Publications by authors named "Pierre Laurent-Puig"

294 Publications

Prognostic value of the PrP-ILK-IDO1 axis in the mesenchymal colorectal cancer subtype.

Oncoimmunology 2021 28;10(1):1940674. Epub 2021 Jun 28.

Centre de Recherche Des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France.

The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrP is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrP downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the integrin-linked kinase ILK as a proximal effector of PrP that mediates its control on the CMS4 phenotype. We further leveraged three independent large CRC cohorts to assess correlations in gene expression pattern with patient outcomes and found that ILK is overexpressed in CMS4 mesenchymal tumors and confers a poor prognosis, especially when combined with high expression of the PrP encoding gene . Of note, we discovered that the PrP-ILK signaling axis controls the expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase IDO1, a key player in immune tolerance. In addition, we monitored alterations in the levels of tryptophan and its metabolites of the kynurenine pathway in the plasma of metastatic CRC patients (n = 325) and we highlight their prognostic value in combination with plasma PrP levels. Thus, the PrP-ILK-IDO1 axis plays a key role in the mesenchymal subtype of CRC. PrP and IDO1-targeted strategies may represent new avenues for patient stratification and treatment in CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2021.1940674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244775PMC
June 2021

Pembrolizumab with Capox Bevacizumab in patients with microsatellite stable metastatic colorectal cancer and a high immune infiltrate: The FFCD 1703-POCHI trial.

Dig Liver Dis 2021 Jun 29. Epub 2021 Jun 29.

Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, Poitiers, France. Electronic address:

Pembrolizumab, a PD1 immune checkpoint inhibitor (ICI), was recently reported to be very effective in patients with microsatellite instable/deficient mismatch repair metastatic colorectal cancer (MSI/dMMR mCRC), unlike patients with microsatellite stable/proficient MMR (MSS/pMMR) mCRC, in whom ICIs are generally ineffective. However, about 15% of MSS/pMMR CRCs are highly infiltrated by tumour infiltrating lymphocytes. In addition, both oxaliplatin and bevacizumab have been shown to have immunomodulatory properties that may increase the efficacy of an ICI. We formulated the hypothesis that patients with MSS/pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin and bevacizumab-based chemotherapy. POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of Pembrolizumab with Capox Bevacizumab as first-line treatment of MSS/pMMR mCRC with a high immune infiltrate for which we plan to enrol 55 patients. Primary endpoint is progression-free survival (PFS) at 10 months, which is expected greater than 50%, but a 70% rate is hoped for. Main secondary objectives are overall survival, secondary resection rate and depth of response. Patients must have been resected of their primary tumour so as to evaluate two different immune scores (Immunoscore® and TuLIS) and are eligible if one score is "high". The first patient was included on April 20, 2021.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2021.06.009DOI Listing
June 2021

Intratumor CMS heterogeneity impacts patient prognosis in localized colorectal cance.

Clin Cancer Res 2021 Jun 24. Epub 2021 Jun 24.

UMR-S1138, Université Paris Descartes

Purpose: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of inter-tumor heterogeneity in colon cancer (CC). Intra-tumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of CC and understanding its potential prognostic implications Experimental Design: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 CC cell lines as weighted sums of the 4 CMS, using the WISP algorithm. We assigned to each tumor and cell line a combination of up to 3 CMS subtypes with a threshold above 20%.

Results: Over 55% of tumors corresponded to mixtures of at least two CMS, demonstrating pervasive ITH in CC. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival (OS), (hazard ratio 1.34, 95%CI [1.12-1.59], 1.40, 95%CI [1.14-1.71] respectively). Moreover, we uncovered specific combinations of CMS associated with dismal prognosis. In multivariate analysis, ITH represents the third parameter explaining DFS variance, after T and N stages. At a cellular level, combined WISP and single-cell transcriptomic analysis revealed that most CC cell lines are mixture of cells falling into different CMS, indicating that ITH may correspond to distinct functional statuses of CC cells.

Conclusions: This study shows that CMS-based transcriptomic ITH is frequent in CC and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of CC cells suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0529DOI Listing
June 2021

Risk of lung cancer among women in relation to lifetime history of tobacco smoking: a population-based case-control study in France (the WELCA study).

BMC Cancer 2021 Jun 16;21(1):711. Epub 2021 Jun 16.

