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. 2025 Mar 12:jcp-2025-210095.
doi: 10.1136/jcp-2025-210095. Online ahead of print.

Patterns of HER2 expression and genomic correlates in lung cancer, with a focus on preanalytical variables impacting immunohistochemical staining results

Cristiana M Pineda  1 , Lauren O'Loughlin  2 , Heather L Benjamin  2 , Deepa Rangachari  2 , Hollis Viray  2 , Page C Widick  2 , Zoe Guan  3 , Jason A Beattie  4 , Kai E Swenson  4 , Mihir S Parikh  4 , Adnan Majid  4 , Daniel B Costa  2 , Paul A VanderLaan  5
Affiliations

Patterns of HER2 expression and genomic correlates in lung cancer, with a focus on preanalytical variables impacting immunohistochemical staining results

Cristiana M Pineda et al. J Clin Pathol. .

Abstract

Aims: Fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved for advanced stage or metastatic solid tumours with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) 3+ staining. Data on HER2 IHC testing and knowledge of genomic correlates in lung cancer are scarce. This study analyses genomic characteristics of HER2-expressing tumours and addresses issues with preanalytical variables for lung cancer specimens.

Methods: HER2 IHC staining was performed on selected archival cytology and surgical pathology lung cancer specimens for patients eligible for T-DXd therapy. Patient and tumour characteristics and next-generation sequencing (NGS) data were correlated with HER2 IHC results.

Results: 166 patients with thoracic tumour samples had HER2 expression assessed: 46% were IHC 0, 28% IHC 1+, 13% IHC 2+ and 13% IHC 3+. HER2 IHC scores were overall lower for cytology cell blocks as compared with surgical pathology specimens; 79% of cases with paired specimens had a decrease in their HER2 IHC score from their surgical specimen to their paired cytology specimen. Of specimens with HER2 IHC 3+ and NGS available, only 14% (3/21) had concomitant ERBB2 alterations. Among all specimens, ERBB2 point mutations were noted in 4% (4/110) and ERBB2 amplification in 3% (3/110). The majority of HER2 3+ cases with paired NGS (17/21, 81%) had non-ERBB2 genomic alterations, including: KRAS, TP53, and STK11 mutations.

Conclusions: HER2 IHC 3+ is seen in a small but clinically significant proportion of samples and is associated with a variety of co-occurring non-ERBB2 genomic alterations. Preanalytical variables including specimen fixation can significantly impact the assessment of HER2 expression via immunohistochemistry.

Keywords: Cytological Techniques; IMMUNOHISTOCHEMISTRY; LUNG CANCER; Lung Neoplasms; Pathology, Molecular.

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Conflict of interest statement

Competing interests: CP reports her partner is an employee at AstraZeneca. DR reports receiving personal fees (consulting fees and honoraria) from Teladoc Health, DynaMed and AstraZeneca; non-financial support (institutional research support) from Bristol Myers Squibb, Novocure and AbbVie/Stemcentrx; all outside the submitted work. MSP reports role as an educational consultant for Intuitive Surgical, unrelated to the current work. AM reports receiving consulting fees and honoraria from Olympus America and Latin America, Boston Scientific, Cook Medical, Pulmonx, Praxis Medical, STERIS, Pinnacle Biologics and UpToDate, unrelated to the current work. DBC reports receiving consulting fees and honoraria from Takeda/Millennium Pharmaceuticals, AstraZeneca, Pfizer, Blueprint Medicines and Janssen, institutional research support from Takeda/Millennium Pharmaceuticals, AstraZeneca, Pfizer, Merck Sharp and Dohme, Merrimack Pharmaceuticals, Bristol Myers Squibb, Clovis Oncology, Spectrum Pharmaceuticals, Tesaro and Daiichi Sankyo, consulting fees from Teladoc and Grand Rounds by Included Health and royalties from Life Technologies, all outside the submitted work. PAV reports personal fees (consulting fees) from Gala Therapeutics, Galvanize Therapeutics, Ruby Robotics, Veracyte and Agilent Technologies; all outside the submitted work. HLB, LO’L, HV, PCW, ZG, JAB, KES have no disclosures to report.

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