Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Feb;86(3):441-449.
doi: 10.1111/his.15346. Epub 2024 Oct 17.

Discordance of human epidermal growth factor receptor 2-low status between breast primary and distant metastases with clinical-pathological correlation

Ellen Yang  1 , Timothy M D'Alfonso  2 , Monica Morrow  3 , Edi Brogi  4 , Hannah Y Wen  4
Affiliations

Discordance of human epidermal growth factor receptor 2-low status between breast primary and distant metastases with clinical-pathological correlation

Ellen Yang et al. Histopathology. 2025 Feb.

Abstract

Aims: Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in-situ hybridisation (ISH) (HER2-low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical-pathological correlation, with specific interest in HER2-low.

Methods: Biomarker studies and clinical-pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed.

Results: One hundred and forty-seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty-six (86%) were initially classified as 'HER2-negative'; of these, 67 (46%) were reclassified as HER2-low. Patients with HER2-positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2-low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty-nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as 'HER2-negative', and 62 (37%) were reclassified as HER2-low. Like HER2-low primaries, HER2-low metastases were frequently ER-positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2-positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2-low to HER2 0 (33 of 169, 20%), HER2 0 to HER2-low (17 of 169, 10%) and HER2-low to positive (10 of 169, 6%). All HER2-low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2-low to HER2 0 (16 of 47, 34%).

Conclusion: A significant proportion of previous 'HER2-negative' primaries and DM cases were reclassified as HER2-low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis.

Keywords: HER2 0; HER2‐low; breast carcinoma; clinicopathological correlation; distant metastasis.

PubMed Disclaimer

References

    1. Wolff AC, Somerfield MR, Dowsett M et al. Human epidermal growth factor receptor 2 testing in breast cancer: ASCO‐College of American pathologists guideline update. J. Clin. Oncol. 2023; 41; 3867–3872.
    1. Marchiò C, Annaratone L, Marques A, Casorzo L, Berrino E, Sapino A. Evolving concepts in HER2 evaluation in breast cancer: Heterogeneity, HER2‐low carcinomas and beyond. Semin. Cancer Biol. 2021; 72; 123–135.
    1. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS‐8201a, a novel anti‐human epidermal growth factor receptor 2 antibody‐drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016; 107; 1039–1046.
    1. Modi S, Jacot W, Yamashita T et al. Trastuzumab deruxtecan in previously treated HER2‐low advanced breast cancer. N. Engl. J. Med. 2022; 387; 9–20.
    1. Almstedt K, Krauthauser L, Kappenberg F et al. Discordance of HER2‐low between primary tumors and matched distant metastases in breast cancer. Cancers (Basel) 2023; 15; 1413.