Université Paris-Saclay, UVSQ, Inserm U1018, CESP, Team Exposome and Heredity, Villejuif, France.

Background: This study aims to provide new insights on the role of smoking patterns and cigarette dependence in female lung cancer, and to examine differences by histological subtype.

Methods: We conducted a population-based case-control study in the great Paris area among women including 716 incident cases diagnosed between 2014 and 2017 and 757 age-matched controls. Detailed data on smoking history was collected during in-person interviews to assess intensity and duration of tobacco smoking, time since cessation, smoking habits (depth of smoke inhalation, use of filter, type of tobacco, and type of cigarettes) and Fagerström test for cigarette dependence. The comprehensive smoking index (CSI), a score modelling the combined effects of intensity, duration and time since quitting smoking was determined for each subject. Multivariable logistic regression models were fitted to calculate odds ratios (ORs) and their confidence intervals (95%CI) of lung cancer associated with smoking variables.

Results: Lung cancer risk increased linearly with intensity and duration of tobacco smoking while it decreased with time since cessation, to reach the risk in never-smokers after 20 years of abstinence. The combined effect of intensity and duration of tobacco smoking was more than multiplicative (p-interaction 0.012). The OR in the highest vs the lowest quartile of CSI was 12.64 (95%CI 8.50; 18.80) (p-trend < 0.001). The risk of small cell or squamous cell carcinomas increased with the CSI more sharply than the risk of adenocarcinomas. Deep smoke inhalation, dark vs blond tobacco, conventional vs light cigarettes, and unfiltered vs filtered cigarettes, as well as having mixed smoking habits, were found to be independent risk factors. Having high cigarette addiction behaviours also increased the risk after adjusting for CSI.

Conclusion: This study provides additional insights on the effects of tobacco smoking patterns on lung cancer risk among women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08433-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207748PMC
June 2021

Characterization of Plasma Cell-Free DNA Integrity Using Droplet-Based Digital PCR: Toward the Development of Circulating Tumor DNA-Dedicated Assays.

Front Oncol 2021 6;11:639675. Epub 2021 May 6.

Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, USPC, Université de Paris, Equipe labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, Paris, France.

Cellular-cell free-DNA (ccfDNA) is being explored as a diagnostic and prognostic tool for various diseases including cancer. Beyond the evaluation of the ccfDNA mutational status, its fragmentation has been investigated as a potential cancer biomarker in several studies. However, probably due to a lack of standardized procedures dedicated to preanalytical and analytical processing of plasma samples, contradictory results have been published. ddPCR assays allowing the detection of wild-type and mutated sequences ( p.G12V, pG12D, and pG13D) were designed to target different fragments sizes. Once validated on fragmented and non-fragmented DNA extracted from cancer cell lines, these assays were used to investigate the influence of the extraction methods on the non-mutated and mutated ccfDNA integrity reflected by the DNA integrity index (DII). The DII was then analyzed in two prospective cohorts of metastatic colorectal cancer patients (RASANC study = 34; PLACOL study = 12) and healthy subjects ( = 49). Our results demonstrate that ccfDNA is highly fragmented in mCRC patients compared with healthy individuals. These results strongly suggest that the characterization of ccfDNA integrity hold great promise toward the development of a universal biomarker for the follow-up of mCRC patients. Furthermore, they support the importance of standardization of sample handling and processing in such analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.639675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174096PMC
May 2021

Prognostic value and relation with adjuvant treatment duration of ctDNA in stage III colon cancer: a post-hoc analysis of the PRODIGE-GERCOR IDEA-France trial.

Clin Cancer Res 2021 Jun 3. Epub 2021 Jun 3.

UMR-S1138, Université Paris Descartes.

Purpose: Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.

Experimental Design: ctDNA was tested for and by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).

Results: Of 2010 randomized patients, 1345 had available ctDNA samples (1017 collected both post-surgery and pre-chemotherapy). More ECOG PS of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (=1017) versus not analyzed (=993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (=0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR=1.55, 95% CI 1.13-2.12, =0.006) and OS (HR=1.65, 95% CI 1.12-2.43, =0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1-3/N1 tumors.

Conclusions: In this first ctDNA assessment of a large series of stage III colon cancer patients enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0271DOI Listing
June 2021

Circulating tumor DNA in advanced non-small-cell lung cancer patients with HIV is associated with shorter overall survival: Results from a Phase II trial (IFCT-1001 CHIVA).

