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Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancer

ABSTRACT: Divergent estrogen receptor (ER) and HER2 status with breast cancer disease progression has important consequences for clinical management and long-term survival.  Molecular subtype expression is dynamic and influenced by therapeutic intervention and the metastatic environment. HER2 status, ER expression levels and global DNA methylation was assessed in pre-treatment biopsies, in post-treatment samples in patients with residual disease and, where relevant, in metastatic tumour samples. Mapping of the methylation landscape revealed global gains in hypomethylation following treatment (n=7 matched tumours, 16 samples) in contrast to hypermethylation on metastasis (n=5 matched tumours, 14 samples). Differential methylation of key signalling pathways, including estrogen response, epithelial to mesenchymal transition and PI3K/AKT/mTOR, is conserved between post-treatment and metastasis. However, where core pathway genes were hypomethylated following treatment, there was a shift to hypermethylation on metastasis, facilitating alterations in the tumour phenotype. This study unlocks DNA methylation as a key process in breast cancer progression providing vital insights into the effects of targeted HER2 treatment. This work provides a clear rationale to develop combined HER2 inhibitor and endocrine therapeutic strategies to enhance long-term survival in HER2 positive patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283272 | GEO | 2024/12/16

REPOSITORIES: GEO

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Project description:Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2- primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2- circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2+ and HER2- circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance. Seventy-four single candidate CTCs from two representative ER+/HER2- patients (BRx-42 and BRx-82) and 14 triple negative patients were isolated via micromanipulation and subjected to single-cell RNA-sequencing. Thirteen candidate CTCs expressed PTPRC at a level higher than 10 reads-per-million, so were deemed potential White Blood Cells and therefore dropped from further consideration. Expression profiles of CTCs expressing ERBB2 at a level greater than 10 RPM were compared with those expressing ERBB2 at a level less than 10 RPM.

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Neoadjuvant HER2 inhibition induces ESR1 DNA methylation alterations resulting in clinically relevant ER expression changes in breast cancer

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