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A Comprehensive Analysis of HER2 status Heterogeneity Using Matched Samples among Potential Beneficiaries of
Haiyue Wang1, Wei Sun1, Chenglong Wang1
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China.
Background:
HER2 overexpression is defined as immunohistochemistry (IHC) 2+/3+, and trastuzumab deruxtecan (T-DXd) is approved for treating unresectable or metastatic solid tumors with HER2 3+. HER2 spatiotemporal heterogeneity is crucial for identifying patients responsive to T-DXd. While extensively studied in gastric and breast cancers, research in non-small cell lung cancer (NSCLC) is limited. We aim to examine HER2 expression and their implications for optimizing specimen selection in potential T-DXd beneficiaries.
Materials And Methods:
We retrospectively collected NSCLC cases from Peking University Cancer Hospital (2015-2024) with HER2 testing, matched specimens (resection vs. biopsy; primary vs. metastasis), at least 1 lesion with HER2 2+ or 3+. Two pathologists independently re-evaluated enrolled cases using gastric cancer criteria.
Results:
A total of 5211 cases underwent HER2 testing, with 2+ expression in 773 (14.8%) and 3+ in 35 (0.7%) cases. Ultimately, 129 patients met inclusion criteria, comprising 88 surgical/biopsy and 102 primary/metastatic samples. Concordance between biopsy and resection was 51.4% (38/74) for HER2 2+ and 21.4% (3/14) for HER2 3+, with significantly higher concordance for 2+ (P = .040). Concordance was 39.4% (28/85) for HER2 2+ and 35.4% (5/14) for HER2 3+ in primary vs metastatic tumors, with no significant difference between lymph node and distant metastases. Both biopsy and metastatic samples underestimated HER2 2+ and 3+ expression.
Conclusions:
Our study demonstrates that in potential NSCLC beneficiaries of T-DXd therapy, HER2 expression is underestimated in biopsy samples and metastatic lesions compared to resected and primary sites. This heterogeneity holds great significance for guiding clinical sample selection.
Insights
HER2 expression in non-small cell lung cancer (NSCLC) is often underestimated in biopsies and metastases. This finding is critical for selecting patients who may benefit from trastuzumab deruxtecan (T-DXd) therapy.
Area of Science:
- Oncology
- Molecular Diagnostics
- Cancer Therapeutics
Background:
- HER2 overexpression, defined by immunohistochemistry (IHC) 2+/3+, is a key biomarker.
- Trastuzumab deruxtecan (T-DXd) is approved for HER2 3+ unresectable or metastatic solid tumors.
- HER2 heterogeneity impacts T-DXd response, with limited research in non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To investigate HER2 expression in NSCLC.
- To evaluate HER2 spatiotemporal heterogeneity.
- To optimize specimen selection for potential T-DXd therapy beneficiaries.
Main Methods:
- Retrospective collection of NSCLC cases with HER2 testing (2015-2024).
- Inclusion of matched specimens: resection vs. biopsy, primary vs. metastasis.
- Independent re-evaluation of HER2 expression by two pathologists using gastric cancer criteria.
Main Results:
- Out of 5211 cases tested, 14.8% showed HER2 2+ and 0.7% showed HER2 3+.
- Concordance between biopsy and resection was 51.4% for HER2 2+ and 21.4% for HER2 3+.
- Biopsy and metastatic samples significantly underestimated HER2 2+ and 3+ expression compared to resected and primary sites.
Conclusions:
- HER2 expression is frequently underestimated in NSCLC biopsy and metastatic samples.
- Significant HER2 heterogeneity exists between primary and metastatic sites, and between biopsy and resection specimens.
- Findings emphasize the importance of careful clinical sample selection for T-DXd therapy eligibility in NSCLC.
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