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Correlation Between Circulating Tumour Markers Early Variations and Clinical Response in First Line Treatment of Metastatic Colorectal Cancer

ABSTRACT: The chemotherapy monitoring is currently based on radiological (RECIST 1.1 guideline) and clinical evaluation every 3 months. Circulating markers as Carcino Embryonic Antigen (CEA), circulating tumour DNA and total cell free DNA represent an alternative approach to evaluate the response. In the field of metastatic colorectal cancer (mCRC) recent studies suggest that early evaluation could be clinically relevant. Indeed, early tumoral response seems to be correlated to overall survival. Moreover, post-operative morbidity increases with the number of prior chemotherapy treatments. Early evaluation could allow to modify chemotherapy regimens when response appears to be insufficient. The aim of the present study is to evaluate, in a prospective cohort of patients treated with systemic IV chemotherapy (5 Fluorouracil +/- oxaliplatin +/- irinotecan) +/- targeted therapy as first line treatment for a mCRC, the correlation between early variations of circulating tumour markers including CEA, circulating tumour DNA and total cell free DNA, and the 3 months objective response as defined in the RECIST 1.1 guideline.

DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms,Circulating Markers

PROVIDER: 2222855 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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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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Correlation Between Circulating Tumour Markers Early Variations and Clinical Response in First Line Treatment of Metastatic Colorectal Cancer

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