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Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells

Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells

Published on: May 9, 2025

Clinical Outcomes and Efficacy of Human Epidermal Growth Factor Receptor 2-Targeted Therapy in Breast Cancer With

Qianchen Zhang¹, Jincong Q Freeman^2,3, Fangyuan Zhao²

¹Committee on Computational and Applied Mathematics, The University of Chicago, Chicago, IL.

JCO Oncology Advances

|September 12, 2025

Abstract

Purpose:

Human epidermal growth factor receptor 2 (HER2)-targeted therapy improves outcomes in HER2+ breast cancer, but efficacy in cases with discordant immunohistochemistry (IHC) and in situ hybridization (ISH) results or with ASCO/College of American Pathologists (CAP) group 2-4 ISH results remains uncertain.

Methods:

This retrospective study included patients from the National Cancer Database diagnosed from 2013 to 2021. Cases were classified as classically HER2+ (HER2/centromeric region of chromosome 17 [CEP17] ratio ≥2 with HER2 copy number ≥4, IHC 2-3+), HER2- (ratio <2, copy number <4, IHC 0-2+), discordant ISH/IHC, or HER2+ with ISH group 2 (ratio ≥2, copy number <4), group 3 (ratio <2, copy number ≥6), or group 4 (ratio <2, copy number ≥4 and <6) per ASCO/CAP guidelines. Adjusted odds ratio (aOR) for pathologic complete response (pCR) for these subgroups receiving HER2-targeted therapy was calculated compared with HER2- controls.

Results:

We identified N = 144,013 patients with IHC and dual-probe ISH. Of HER2 IHC 3+ cases (n = 8,579), 8.2%, 2.8%, 4.2%, and 8.8% had ISH categorized as groups 2, 3, 4, and 5 (discordant negative), respectively. Classically, HER2+ (aOR, 2.9 [95% CI, 2.65 to 3.18], P < .001) and group 2 (aOR, 2.38 [95% CI, 1.42 to 3.96], P < .001) treated with HER2-targeted therapy had higher pCR than HER2- controls. Benefit was also seen in group 3 (aOR, 1.63 [95% CI, 1.24 to 2.13], P < .001) and cases with discordant ISH+/IHC- (aOR, 1.61 [95% CI, 1.13 to 2.30], P = .008)-but this was only significant in group 3 cases with copy number ≥8 and discordant ISH+/IHC- cases with HER2/CEP17 ratio ≥3. Group 4 ISH cases and cases with ISH-/IHC+ did not benefit.

Conclusion:

Patients with ASCO/CAP group 4, discordant ISH-/IHC+ results, and weakly amplified group 3 and discordant ISH+/IHC- have low benefit from HER2 therapy, and alternative approaches for such patients are needed.

Insights

HER2-targeted therapy benefits patients with classically HER2+ or ASCO/CAP group 2 breast cancer. However, limited benefit is observed in certain discordant or weakly amplified HER2 cases, necessitating alternative treatment strategies.

Area of Science:

Oncology
Molecular Diagnostics
Clinical Pathology

Background:

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have improved outcomes for HER2-positive (HER2+) breast cancer patients.
Uncertainty exists regarding the efficacy of these therapies in cases with discordant immunohistochemistry (IHC) and in situ hybridization (ISH) results or specific ASCO/College of American Pathologists (CAP) ISH classifications (groups 2-4).

Purpose of the Study:

To evaluate the efficacy of HER2-targeted therapy in HER2+ breast cancer patients with varying IHC and ISH results, including discordant cases and specific ASCO/CAP ISH groups.
To compare the pathologic complete response (pCR) rates among different HER2 subgroups receiving HER2-targeted therapy.

Main Methods:

Retrospective analysis of 144,013 patients from the National Cancer Database (2013-2021) with IHC and dual-probe ISH testing.
Classification of cases into classically HER2+, HER2-, discordant ISH/IHC, and specific ASCO/CAP ISH groups (2, 3, 4).
Calculation of adjusted odds ratios (aOR) for pCR in subgroups treated with HER2-targeted therapy compared to HER2- controls.

Main Results:

Classically HER2+ and ASCO/CAP group 2 cases showed significantly higher pCR rates with HER2-targeted therapy (aOR 2.9 and 2.38, respectively).
Benefit was observed in ASCO/CAP group 3 (aOR 1.63) and discordant ISH+/IHC- cases (aOR 1.61), particularly with higher HER2/CEP17 ratios or copy numbers.
No significant benefit was found for ASCO/CAP group 4 ISH cases or ISH-/IHC+ cases.

Conclusions:

HER2-targeted therapy demonstrates significant benefit in classically HER2+ and ASCO/CAP group 2 breast cancer.
Patients with ASCO/CAP group 4, discordant ISH-/IHC+, or weakly amplified group 3 and discordant ISH+/IHC- HER2 statuses derive limited benefit from current HER2-targeted therapies.
Alternative treatment strategies should be considered for patients with limited benefit from HER2-targeted therapy.

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