Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer

Abstract

Background: The importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options.

Methods: Breast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared.

Results: Of the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]).

Conclusions: This study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy.

Keywords: breast cancer; discordance rate; fluorescence in situ hybridization; human epidermal growth factor receptor 2; immunohistochemistry; local and central HER2 testing.

Figure 1

Flowchart of patient samples that were tested. Abbreviation: HER2, human epidermal growth factor receptor 2.

Figure 2

Example of discordant immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) testing results (courtesy of Clarient, Inc.).

Figure 3

Estimated number of patients in the United States diagnosed annually with human epidermal growth factor receptor 2 (HER2)-negative tumors by local testing, but HER2-positive by central testing based on a discordance rate of 4.0%. ^aBased on American Cancer Society estimates of N = 229,060 new cases of breast cancer in 2012 and 80% HER2-negative.