Intra-patient and inter-metastasis heterogeneity of HER2-low status in metastatic breast cancer

• Published in: European journal of cancer (1990) Vol. 188; pp. 152 - 160
• Main Authors: Geukens, Tatjana, De Schepper, Maxim, Richard, François, Maetens, Marion, Van Baelen, Karen, Mahdami, Amena, Nguyen, Ha-Linh, Isnaldi, Edoardo, Leduc, Sophia, Pabba, Anirudh, Zels, Gitte, Mertens, Freya, Vander Borght, Sara, Smeets, Ann, Nevelsteen, Ines, Punie, Kevin, Neven, Patrick, Wildiers, Hans, Van Den Bogaert, Wouter, Floris, Giuseppe, Desmedt, Christine
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2023
• Subjects: Antibody-drug conjugate; Biomarkers, Tumor - analysis; Biopsy; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Female; HER2-low; Heterogeneity; Humans; In Situ Hybridization; Metastasis; Receptor, ErbB-2 - genetics; Heterogeneity; HER2-low; Breast cancer; Metastasis; Antibody-drug conjugate
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2023.04.026

Anti-HER2 antibody-drug conjugates (ADCs) have shown important efficacy in HER2-low metastatic breast cancer (mBC). Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy. We assessed the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative mBC. We included samples of 10 patients (7 ER-positive and 3 ER-negative) donated in the context of our post-mortem tissue donation program UPTIDER. Excisional post-mortem biopsies of 257 metastases and 8 breast tumours underwent central HER2 immunohistochemistry (IHC), alongside 41 pre-mortem primary or metastatic samples. They were classified as HER2-zero, HER2-low (HER2-1+ or HER2-2+, in situ hybridisation [ISH] negative) or HER2-positive (HER2-3+ or HER2-2+, ISH-positive) following ASCO/CAP guidelines 2018. HER2-zero was further subdivided into HER2-undetected (no staining) and HER2-ultralow (faint staining in ≤10% of tumour cells). Median post-mortem interval was 2.5 h. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%. A total of 32% of metastases currently classified as HER2-zero were HER2-ultralow. Intra-organ inter-metastasis heterogeneity of HER2-scores was observed in the liver in 3/6 patients. Patients with primary ER-positive disease had a higher proportion of HER2-low metastases as compared to ER-negative disease (46% versus 8%, respectively). At the metastasis level, higher percentages of ER-expressing cells were observed in HER2-low or -ultralow as compared to HER2-undetected metastases. Important intra-patient inter-metastasis heterogeneity of HER2-low status exists. This questions the validity of HER2-low in its current form as a theranostic marker. [Display omitted] •HER2-low metastatic breast cancer is now clinically actionable.•It’s unknown how discordant HER2 status is between multiple metastases in a patient.•We assessed HER2 in 306 post- and pre-mortem samples from 10 HER2-negative patients.•In 8/10 patients, HER2-low and HER2-zero metastases co-existed.•This intra-patient heterogeneity of HER2 status complicates its theranostic value.