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Review
. 2025 Jun;57(4):403-414.
doi: 10.1016/j.pathol.2025.02.003. Epub 2025 Mar 19.

HER2-low across solid tumours: different incidences and definitions

Ximena Baez-Navarro  1 , Floris H Groenendijk  2 , Lindsey Oudijk  2 , Jan von der Thüsen  2 , Nicola Fusco  3 , Giuseppe Curigliano  4 , Carolien H M van Deurzen  2
Affiliations
Review

HER2-low across solid tumours: different incidences and definitions

Ximena Baez-Navarro et al. Pathology. 2025 Jun.

Abstract

Antibody-drug conjugates, particularly trastuzumab deruxtecan (T-DXd), have emerged as effective therapies for various solid tumours. Clinical trials show that T-DXd improves survival in both HER2-positive and HER2-low breast cancer patients. Additionally, it improves survival in HER2-positive gastro-oesophageal cancer and elicits objective responses in HER2-low tumours. Responses have also been noted in lung and gynaecological cancers with HER2 expression, although subgroup analyses for HER2-low cases are lacking. This review assesses HER2 protein expression levels and gene amplification across solid tumours where T-DXd shows potential benefits. We focus on the accuracy and limitations of HER2 testing methods, particularly for identifying HER2-low cancer. A semi-systematic approach was employed, searching EMBASE, Medline, Cochrane, and PubMed databases. We calculated median incidences of HER2-positive, HER2-low, and HER2-0 by immunohistochemistry (IHC), and HER2 amplification by in situ hybridisation (ISH). A total of 144 studies were included, covering breast (n=57), gastro-oesophageal (n=33), lung (n=17), gynaecological (n=24), and various other carcinomas (n=13). The median incidences of HER2-low were 52%, 16%, 58%, and 17% in breast, gastro-oesophageal, endometrial, and ovarian cancers, respectively, with unknown incidences in lung and cervical cancers. Factors influencing HER2-low detection include tumour heterogeneity, antibody clones, observer variability, and lack of validated scoring criteria. Given the significant proportion of HER2-low cases, many patients could benefit from T-DXd, but limitations in detection accuracy necessitate further research and standardisation in diagnostic methods and criteria to advance the clinical utility of T-DXd for HER2-low tumours.

Keywords: HER2-expression; HER2-low; NSCLC; breast cancer; gastro-oesophageal cancer; gene amplification; gynaecological cancer; immunohistochemistry; in situ hybridisation.

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