an alternative test should show at least 95% concordance for positive and negative values with the validated assay to which it is compared. Individuals interpreting the assay must also have their concordance confirmed externally, and this concordance should also be at least 95%.[12]

According to the ASCO/CAP guidelines, a positive HER2 test is defined as either "IHC result of 3+ cell surface protein expression" or a "FISH result of amplified HER2 gene copy number" or a "HER2/CEP 17 ratio of more than 2.2".[12] A negative result for IHC is HER2 protein expression of IHC 0 or 1+ and for HER2 gene amplification, a FISH ratio less than 1.8 or HER2 gene copy less than 4.0.

Regarding equivocal results, in the case of IHC, this consists of samples scored 2+ and may include up to 15% of samples. Equivocal results are confirmed with a validated assay for gene amplification, such as FISH. Originally, FISH test results were defined as either positive or negative, but an equivocal category has since been postulated. The equivocal range for FISH assays is defined as "HER2/CEP 17 ratios from 1.8–2.2 or average gene copy numbers between 4.0 and 6.0 for those systems without an internal control probe".[12] Approximately 2% of breast cancers have HER2 FISH ratios in the 1.8–2.2 range.[13,14] Before the introduction of an equivocal category, FISH ratios between 2.0 and 2.2 were considered HER2 positive and were eligible for treatment in the AT clinical trials.[12] Equivocal FISH results may be confirmed with a retest, counting of additional cells or testing with IHC.[12]

With the US FDA approval of chromogenic in situ hybridization (CISH) in July 2008[101] and several publications comparing CISH test results to IHC and FISH test results, there is increased interest in incorporating CISH within testing algorithms.[15–18,101] CISH is an extension of FISH, but is performed using bright-field microscopy with added benefits relative to FISH of observation of morphological features and permanent archiving of slides.[19] CISH may be performed using a single-color detection of the HER2 gene, with detection of chromosome 17 included in the test assay when completed on another slide. Alternatively, dual-color CISH is based on single-color detection of a dioxigenin-labeled HER2 probe and a biotin-labeled probe for chromosome 17.[20]

A third gene-based assay is silver-enhanced in situ hybridization (SISH), a rapid, fully automated assay that uses bright-field microscopy with molecular analysis. Chromogenic signals are detected through the use of silver deposition technology. SISH is technically comparable with FISH, but as with CISH does not require a fluorescence microscope for its interpretation.[21]

While several studies comparing CISH, IHC and FISH test results have been performed, CISH has been researched less than FISH and the body of evidence relating to its concordance with treatment outcome is scarce.[101] Furthermore, CISH is seldom referenced in recent systematic clinical reviews and was not specifically included in recent economic analyses of alternative HER2 testing strategies.[10,22–26] This analysis creates clarity regarding the IHC and FISH testing algorithms and their associated likely clinical and economic outcomes and provides a first systematic, comparative analysis of potential clinical and economic outcomes of CISH, SISH and FISH-guided AT therapy.

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