Biomarqueurs tumoraux circulants

Publications

Année de publication : 2019

Nicolas Kiavue, Luc Cabel, Samia Melaabi, Guillaume Bataillon, Celine Callens, Florence Lerebours, Jean-Yves Pierga, Francois-Clement Bidard (2019 Sep 15)

ERBB3 mutations in cancer: biological aspects, prevalence and therapeutics.

Oncogene : 487-502 : DOI : 10.1038/s41388-019-1001-5 En savoir plus
Résumé

HER3, a member of the EGFR family of receptor tyrosine kinases coded by the ERBB3 gene, plays an important role in cancer, despite its lack of intrinsic kinase activity. As with genes coding for potential heterodimeric partners of HER3, EGFR, and HER2, oncogenic mutations of ERBB3 have been explored by several studies. In this review, we discuss the evidence presenting ERBB3 somatic mutations as potential tumoral drivers. We then show that ERBB3 mutations are not uncommon in many cancer types. Finally, we present the recent results of several studies evaluating different therapeutic approaches for treating patients with oncogenic ERBB3 mutations.

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Marcela Carausu, François-Clément Bidard, Celine Callens, Samia Melaabi, Emmanuelle Jeannot, Jean-Yves Pierga, Luc Cabel (2019 Jun 13)

ESR1 mutations: a new biomarker in breast cancer.

Expert review of molecular diagnostics : 599-611 : DOI : 10.1080/14737159.2019.1631799 En savoir plus
Résumé

: In hormone receptor-positive breast cancer, mutations have emerged as a key mechanism of resistance to endocrine therapy. : Here, we review currently available data on mutations, regarding their functional impact, prevalence at different stages (and according to the material used: tissue-based analysis vs. liquid biopsy), prognostic impact and predictive value of resistance to aromatase inhibitors. Possible strategies to overcome this resistance by using selective estrogen receptor downregulators (such as fulvestrant) are also discussed. : mutation detection will probably become a prognostic and predictive biomarker in the future, used in clinical practice for hormone-receptor breast cancer, especially in the metastatic setting. In the future, we should expect to assess mutations, using liquid biopsy (by digital-PCR or next-generation sequencing), in the same way as other prognostic or predictive biomarkers, such as mutations in lung cancer, and possibly even have targeted-therapies against these mutations.

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François-Clément Bidard, Nicolas Kiavue, Marc Ychou, Luc Cabel, Marc-Henri Stern, Jordan Madic, Adrien Saliou, Aurore Rampanou, Charles Decraene, Olivier Bouché, Michel Rivoire, François Ghiringhelli, Eric Francois, Rosine Guimbaud, Laurent Mineur, Faiza Khemissa-Akouz, Thibault Mazard, Driffa Moussata, Charlotte Proudhon, Jean-Yves Pierga, Trevor Stanbury, Simon Thézenas, Pascale Mariani (2019 May 31)

Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial.

Cells : DOI : E516 En savoir plus
Résumé

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p=0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p<0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

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Luc Cabel, Charles Decraene, Ivan Bieche, Jean-Yves Pierga, Mostefa Bennamoun, David Fuks, Jean-Marc Ferraz, Marine Lefevre, Sylvain Baulande, Virginie Bernard, Sophie Vacher, Pascale Mariani, Charlotte Proudhon, Francois-Clement Bidard, Christophe Louvet (2019 Mar 24)

Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients.

Cancers : DOI : E396 En savoir plus
Résumé

This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, before and after surgery (NCT02220556). In each patient, mutations retrieved by targeted next-generation sequencing (NGS) on tumor samples were then tracked in circulating cell-free DNA from 4 mL of plasma by droplet digital PCR. Thirty-two patients with a diagnosis of non-metastatic gastric adenocarcinoma were included. A trackable mutation was identified in the tumor in 20 patients, seven of whom experienced relapse during follow-up. ctDNA was detectable in four patients ( = 4/19, sensitivity: 21%; 95% confidence interval CI = 8.5⁻43%, no baseline plasma sample was available for one patient), with a median allelic frequency (MAF) of 1.6% (range: 0.8⁻2.3%). No patient with available plasma samples ( = 0/18) had detectable ctDNA levels before surgery. After surgery, one of the 13 patients with available plasma samples had a detectable ctDNA level with a low allelic frequency (0.7%); this patient experienced a very short-term distant relapse only 3 months after surgery. No ctDNA was detected after surgery in the other four patients with available plasma samples who experienced a later relapse (median = 14.4, range: 9.3⁻26 months). ctDNA monitoring during preoperative chemotherapy and after surgery does not appear to be a useful tool in clinical practice for non-metastatic gastric cancer to predict the efficacy of chemotherapy and subsequent relapse, essentially due to the poor sensitivity of ctDNA detection.