Lung Cancer 2021 07 13;157:124-130. Epub 2021 May 13.

Université de Paris, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Team Inflammation, Complement, and Cancer, F-75006 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Georges Pompidou, Hôpital Cochin, Hôpital Necker, Paris Cancer Institute CARPEM, Paris, France.

Introduction: HIV is an exclusion criterion for most lung cancer (LC) trials, however LC is the most common non-AIDS-defined malignancy in people living with HIV (PLHIV), poorer prognosis than the general population. Circulating tumor DNA (ctDNA) was a prognostic marker in LC patients from the general population. This study assessed ctDNA's prognostic value in PLHIV from a dedicated phase II trial.

Methods: Overall, 61 PLHIV with advanced non-squamous non-small-cell lung cancer (NSCLC) participated in the IFCT Phase II trial evaluating first-line four-cycle carboplatin (Ca) AUC5 pemetrexed (P) 500 mg/m induction therapy every 3 weeks, followed by P maintenance therapy. Blood samples collected before treatment were analyzed to detect ctDNA using ultra-deep targeted next-generation-sequencing (NGS).

Results: Appropriate samples were available from 55 PLVIH and analyzed for ctDNA detection. Including 42 males (76.4 %), 52.9 years median age, 51 smokers (92.7 %), five with non-squamous NSCLC Stage III (9%), 50 Stage IV (91 %), and performance status (PS) 0-2. ctDNA was detected in 35 patients (64 %), 22 with high and 13 with low ctDNA levels. Overall, 77 % were positive for TP53, 29 % for KRAS, and 11 % for STK11 mutations, more than one alteration was detected in 43 % of samples. Multivariate analysis showed that positive ctDNA was significantly associated with shorter PFS (HR, 4.31, 95 %CI: 2.06-8.99, p < 0.0001), and shorter OS (HR, 3.52, 95 %CI: 1.72-7.19, p < 0.001). Moreover, OS was significantly longer for patients with low ctDNA levels at diagnosis as compared to high (p = 0.01).

Conclusion: We show that ctDNA detection using ultra-deep NGS is an independent prognostic factor in PLHIV with advanced NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.05.013DOI Listing
July 2021

Gene network and biological pathways associated with susceptibility to differentiated thyroid carcinoma.

Sci Rep 2021 Apr 26;11(1):8932. Epub 2021 Apr 26.

Inserm, U900, Institut Curie, PSL University, Mines ParisTech, 75248, Paris, France.

Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88253-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076215PMC
April 2021

Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies.

Cancer Epidemiol Biomarkers Prev 2021 Jun 7;30(6):1208-1217. Epub 2021 Apr 7.

INSERM, Centre for Research in Epidemiology and Population Health (CESP), 94800 Villejuif, France.

Background: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer.

Methods: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case-control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies.

Results: The OR/mGy was 1.02 (95% confidence interval, 1.00-1.03). We found significant associations between DTC and rs7164173 in CHD2 ( = 5.79 × 10), rs6067822 in NFATc2 ( = 9.26 × 10), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses ( = 3.40 × 10).

Conclusions: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk.

Impact: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1142DOI Listing
June 2021

Practices and expectations on the use of circulating tumor DNA in colorectal cancer patients: A bi-national AGEO/AIOM/GERCOR/FFCD/FRENCH survey.

Clin Res Hepatol Gastroenterol 2021 May 27;45(3):101681. Epub 2021 Mar 27.

Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, APHP, Paris Descartes-Université de Paris, Paris, France. Electronic address:

Background: Increasing evidence shows that circulating tumor DNA (ctDNA) is a valuable tool in providing molecular, prognostic, predictive and dynamic information in colorectal cancer (CRC) patients. This study aimed to make a picture of knowledge, practice, attitudes and expectations about ctDNA in CRC patients.

Material And Methods: An online CRC-ctdna survey was distributed from November 2019 to January 2020 to French and Italian cooperative and scientific groups of Hepato-Gastroenterologists (HGE), Medical Oncologists (MO), Radiotherapists (RT) and Digestive Surgeons (DS).

