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Cocktail & Poster Display session

58P - Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low-expressing breast cancer cells and organoid mode


06 Mar 2023


Cocktail & Poster Display session


Maryam Arshad


Annals of Oncology (2023) 8 (1suppl_2): 100896-100896. 10.1016/esmoop/esmoop100896


M. Arshad

Author affiliations

  • Cancer And Pharmaceutical Sciences, KCL - King's College London, WC2R 2LS - London/GB


This content is available to ESMO members and event participants.

Abstract 58P


Several studies suggested that a subset of the HER2-low breast tumours may respond to anti-HER2 treatments. The aim of this study is to understand the mechanisms of resistance to trastuzumab monotherapy and the effects of HER2 targeting treatments in HER2-low breast cancer cells.


The HER2 expression of a panel of eight breast cancer lines was assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) and their responses to trastuzumab were investigated. We further investigated the effect of different anti-HER2 treatments and/or ADAM10/17 inhibitor in two HER2 lower expressing cells.


We established a panel of patient-derived organoids (PDOs) from the cancer tissues obtained from breast cancer patients to assess the effects of these drugs. Compared to sensitive high (IHC3+) HER2 expressing breast cancer cells, moderately low HER2 expressing (IHC 2+) MDA-MB-361 and MDA-MB-453 cells showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in activation of HER receptors, which could account for trastuzumab insensitivity in these cells. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability in HER2-low breast cancer cells and PDOs. Nevertheless, a pan-HER inhibitor, neratinib monotherapy or in the combination with trastuzumab was effective in decreasing the activation of HER family receptors in HER2-low breast cancer cells. Furthermore, neratinib was effective in reducing cell viability in PDOs, although a greater effect was seen in the combination treatment.


This study highlighted that neratinib in combination with trastuzumab may be effective in a small subset of moderate to low HER2 expressing breast cancers and will require further validation in a larger panel of PDOs and in future clinical studies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

M. Arshad.


PUMA Biotechnology.


The author has declared no conflicts of interest.

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