DDB2 expression lights the way for precision radiotherapy response in PDAC cells, with or without olaparib.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Therapeutic options for PDAC are primarily restricted to surgery in the early stages of the disease or chemotherapy in advanced disease. Only a subset of patients with germline defects in BRCA1/2 genes can potentially benefit from personalized therapy, with the PARP inhibitor olaparib serving as a maintenance treatment for metastatic disease.

[Development of an artificial intelligence system to improve cancer clinical trial eligibility screening].

Introduction: The recruitment step of all clinical trials is time consuming, harsh and generate extra costs. Artificial intelligence tools could improve recruitment in order to shorten inclusion phase. The objective was to assess the performance of an artificial intelligence driven tool (text mining, machine learning, classification…) for the screening and detection of patients, potentially eligible for recruitment in one of the clinical trials open at the "Institut de Cancérologie de Lorraine".

Tumor-derived cell-free DNA and circulating tumor cells: partners or rivals in metastasis formation?

The origin of metastases is a topic that has sparked controversy. Despite recent advancements, metastatic disease continues to pose challenges. The first admitted model of how metastases develop revolves around cells breaking away from the primary tumor, known as circulating tumor cells (CTCs).

Integrated Molecular Characterization of HER2-Low Breast Cancer Using Next Generation Sequencing (NGS).

Based on immunohistochemistry (IHC) and in situ hybridization (ISH), HER2-low breast cancers (BC) subtype-defined as IHC1+ or IHC2+/ISH- tumors-emerged and represent more than half of all BC. We evaluated the performance of NGS for integrated molecular characterization of HER2-low BC, including identification of actionable molecular targets, copy number variation (CNV), and microsatellite instability (MSI) analysis. Thirty-one BC specimens (11 HER2+, 10 HER2-, and 10 HER2-low) were routinely analyzed using IHC and ISH, and were selected and analyzed using NGS for gene mutations including , , , , , , and , CNV, and MSI.

Gene Mutations and Liquid Biopsy in ER-Positive Breast Cancers: A Small Step Forward, a Giant Leap for Personalization of Endocrine Therapy?

The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators.

CRISPR/Cas9-mediated knock-in of BRCA1/2 mutations restores response to olaparib in pancreatic cancer cell lines.

Pancreatic cancer is one of the most aggressive diseases with a very poor outcome. Olaparib, a PARP inhibitor, as maintenance therapy showed benefits in patients with metastatic pancreatic adenocarcinoma bearing germline BRCA1/2 mutations. However, germline BRCA mutation has been described in only 4-7% of patients with pancreatic adenocarcinoma.

Validation of the Idylla GeneFusion assay to detect fusions and MET exon-skipping in non-small cell lung cancers.

Gene fusions and MET exon skipping drive oncogenesis in 8-9% and 3% of non-small cell lung cancers (NSCLC) respectively. Their detection are essential for the management of patients since they confer sensitivity to specific targeted therapies with significant clinical benefit over conventional chemotherapy. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) account for historical reference techniques however molecular-based technologies (RNA-based sequencing and RT-PCR) are emerging as alternative or complementary methods.

Personalized follow-up of circulating DNA in resected stage III/IV melanoma: PERCIMEL multicentric prospective study protocol.

Background: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors.

DDB2 represses epithelial-to-mesenchymal transition and sensitizes pancreatic ductal adenocarcinoma cells to chemotherapy.

Introduction: Damage specific DNA binding protein 2 (DDB2) is an UV-indiced DNA damage recognition factor and regulator of cancer development and progression. DDB2 has dual roles in several cancers, either as an oncogene or as a tumor suppressor gene, depending on cancer localization. Here, we investigated the unresolved role of DDB2 in pancreatic ductal adenocarcinoma (PDAC).

Conversational hypnosis versus standard of care to reduce anxiety in patients undergoing marker placement under radiographic control prior to breast cancer surgery: A randomized, multicenter trial.

Background: Surgery is a cornerstone of breast cancer management. Prior to surgery, a wire marker is placed at the site of the tumor, to enable the surgeon to accurately localize the lesion during later surgery. This procedure can generate considerable anxiety for many patients.

Deciphering Tumour Heterogeneity: From Tissue to Liquid Biopsy.

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus molecular classifications for specific cancers.

Intraoperative prediction of non-sentinel lymph node metastases in breast cancer using cytokeratin 19 mRNA copy number: A retrospective analysis.

One-step nucleic acid amplification (OSNA) is a molecular procedure used intraoperatively for the detection of sentinel lymph node (SLN) metastases. The aim of the present study was to define a cut-off of cytokeratin (CK)19 mRNA copy number predictive of positive completion axillary lymph node dissection (ALND). The OSNA procedure was employed for SLN analysis in 812 patients with T1-T2 N0 breast cancer.

A phase II randomised study of preoperative trastuzumab alone or combined with everolimus in patients with early HER2-positive breast cancer and predictive biomarkers (RADHER trial).