Results: Overall, 307 physicians completed the survey (57% Italian; 43% French). Most of them were MO (62%) and HGE (24%). Affiliations were University Hospital (48%), Cancer Center (21%), General Hospital (21%) and Private Hospital (10%). Notably, half of respondents declared to have access to ctDNA in their daily practice. Of them, 53% uses ctDNA to assess RAS/BRAF status only, 46% for RAS/BRAF with other mutations and 1% only for other mutations. MO and HGE identified quick RAS profiling (P = 0.031) as the main reason of interest in the use of ctDNA. Physicians from University Hospitals and Cancer Centers prescribed more ctDNA (P < 0.001) and more often in house (P < 0.001). The main future expectations concerning ctDNA were to guide therapeutic strategies in metastatic (78%) and adjuvant (73%) settings, and to better/quicker profile disease at baseline (56%).

Conclusion: Half of participants can order ctDNA in their daily practice. Molecular profiling of metastatic patients remains the main goal of ctDNA use and ctDNA-based therapeutic strategies are an expectation for the future in both adjuvant and metastatic settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinre.2021.101681DOI Listing
May 2021

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Oncotarget 2021 Mar 2;12(5):493-506. Epub 2021 Mar 2.

University Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Exposome and Heredity Team, Villejuif, France.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in . This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, = 1.9 x 10). It is also associated with expression of and of the nearby gene in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, = 7.6 x 10) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, = 0.001). These SNPs are linked to the expression of in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939525PMC
March 2021

Deciphering the Role of Intestinal Crypt Cell Populations in Resistance to Chemotherapy.

Cancer Res 2021 May 19;81(10):2730-2744. Epub 2021 Mar 19.

Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France.

Intestinal crypts are composed of heterogeneous and highly plastic cell populations. Lgr5-stem cells (SC) are responsible for homeostatic renewal, but other cells can revert to an SC-like phenotype to maintain epithelial integrity. Despite their distinct roles in orchestrating homeostasis, both populations have been designated as the putative "cell-of-origin" of colorectal cancer. However, their respective involvement in the emergence of drug-resistant cancer SCs (CSC), responsible for tumor relapse and associated with poor outcome of colorectal cancer, remains elusive. In this context, the intestinal SC/progenitor-marker Musashi1 (MSI1) is interesting as it plays important functions in intestinal homeostasis and is frequently overexpressed in human colorectal cancer. Therefore, our aims were: (i) to study the impact of chemotherapy on Lgr5-expressing and MSI1-expressing cell populations, (ii) to explore the effect of increased MSI1 levels in response to treatment, and (iii) to evaluate the relevance in human colorectal cancer. Engineered mouse models treated with the therapeutic agent 5-fluorouracil showed that upon increased MSI1 levels, Lgr5 SCs remain sensitive while Lgr5 progenitors reprogram to a drug-resistant phenotype. This resulted in the expansion of an MSI1-expressing cell subpopulation with improved resistance to DNA damage and increased detoxification, typical properties of dormant-CSCs that can reactivate after chemotherapy. Analysis in patients with colorectal cancer revealed a correlation between MSI1 levels and tumor grading, CSC phenotype, and chemoresistance. Altogether, these results shed new light on the biology and plasticity of normal crypt and cancer cell populations and also open new perspectives to target MSI1 to improve chemotherapy outcome. SIGNIFICANCE: This study unveils paradoxical roles for MSI1, underlining its importance in facilitating intestinal regeneration upon injury but also unraveling its new function in drug-resistant colorectal cancer stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-2450DOI Listing
May 2021

Facing new challenges to informed consent processes in the context of translational research: the case in CARPEM consortium.

BMC Med Ethics 2021 03 2;22(1):21. Epub 2021 Mar 2.

Centre de Recherche Des Cordeliers (UMRS 1138), INSERM, Sorbonne Université, Université de Paris, Team ETREs, 75006, Paris, France.

Background: In the context of translational research, researchers have increasingly been using biological samples and data in fundamental research phases. To explore informed consent practices, we conducted a retrospective study on informed consent documents that were used for CARPEM's translational research programs. This review focused on detailing their form, their informational content, and the adequacy of these documents with the international ethical principles and participants' rights.

Methods: Informed consent forms (ICFs) were collected from CARPEM investigators. A content analysis focused on information related to biological samples and data treatment (context of sampling and collect, aims, reuse, consent renewal), including the type of consent. An automatic assessment of the readability of the ICFs were performed with the IT program "Flesch Score".