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Massimo Cristofanilli, Jean-Yves Pierga, James Reuben, Alfred Rademaker, Andrew A Davis, Dieter J Peeters, Tanja Fehm, Franco Nolé, Rafael Gisbert-Criado, Dimitrios Mavroudis, Salvatore Grisanti, Mario Giuliano, Jose A Garcia-Saenz, Justin Stebbing, Carlos Caldas, Paola Gazzaniga, Luis Manso, Rita Zamarchi, Angela Fernandez de Lascoiti, Leticia De Mattos-Arruda, Michail Ignatiadis, Luc Cabel, Steven J van Laere, Franziska Meier-Stiegen, Maria-Teresa Sandri, Jose Vidal-Martinez, Eleni Politaki, Francesca Consoli, Daniele Generali, Maria Rosa Cappelletti, Eduardo Diaz-Rubio, Jonathan Krell, Sarah-Jane Dawson, Cristina Raimondi, Annemie Rutten, Wolfgang Janni, Elisabetta Munzone, Vicente Carañana, Sofia Agelaki, Camillo Almici, Luc Dirix, Erich-Franz Solomayer, Laura Zorzino, Lauren Darrigues, Jorge S Reis-Filho, Lorenzo Gerratana, Stefan Michiels, François-Clément Bidard, Klaus Pantel (2019 Feb 18)

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper.

Critical reviews in oncology/hematology : 39-45 : DOI : S1040-8428(18)30510-9 En savoir plus
Résumé

The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease.

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Année de publication : 2018

Alice Bernard-Tessier, Emmanuelle Jeannot, David Guenat, Alice Debernardi, Marc Michel, Charlotte Proudhon, Anne Vincent-Salomon, Ivan Bièche, Jean-Yves Pierga, Bruno Buecher, Aurélia Meurisse, Éric François, Romain Cohen, Marine Jary, Véronique Vendrely, Emmanuelle Samalin, Farid El Hajbi, Nabil Baba-Hamed, Christophe Borg, François-Clément Bidard, Stefano Kim (2018 Dec 4)

Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial.

Clinical cancer research : an official journal of the American Association for Cancer Research : 2109-2115 : DOI : 10.1158/1078-0432.CCR-18-2984 En savoir plus
Résumé

Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.

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Charles Decraene, Amanda Bortolini Silveira, Marc Michel, François-Clément Bidard, Jean-Yves Pierga, Marc-Henri Stern, Charlotte Proudhon (2018 Oct 16)

Single Droplet Digital Polymerase Chain Reaction for Comprehensive and Simultaneous Detection of Mutations in Hotspot Regions.

Journal of visualized experiments : JoVE : DOI : 10.3791/58051 En savoir plus
Résumé

Droplet digital polymerase chain reaction (ddPCR) is a highly sensitive quantitative polymerase chain reaction (PCR) method based on sample fractionation into thousands of nano-sized water-in-oil individual reactions. Recently, ddPCR has become one of the most accurate and sensitive tools for circulating tumor DNA (ctDNA) detection. One of the major limitations of the standard ddPCR technique is the restricted number of mutations that can be screened per reaction, as specific hydrolysis probes recognizing each possible allelic version are required. An alternative methodology, the drop-off ddPCR, increases throughput, since it requires only a single pair of probes to detect and quantify potentially all genetic alterations in the targeted region. Drop-off ddPCR displays comparable sensitivity to conventional ddPCR assays with the advantage of detecting a greater number of mutations in a single reaction. It is cost-effective, conserves precious sample material, and can also be used as a discovery tool when mutations are not known a priori.