Introduction: Resistance to trastuzumab in breast cancer is an ongoing challenge. Clinical and biological effects of co-targeting HER2 and mammalian target of rapamycin (mTOR) in patients with HER2-positive early operable breast cancer via the addition of everolimus to preoperative trastuzumab were evaluated in a phase II randomised study.

Methods: Patients were randomised 1:1 to receive trastuzumab (4 mg/kg initial dose then 2 mg/kg weekly for 5 weeks) alone or combined with everolimus (10 mg/day for 6 weeks) and then underwent surgery.

Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities.

Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis.

A NGS-based Blood Test For the Diagnosis of Invasive HPV-associated Carcinomas with Extensive Viral Genomic Characterization.

Purpose: Use of circulating tumor DNA (ctDNA) for diagnosis is limited regarding the low number of target molecules in early-stage tumors. Human papillomavirus (HPV)-associated carcinomas represent a privileged model using circulating viral DNA (ctHPV DNA) as a tumor marker. However, the plurality of HPV genotypes represents a challenge.

Evaluation of the Idylla ctEGFR mutation assay to detect EGFR mutations in plasma from patients with non-small cell lung cancers.

The assessment of EGFR mutations is recommended for the management of patients with non-small cell lung cancer (NSCLC). Presence of EGFR mutation is associated with response or resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Liquid biopsy is nowadays widely used for the detection of resistance to EGFR-TKI.

Detection of Microsatellite Instability: State of the Art and Future Applications in Circulating Tumour DNA (ctDNA).

Microsatellite instability (MSI) is a molecular scar resulting from a defective mismatch repair system (dMMR) and associated with various malignancies. MSI tumours are characterized by the accumulation of mutations throughout the genome and particularly clustered in highly repetitive microsatellite (MS) regions. MSI/dMMR status is routinely assessed in solid tumours for the initial screening of Lynch syndrome, the evaluation of cancer prognosis, and treatment decision-making.

Advanced co-culture 3D breast cancer model for investigation of fibrosis induced by external stimuli: optimization study.

Radiation-induced fibrosis (RIF) is the main late radiation toxicity in breast cancer patients. Most of the current 3D in vitro breast cancer models are composed by cancer cells only and are unable to reproduce the complex cellular homeostasis within the tumor microenvironment to study RIF mechanisms. In order to account complex cellular interactions within the tumor microenvironment, an advanced 3D spheroid model, consisting of the luminal breast cancer MCF-7 cells and MRC-5 fibroblasts, was developed.

Evaluation of 3 molecular-based assays for microsatellite instability detection in formalin-fixed tissues of patients with endometrial and colorectal cancers.

Microsatellite instability (MSI) status is routinely assessed in patients with colorectal and endometrial cancers as it contributes to Lynch syndrome initial screening, tumour prognosis and selecting patients for immunotherapy. Currently, standard reference methods recommended for MSI/dMMR (deficient MisMatch Repair) testing consist of immunohistochemistry and pentaplex PCR-based assays, however, novel molecular-based techniques are emerging. Here, we aimed to evaluate the performance of a custom capture-based NGS method and the Bio-Rad ddPCR and Idylla approaches for the determination of MSI status for theranostic purposes in 30 formalin-fixed paraffin embedded (FFPE) tissue samples from patients with endometrial (n = 15) and colorectal (n = 15) cancers.

SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade.

Evaluation of KRAS, NRAS and BRAF mutations detection in plasma using an automated system for patients with metastatic colorectal cancer.

Background: Cell-free DNA detection is becoming a surrogate assay for tumor genotyping. Biological fluids often content a very low amount of cell-free tumor DNA and assays able to detect very low allele frequency mutant with a few quantities of DNA are required. We evaluated the ability of the fully-automated molecular diagnostics platform Idylla for the detection of KRAS, NRAS and BRAF hotspot mutations in plasma from patients with metastatic colorectal cancer (mCRC).

Identification of Specific Tumor Markers in Vulvar Carcinoma Through Extensive Human Papillomavirus DNA Characterization Using Next Generation Sequencing Method.

Objectives: A subset of vulvar carcinomas (VC) are associated with human papillomavirus (HPV) DNA. This trait can be used to identify tumor markers for patient's follow-up. A large diversity of HPV prevalence in VC has been reported, but no data are available concerning the insertional HPV status in this tumor type.

Rapid fully-automated assay for routine molecular diagnosis of mutations for personalized therapy of low grade gliomas.

mutation analysis is important to personalize the management with low-grade gliomas (LGG) in children and adults, with therapeutic and prognostic impacts. In recurrent tumors, targeted therapies such as BRAF inhibitors had been reported to induce disease stabilization and significant radiographic responses. This highlights the potential interest of mutation to stratify patients for targeted therapy.

Emerging Roles of DDB2 in Cancer.

Damage-specific DNA-binding protein 2 (DDB2) was originally identified as a DNA damage recognition factor that facilitates global genomic nucleotide excision repair (GG-NER) in human cells. DDB2 also contributes to other essential biological processes such as chromatin remodeling, gene transcription, cell cycle regulation, and protein decay. Recently, the potential of DDB2 in the development and progression of various cancers has been described.