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

Abstract

BACKGROUNDThe 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.METHODSBreast 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.RESULTSOf 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]).CONCLUSIONSThis 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. Cancer 2014;120:2657–2664.

Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK)

“…misjudgment, we would like to recommend 28.0 ng/ml as a cut-off value for advanced gastric cancer, limiting the purpose to identify tissue HER2 false-negative cases. The inter-laboratory discrepancy of tissue HER2 assessment was substantial in our study, and it has also demonstrated in breast cancer [25,26]. Perez et al evaluated diagnostic agreement rates of tissue HER2 status among local, central and reference laboratories in a large scale adjuvant trastuzumab trial for breast cancer [25].…”

Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma

“…Studies have shown a HER2 testing discrepancy between local and large reference laboratories, resulting in 14%-16% false-positive and 4% false-negative results (3,4). Such misclassification gives rise to unnecessary toxicity and cost for the former while denying a potentially efficacious therapy for the latter.…”

Relevance of deep learning to facilitate the diagnosis of HER2 status in breast cancer

“…Negative cases are not considered for anti-HER2 therapy. Significant diagnostic variability has been reported between pathologists5678910 and it is inferred that 4% of negative cases and 18% of positive cases are misdiagnosed711. In particular, scoring variability has been shown to be important for cases that show heterogeneous HER2 expression within the tumour cell population1213.…”