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Fabien Mignot, Delphine Loirat, Sylvain Dureau, Guillaume Bataillon, Martial Caly, Anne Vincent-Salomon, Frédérique Berger, Alain Fourquet, Jean-Yves Pierga, Youlia M Kirova, Francois-Clément Bidard (2018 Oct 7)

Disseminated Tumor Cells Predict Efficacy of Regional Nodal Irradiation in Early Stage Breast Cancer.

International journal of radiation oncology, biology, physics : 389-396 : DOI : S0360-3016(18)33813-6 En savoir plus
Résumé

Disseminated tumor cells (DTCs) collect in the bone marrow and indicate micrometastatic spread. We previously reported that DTCs could be a predictive factor for the efficacy of regional node irradiation (internal mammary nodes [IMNs]/supra- and infraclavicular nodes [SCNs]). In this article, we report the long-term results (>10 years) on the impact of DTC status in early stage breast cancer.

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J Castelli, L Cabel, F-C Bidard, L Duvergé, J-B Bachet (2018 Aug 23)

[Circulating tumour DNA: Current detection methods, use in radiotherapy and future development].

Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique : 653-659 : DOI : S1278-3218(18)30267-1 En savoir plus
Résumé

Recent technological developments enable the detection and quantification of circulating tumour DNA in the blood, with potentially major clinical implications, particularly for cancers treated with curative intent. Circulating tumour DNA has a potential impact before, during and after treatment. If limitations of this approach remain, requiring further development, it is important to know the principles and applications in view of the potential impact on the clinical practice. In this review, we will discuss the current detection methods, then the place of circulating tumour DNA in oncology and more particularly in radiotherapy.

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Luc Cabel, Emmanuelle Jeannot, Ivan Bieche, Sophie Vacher, Celine Callens, Louis Bazire, Adeline Morel, Alice Bernard-Tessier, Walid Chemlali, Anne Schnitzler, Astrid Lièvre, Joelle Otz, Mathieu Minsat, Anne Vincent-Salomon, Jean-Yves Pierga, Bruno Buecher, Pascale Mariani, Charlotte Proudhon, François-Clément Bidard, Wulfran Cacheux (2018 Jul 29)

Prognostic Impact of Residual HPV ctDNA Detection after Chemoradiotherapy for Anal Squamous Cell Carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research : 5767-5771 : DOI : 10.1158/1078-0432.CCR-18-0922 En savoir plus
Résumé

Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. This study was designed to monitor human papillomavirus (HPV) circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC. We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR. HPV ctDNA was detected before CRT in 29 of 33 patients with stages II-III ASCC [sensitivity: 88%; 95% confidence interval (CI), 72-95]; ctDNA positivity rate was associated with tumor stage (64% and 100% in stages II and III, respectively; = 0.008). Among ctDNA-positive patients at baseline, ctDNA levels were higher in N than in N tumors (median 85 copies/mL, range = 8-9,333 vs. 32 copies/mL, range = 3-1,350; = 0.03). ctDNA detection at baseline had no significant prognostic impact. After CRT, three of 18 (17%) patients displayed residual detectable HPV ctDNA; ctDNA detection after CRT was strongly associated with shorter disease-free survival ( < 0.0001). This is the first proof-of-concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV ctDNA can be detected before CRT and becomes undetectable during CRT. In this study, we show that residual ctDNA levels after CRT are associated with very poor outcome. .

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Luc Cabel, Charlotte Proudhon, Emanuela Romano, Nicolas Girard, Olivier Lantz, Marc-Henri Stern, Jean-Yves Pierga, François-Clément Bidard (2018 Jul 28)

Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy.

