Biomarqueurs tumoraux circulants

Publications

Année de publication : 2017

Charles Decraene, Amanda B Silveira, François-Clément Bidard, Audrey Vallée, Marc Michel, Samia Melaabi, Anne Vincent-Salomon, Adrien Saliou, Alexandre Houy, Maud Milder, Olivier Lantz, Marc Ychou, Marc G Denis, Jean-Yves Pierga, Marc-Henri Stern, Charlotte Proudhon (2017 Nov 11)

Multiple Hotspot Mutations Scanning by Single Droplet Digital PCR.

Clinical chemistry : DOI : clinchem.2017.272518 En savoir plus
Résumé

Progress in the liquid biopsy field, combined with the development of droplet digital PCR (ddPCR)12, has enabled noninvasive monitoring of mutations with high detection accuracy. However, current assays detect a restricted number of mutations per reaction. ddPCR is a recognized method for detecting alterations previously characterized in tumor tissues, but its use as a discovery tool when the mutation is unknown a priori remains limited.

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Hugo Gortais, Catherine Daniel, François-Clément Bidard, Emmanuelle Jeannot, Céline Callens, Luc Cabel (2017 Aug 26)

T790M EGFR Mutation Detection in Cerebrospinal Fluid and Response to Osimertinib in a Lung Cancer Patient with Meningeal Carcinomatosis.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer : e138-e139 : DOI : S1556-0864(17)30355-6 En savoir plus
Résumé

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G Beinse, F Berger, P Cottu, M-E Dujaric, I Kriegel, M-N Guilhaume, V Diéras, L Cabel, J-Y Pierga, F-C Bidard (2017 Aug 6)

Circulating tumor cell count and thrombosis in metastatic breast cancer.

Journal of thrombosis and haemostasis : JTH : 1981-1988 : DOI : 10.1111/jth.13792 En savoir plus
Résumé

Essentials Tumor cells circulating in blood (CTC) may favor thrombotic events in cancer patients. We assessed the impact of CTC on the risk of thrombosis in metastatic breast cancer. Baseline CTC detection was the only independent factor associated with the risk of thrombosis. CTC detection under therapy may be the hidden link between tumor progression & thrombosis.

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Luc Cabel, François-Clément Bidard, Vincent Servois, Wulfran Cacheux, Pascale Mariani, Emanuela Romano, Mathieu Minsat, Ivan Bieche, Fereshteh Farkhondeh, Emmanuelle Jeannot, Bruno Buecher (2017 Jul 4)

HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in metastatic squamous cell carcinoma of the anal canal: A case report.

International journal of cancer : 1667-1670 : DOI : 10.1002/ijc.30863 En savoir plus
Résumé

Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as single-agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single-agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.

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L Cabel, F Riva, V Servois, A Livartowski, C Daniel, A Rampanou, O Lantz, E Romano, M Milder, B Buecher, S Piperno-Neumann, V Bernard, S Baulande, I Bieche, J Y Pierga, C Proudhon, F-C Bidard (2017 May 2)

Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study.

Annals of oncology : official journal of the European Society for Medical Oncology : 1996-2001 : DOI : 10.1093/annonc/mdx212 En savoir plus
Résumé

Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.

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Charlotte K Y Ng, Francois-Clement Bidard, Salvatore Piscuoglio, Felipe C Geyer, Raymond S Lim, Ino de Bruijn, Ronglai Shen, Fresia Pareja, Samuel H Berman, Lu Wang, Jean-Yves Pierga, Anne Vincent-Salomon, Agnes Viale, Larry Norton, Brigitte Sigal, Britta Weigelt, Paul Cottu, Jorge S Reis-Filho (2017 Mar 30)

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases.

Clinical cancer research : an official journal of the American Association for Cancer Research : 4402-4415 : DOI : 10.1158/1078-0432.CCR-16-3115 En savoir plus
Résumé

Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with metastatic disease who had not received local or systemic therapy. Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods. Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including , and were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including , and (), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases. Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. .

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Luc Cabel, Charlotte Proudhon, Hugo Gortais, Delphine Loirat, Florence Coussy, Jean-Yves Pierga, François-Clément Bidard (2017 Feb 27)

Circulating tumor cells: clinical validity and utility.

