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Diagnostic and Prognosis Value of Circulating DNA for CRC Patients’ Surveillance After Curative Treatment

ABSTRACT: Inspite of curative treatment 30-50% patients with ColoRectal Cancer (CRC) develop tumor relapse during the first 3 years after treatment of the primary tumor. Treatment of relapses is based on surgical resection, when possible, chemotherapy and targeted therapies. To detect recurrences or metastases, a surveillance strategy is recommended for patients able to withstand complementary treatment during a five-year period. Over this period, the probability of one false-positive result is 87%. Considering that less than 10% of recurrent patients are suitable for potentially curative treatment and that more intensive programs enable an increase of the overall rate of curative resection but do not result in reduced mortality, less time and cost-consuming, tailored follow-up is necessary. The level of circulating ccfDNA, defined as extra cellular DNA, increases in CRC patients. The Inplex method could validate the use of ccfDNA as a cancer biomarker in terms of prognosis and surveillance. Tubes for ccfDNA analysis will be taken during medical examination at the same time of the CEA dosage (if it was not made before the consultation). Cryotubes of plasma will be sent for analysis in the laboratory INSERM (National Health Institute) of Montpellier and the remaining plasma will be kept in biological collection. Patients will have a consultation of follow-up every 3-4 months during which the dosage of CEA and ccfDNA will be realized as well as a medical examination, a general examination (weight, size, and blood pressure), an evaluation of the indices of performance status and a nutritional evaluation in case of loss of weight.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2218342 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:These experiments were done as part of a larger study that investigated the mode of action of T-cell bispecific (TCB) antibodies (including CEA-TCB [cibisatamab]) by characterizing molecular and cellular features of immune cells and tumors following TCB treatment in vivo in humanized mice and syngeneic tumor models. To characterize the molecular parameters associated with CEA-TCB treatment we performed bulk RNA sequencing of CEA-TCB-treated and untreated tumors derived from MKN-45 tumor-bearing humanized mice. Tumor tissue was analyzed after seven consecutive TCB treatments and compared to matching controls. RNA sequencing analysis revealed a clear distinction between CEA-TCB-treated and control animals, with several genes being upregulated in tumors treated with CEA-TCB as compared to controls. Among the top 15 upregulated genes in CEA-TCB-treated tumors there were many reflective of a strong T-cell activation, migration, immune cell response (CXCL13, GNLY, GZMB, CXCL10, IDO1, SLA, CD2, TRBC2, TIGIT, IL2RB, CXCL9, CX3CL1, CCL4L2, and CD3E). Among the top downregulated ones we found keratin 6A and keratin 20 (KRT6A and KRT20) suggestive of the reduction of tumor cells as the result of TCB-mediated killing. A Gene Set Enrichment Analysis (GSEA) was conducted that further enabled identification of the main biological pathways upon CEA-TCB treatment and confirmed that the main Gene Ontology families that characterize the TCB response consist of T-cell activation (Response to interferon gamma; Adaptive Immune Response; T-cell activation; Inflammatory Response; Activation of Immune response; Cytokine secretion) and migration (Leukocyte Migration; Regulation of Cell Adhesion). We also noticed upregulation of many major histocompatibility class II molecules that are known to be expressed on antigen presenting cells (HLA-DRA, HLA-DRB5, and HLA-DRB1) along with CX3CL1 (fractalkine, a known monocyte/T-cell attractant molecule) and CSF1 (colony stimulating factor 1, macrophage) suggestive of myeloid cell recruitment and activation at tumor sites post TCB treatment. The signature appeared to be robust, as components of the signature were confirmed using complementary techniques: RNA expression analysis and protein expression as determined by flow cytometry and multiplex analysis.

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Diagnostic and Prognosis Value of Circulating DNA for CRC Patients’ Surveillance After Curative Treatment

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