Nature reviews. Clinical oncology : DOI : 10.1038/s41571-018-0074-3 En savoir plus
Résumé

Considerable interest surrounds the use of immune-checkpoint inhibitors in patients with solid tumours following the demonstration of the impressive clinical efficacy of anti-programmed cell death protein 1 and anti-programmed cell death 1 ligand 1 antibodies in several tumour types. However, the emergence of unexpected tumour response patterns, such as pseudoprogression or hyperprogression, might complicate the management of patients receiving these agents. Analysis of circulating tumour DNA (ctDNA) has been shown to have prognostic value by enabling the detection of residual proliferating disease in the adjuvant setting and estimation of tumour burden in the metastatic setting, which are key stratification biomarkers for use of immune-checkpoint inhibition (ICI). Furthermore, examinations of ctDNA for genetic predictors of responsiveness to immunotherapy, such as mutations, tumour mutational load, and microsatellite instability provide a noninvasive surrogate for tumour biopsy sampling. Proof-of-concept reports have also demonstrated that quantitative changes in ctDNA levels early in the course of disease are a promising tool for the assessment of responsiveness to ICI that might complement standard imaging approaches. Other applications of this technology are also currently under investigation, such as early detection of resistance to immunotherapy and characterization of mechanisms of resistance. The aim of this Review is to summarize available data on the application of ctDNA in patients receiving immunotherapy and to discuss the most promising future directions.

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Manuel Rodrigues, Lenha Mobuchon, Alexandre Houy, Alice Fiévet, Sophie Gardrat, Raymond L Barnhill, Tatiana Popova, Vincent Servois, Aurore Rampanou, Aurore Mouton, Stéphane Dayot, Virginie Raynal, Michèle Galut, Marc Putterman, Sarah Tick, Nathalie Cassoux, Sergio Roman-Roman, François-Clément Bidard, Olivier Lantz, Pascale Mariani, Sophie Piperno-Neumann, Marc-Henri Stern (2018 May 16)

Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.

Nature communications : 1866 : DOI : 10.1038/s41467-018-04322-5 En savoir plus
Résumé

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

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L De Mattos-Arruda, B Weigelt, J Cortes, H H Won, C K Y Ng, P Nuciforo, F-C Bidard, C Aura, C Saura, V Peg, S Piscuoglio, M Oliveira, Y Smolders, P Patel, L Norton, J Tabernero, M F Berger, J Seoane, J S Reis-Filho (2018 May 3)

Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle.

Annals of oncology : official journal of the European Society for Medical Oncology : 2268 : DOI : S0923-7534(19)31872-1 En savoir plus
Résumé

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François-Clément Bidard, Stefan Michiels, Sabine Riethdorf, Volkmar Mueller, Laura J Esserman, Anthony Lucci, Bjørn Naume, Jun Horiguchi, Rafael Gisbert-Criado, Stefan Sleijfer, Masakazu Toi, Jose A Garcia-Saenz, Andreas Hartkopf, Daniele Generali, Françoise Rothé, Jeffrey Smerage, Laura Muinelo-Romay, Justin Stebbing, Patrice Viens, Mark Jesus M Magbanua, Carolyn S Hall, Olav Engebraaten, Daisuke Takata, José Vidal-Martínez, Wendy Onstenk, Noriyoshi Fujisawa, Eduardo Diaz-Rubio, Florin-Andrei Taran, Maria Rosa Cappelletti, Michail Ignatiadis, Charlotte Proudhon, Denise M Wolf, Jessica B Bauldry, Elin Borgen, Rin Nagaoka, Vicente Carañana, Jaco Kraan, Marisa Maestro, Sara Yvonne Brucker, Karsten Weber, Fabien Reyal, Dominic Amara, Mandar G Karhade, Randi R Mathiesen, Hideaki Tokiniwa, Antonio Llombart-Cussac, Alessandra Meddis, Paul Blanche, Koenraad d'Hollander, Cottu P, Park JW, Loibl S, Latouche A, Pierga JY, Klaus Pantel (2018 Apr 17)

Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.

Journal of the National Cancer Institute : DOI : 10.1093/jnci/djy018 En savoir plus
Résumé

We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.

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L Cabel, C Proudhon, B Buecher, J-Y Pierga, F-C Bidard (2018 Apr 11)

Circulating tumor DNA detection in hepatocellular carcinoma.

Annals of oncology : official journal of the European Society for Medical Oncology : 1094-1096 : DOI : S0923-7534(19)34563-6 En savoir plus
Résumé

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