Results: 29 ICFs from 25 of 49 studies were analyzed after selection criteria were applied. Three types of consent were identified: 11 broad consents, six specific consents, and two opt-out consents. The Flesch Scores showed that most of the documents were too complex to be fully understood by most of the potential research participants. Most of the biological samples were collected during the healthcare routine, but the information content about secondary use of biological samples varied between ICFs. All documents mentioned personal data treatment but information about their reuse was not standardized in the ICFs.

Conclusions: Our review of current IC procedures of CARPEM showed that practices could be improved considering new translational research methods. "Old fashion written ICFs" should be adapted to the translational research approach, to better respect individual rights and international research ethics principles. In this context, theoretically, a digital tool allowing dynamic information and consent of participants, through an electronic interactive platform may be a good way to promote more active participation in research. Nevertheless, its feasibility in the complex environment of biological samples and data research remains to prove. The way of a combination of a broad consent followed by dynamic information may be alternatively tested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12910-021-00592-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927247PMC
March 2021

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Int J Cancer 2021 Jun 24;148(12):2935-2946. Epub 2021 Feb 24.

Inserm, U1078, GGB, Université de Bretagne Occidentale, EFS, Brest, France.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33488DOI Listing
June 2021

A major genetic accelerator of cancer diagnosis: rs867228 in FPR1.

Oncoimmunology 2021 01 6;10(1):1859064. Epub 2021 Jan 6.

Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1859064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801119PMC
January 2021

Usefulness of Plasma SARS-CoV-2 RNA Quantification by Droplet-based Digital PCR to Monitor Treatment Against COVID-19 in a B-cell Lymphoma Patient.

Stem Cell Rev Rep 2021 02 5;17(1):296-299. Epub 2021 Jan 5.

Service de Microbiologie (Unité de virologie), Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Hôpital Européen Georges Pompidou, Paris, France.

We report the case of an HIV-1-infected patient, treated with anti-CD20 monoclonal antibody for a B-cell lymphoma previously treated by autologous stem cell transplant. He suffered from chronic COVID19 and we monitored by plasma SARS-CoV-2 RNA by highly sensitive droplet-based digital PCR technology (ddPCR). Under tocilizumab therapy and despite a first clinical improvement biologically associated with decreasing inflammatory markers, a slight increase of SARS-CoV-2 RNAaemia quantified by ddPCR was highlighted, confirming the absence of viral efficacy of this treatment and predicting the subsequent observed deterioration. As expected, his complete recovery, finally achieved after COVID-19 convalescent plasmatherapy, strictly paralleled plasma SARS-CoV-2 RNA clearance. With these results, we confirmed the interest of SARS-CoV-2 RNAaemia monitoring by ddPCR in COVID-19 patients, particularly during treatment, and firstly showed that this new and specific biomarker could be helpful to select eligible patient for anti-IL6 receptors therapy considering the variable levels of efficacy recently observed with such therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12015-020-10107-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785125PMC
February 2021

Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial.

Dig Liver Dis 2021 Mar 25;53(3):318-323. Epub 2020 Dec 25.

Gastroenterology Department and Medical Oncology Department, Poitiers University Hospital, Poitiers, France.

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.11.031DOI Listing
March 2021

PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer.

Dig Liver Dis 2021 Apr 6;53(4):420-426. Epub 2021 Jan 6.

Service d'Oncologie Médicale, CHU de Poitiers, Poitiers, France; Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, 2 rue de la Milétrie, Poitiers 86021, France. Electronic address:

Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.11.036DOI Listing
April 2021

Prognostic variables in low and high risk stage III colon cancers treated in two adjuvant chemotherapy trials.

Eur J Cancer 2021 Feb 17;144:101-112. Epub 2020 Dec 17.

Department of Gastroenterology and GI Oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France.

Background: Stratification of patients with stage III colon cancer into low (TN) and high (T and/or N) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group.

Materials & Methods: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2.

Results: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAF/pMMR, subgroups. Specifically, BRAF/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; P<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; P<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; P<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours.

Conclusion: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855426PMC
February 2021

Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort.

Int J Cancer 2021 04 4;148(7):1731-1742. Epub 2021 Jan 4.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33392DOI Listing
April 2021

YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular Subtypes.

Cancers (Basel) 2020 Oct 28;12(11). Epub 2020 Oct 28.

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France.

