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|Ref Type||Journal Article|
|Authors||Jordan NV, Bardia A, Wittner BS, Benes C, Ligorio M, Zheng Y, Yu M, Sundaresan TK, Licausi JA, Desai R, O'Keefe RM, Ebright RY, Boukhali M, Sil S, Onozato ML, Iafrate AJ, Kapur R, Sgroi D, Ting DT, Toner M, Ramaswamy S, Haas W, Maheswaran S, Haber DA|
|Title||HER2 expression identifies dynamic functional states within circulating breast cancer cells.|
|Date||2016 09 01|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 neg ERBB2 pos||Her2-receptor negative breast cancer||sensitive||Paclitaxel + RO4929097||Preclinical||Actionable||In a preclinical study, circulating tumor cells (CTC) from patients with ERBB2 (HER2)-negative breast cancer were demonstrated to contain both ERBB2 (HER2)-positive and ERBB2 (HER2)-negative subpopulations, and the combination of RO4929097 and Taxol (paclitaxel) resulted in increased tumor growth inhibition in CTC-derived xenograft models compared to either agent alone (PMID: 27556950).||27556950|
|ERBB2 neg ERBB2 pos||Her2-receptor negative breast cancer||sensitive||LY411575 + Paclitaxel||Preclinical||Actionable||In a preclinical study, circulating tumor cells (CTC) from patients with ERBB2 (HER2)-negative breast cancer were demonstrated to contain both ERBB2 (HER2)-positive and ERBB2 (HER2)-negative subpopulations, and the combination of LY411575 and Taxol (paclitaxel) resulted in increased tumor growth inhibition in CTC-derived xenograft models compared to either agent alone (PMID: 27556950).||27556950|