Recent advance in the characterization of the heterogeneity of colorectal cancer has led to the definition of a consensus molecular classification within four CMS subgroups, each associated with specific molecular and clinical features. Investigating the signalling pathways that drive colorectal cancer progression in relation to the CMS classification may help design therapeutic strategies tailored for each CMS subtype. The two main effectors of the Hippo pathway YAP and its paralogue TAZ have been intensively scrutinized for their contribution to colon carcinogenesis. Here, we review the knowledge of YAP/TAZ implication in colorectal cancer from the perspective of the CMS framework. We identify gaps in our current understanding and delineate research avenues for future work.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692643PMC
October 2020

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Cancer Discov 2021 Feb 12;11(2):408-423. Epub 2020 Oct 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of . These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in , harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking , suggesting a personalized strategy for compensating for the FPR1 defect..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-0465DOI Listing
February 2021

The consensus Immunoscore in phase 3 clinical trials; potential impact on patient management decisions.

Oncoimmunology 2020 08 28;9(1):1812221. Epub 2020 Aug 28.

Laboratory of Integrative Cancer Immunology, INSERM, Paris, France.

The consensus Immunoscore has a prognostic value that has been confirmed in two randomized phase 3 clinical trials, and it provides a reliable estimate of the recurrence risk in colon cancer. The latest edition of the WHO classification of the Digestive System Tumors introduced for the first time the immune response as an essential and desirable diagnostic criteria for digestive cancers. Therefore, the immune response and Immunoscore evaluation within the tumor microenvironment is clinically relevant. In addition, the evaluation of the Immunoscore in stage III colon cancer patients from the IDEA France clinical trial evaluating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy demonstrated the predictive value of Immunoscore for treatment duration. Immunoscore predicted response to 6 months FOLFOX chemotherapy both in low- and high-risk Stage III patients. Low-risk patients (T, N) with High-Immunoscore had the 3-year DFS of 91.4% when treated with the 6-month FOLFOX, and only 80.8% with the 3-month regimen. The international validation of the prognostic value of the consensus Immunoscore together with its predictive value to guide treatment provides important information for the personalized management of colon cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1812221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480815PMC
August 2020

Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials.

JCO Precis Oncol 2020 26;4. Epub 2020 Feb 26.

Department of Medicine, Mayo Clinic, Rochester, MN.

Purpose: The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers.

Patients And Methods: Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location.

Results: Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic ( mutation and/or methylation) and 99 (28%) had familial tumors ( WT and unmethylated or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant ( = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with -mutant but not WT tumors.

Conclusion: The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446392PMC
February 2020

Predictive molecular pathology in non-small cell lung cancer in France: The past, the present and the perspectives.

Cancer Cytopathol 2020 09;128(9):601-610

UMR-1138, INSERM, Département de Biologie, Hôpital Européen Georges-Pompidou, Paris, France.

The advent of molecular targets for novel therapeutics in oncology, notably for non-small cell lung carcinoma (NSCLC), led the French National Cancer Institute (INCa) to establish a national network of 28 hospital Molecular Genetics Centers for Cancer (MGCC) in 2007. In each University in France, laboratories were established to develop molecular biology testing to evaluate a few genomic alterations, initially a selection of genes, by using specific targeted polymerase chain reaction (PCR) assays. In a second phase, the number of studied genes was increased. In 2015, the MGCC benefited from an additional dedicated budget from the INCa to develop next-generation sequencing (NGS) technology. In the meantime, a new financial regulation for innovative testing has been established for the acts out of nomenclature. Consequently, all private and public laboratories in France have access to funding for molecular biology testing in oncology. The gene-based PCR assays or NGS tests have benefitted from reimbursement of cost testing by the INCa. Today, the laboratories consider this reimbursement to be only partial, and its use to be complex. In 2018, a strategic plan for medical genomic analyses (France Médecine Génomique 2025) was implemented to introduce more systematic sequencing into the health care pathway and oncology practice. The large panel of molecular tests should be centralized to a limited number of molecular genetic centers. This review describes the evolution of the different stages of implementation of molecular pathology testing for NSCLC patients over the last few years in France.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncy.22318DOI Listing
September 2020

Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value.

Clin Infect Dis 2020 Aug 17. Epub 2020 Aug 17.

Assistance Publique Hôpitaux de Paris-Centre (AP-HP.Centre), Service de Microbiologie (Unité de virologie), Hôpital Européen Georges Pompidou, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a global public health problem that has already caused more than 662,000 deaths worldwide. Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients present other severe damage such as cardiovascular, renal and liver injury or/and multiple organ failure, suggesting a spread of the SARS-CoV-2 in blood. Recent ultrasensitive polymerase chain reaction (PCR) technology now allows absolute quantification of nucleic acids in plasma. We herein intended to use the droplet-based digital PCR technology to obtain sensitive detection and precise quantification of plasma SARS-CoV-2 viral load (SARS-CoV-2 RNAaemia) in hospitalized COVID-19 patients.

Methods: Fifty-eight consecutive COVID-19 patients with pneumonia 8 to 12 days after onset of symptoms and 12 healthy controls were analyzed. Disease severity was categorized as mild-to-moderate in 17 patients, severe in 16 patients and critical in 26 patients. Plasma SARS-CoV-2 RNAaemia was quantified by droplet digital Crystal Digital PCR™ next-generation technology (Stilla Technologies, Villejuif, France).

Results: Overall, SARS-CoV-2 RNAaemia was detected in 43 (74.1%) patients. Prevalence of positive SARS-CoV-2 RNAaemia correlated with disease severity, ranging from 53% in mild-to-moderate patients to 88% in critically ill patients (p=0.036). Levels of SARS-CoV-2 RNAaemia were associated with severity (p=0.035). Among nine patients who experienced clinical deterioration during follow-up, eight had positive SARS-CoV-2 RNAaemia at baseline while only one critical patient with undetectable SARS-CoV-2 RNAaemia at the time of analysis died at day 27.

Conclusion: SARS-CoV-2 RNAaemia measured by droplet-based digital PCR constitutes a promising prognosis biomarker in COVID-19 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454373PMC
August 2020

Effectiveness of a dedicated small bowel neoplasia screening program by capsule endoscopy in Lynch syndrome: 5 years results from a tertiary care center.

Therap Adv Gastroenterol 2020 29;13:1756284820934314. Epub 2020 Jul 29.

Gastroenterology and Endoscopy Unit, Georges Pompidou European Hospital, Paris, France.

Background And Aims: The role of small bowel neoplasia (SBN) screening in asymptomatic patients with Lynch syndrome (LS) is uncertain. The aim of our study was to assess the effectiveness of screening by capsule endoscopy (CE) in these patients.

Methods: This study was an observational, analytical, and retrospective single-center study within the PRED-IdF network. All consecutive asymptomatic patients older than 35 years-old with confirmed LS and no personal history of SBN who started the screening from 2010-2015 were included. The baseline screening and 24 months follow-up were performed by CE. The CE diagnostic yield (positive tumor or polyp) and accuracy, using the follow-up as gold standard, were evaluated.

Results: A total of 150 patients underwent the SBN screening program and 135 (52.7 ± 11.2 years-old, 37.8% male) met the inclusion criteria. The baseline CE diagnostic yield was 4.4% (3 polyps, 3 tumors) and the proximal small bowel was the most common location ( = 4, 66.7%). In total, 87 patients underwent follow-up and the diagnostic yield was 4.6%.Four patients were considered positive at follow-up (2 adenomas, 2 adenocarcinomas). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CE were 60%, 100%, 100%, 96.9%, and 97%, respectively.

Conclusions: CE is an accurate procedure for baseline screening of SBN in LS patients and may be efficient for follow-up procedures. However, the optimal starting age of screening and intervals of follow-up must be clarified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1756284820934314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391432PMC
July 2020

Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study.

Dig Liver Dis 2020 10 31;52(10):1143-1147. Epub 2020 Jul 31.

University hospital Saint Louis, APHP, Paris, France.

Background: Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens.

Methods: BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) - but remains unresectable - after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.06.034DOI Listing
October 2020

Feasibility of high-throughput sequencing in clinical routine cancer care: lessons from the cancer pilot project of the France Genomic Medicine 2025 plan.

ESMO Open 2020 07;5(4)

U1147, Centre universitaire des Saint-Pères, Institut national de la santé et de la recherche médicale, Paris, France.

Background: Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame-that is, compatible with the clinical pathway-is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli).

Methods: Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonié's Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified.

Results: Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days.

Conclusion: Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2020-000744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383956PMC
July 2020

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors.

Biomolecules 2020 07 16;10(7). Epub 2020 Jul 16.

Centre de Recherche des Cordeliers, INSERM UMR-S1138, Sorbonne Université, Université de Paris, 75006 Paris, France.

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, and mutations, oncogene fusions or inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10071061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407667PMC
July 2020
-->