International journal of clinical oncology : 421-430 : DOI : 10.1007/s10147-017-1105-2 En savoir plus
Résumé

Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed-(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.

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L Cabel, C Proudhon, P Mariani, D Tzanis, G Beinse, I Bieche, J-Y Pierga, F-C Bidard (2017 Feb 11)

Circulating tumor cells and circulating tumor DNA: What surgical oncologists need to know?

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology : 949-962 : DOI : S0748-7983(17)30060-4 En savoir plus
Résumé

As a result of recent progress in detection techniques, circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) can now be accurately detected in the blood of most cancer patients. While these new biomarkers can provide a better understanding of key biological mechanisms underlying cancer growth and dissemination, they also open up a wide range of possible clinical applications in medical oncology, radiation oncology and surgical oncology. In this review, we summarize the results obtained with ctDNA and CTC together with their potential future clinical applications in the field of surgical oncology, with particular focus on the perioperative setting of various types of cancer. These applications include, but are not limited to, cancer screening, early diagnosis, prognostic assessment, evaluation and management of preoperative systemic or local therapies, post-surgical detection of minimal residual disease and early detection of cancer relapse.

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J-Y Pierga, F-C Bidard, A Autret, T Petit, F Andre, F Dalenc, C Levy, J-M Ferrero, G Romieu, J Bonneterre, F Lerebours, T Bachelot, P Kerbrat, M Campone, J-C Eymard, M-A Mouret-Reynier, J Gligorov, A-C Hardy-Bessard, A Lortholary, P Soulie, J-M Boher, C Proudhon, E Charafe-Jaufret, J Lemonnier, F Bertucci, P Viens (2017 Feb 9)

Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab.

Annals of oncology : official journal of the European Society for Medical Oncology : 103-109 : DOI : 10.1093/annonc/mdw535 En savoir plus
Résumé

We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.

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Francesca Riva, Francois-Clement Bidard, Alexandre Houy, Adrien Saliou, Jordan Madic, Aurore Rampanou, Caroline Hego, Maud Milder, Paul Cottu, Marie-Paule Sablin, Anne Vincent-Salomon, Olivier Lantz, Marc-Henri Stern, Charlotte Proudhon, Jean-Yves Pierga (2017 Jan 12)

Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

Clinical chemistry : DOI : clinchem.2016.262337 En savoir plus
Résumé

In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery.

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Karla Perez-Toralla, Guillaume Mottet, Ezgi Tulukcuoglu-Guneri, Jérôme Champ, François-Clément Bidard, Jean-Yves Pierga, Jerzy Klijanienko, Irena Draskovic, Laurent Malaquin, Jean-Louis Viovy, Stéphanie Descroix (2017 Jan 4)

FISH-in-CHIPS: A Microfluidic Platform for Molecular Typing of Cancer Cells.

Methods in molecular biology (Clifton, N.J.) : 211-220 : DOI : 10.1007/978-1-4939-6734-6_16 En savoir plus
Résumé

Microfluidics offer powerful tools for the control, manipulation, and analysis of cells, in particular for the assessment of cell malignancy or the study of cell subpopulations. However, implementing complex biological protocols on chip remains a challenge. Sample preparation is often performed off chip using multiple manually performed steps, and protocols usually include different dehydration and drying steps that are not always compatible with a microfluidic format.Here, we report the implementation of a Fluorescence in situ Hybridization (FISH) protocol for the molecular typing of cancer cells in a simple and low-cost device. The geometry of the chip allows integrating the sample preparation steps to efficiently assess the genomic content of individual cells using a minute amount of sample. The FISH protocol can be fully automated, thus enabling its use in routine clinical practice.

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Année de publication : 2016

Gabrielle Deniziaut, Jean Christophe Tille, François-Clément Bidard, Sophie Vacher, Anne Schnitzler, Walid Chemlali, Laurence Trémoulet, Laetitia Fuhrmann, Paul Cottu, Roman Rouzier, Ivan Bièche, Anne Vincent-Salomon (2016 Sep 8)

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas.

Oncotarget : 73337-73346 : DOI : 10.18632/oncotarget.11819 En savoir plus
Résumé

ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.

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H Bonnefoi, T Grellety, O Tredan, M Saghatchian, F Dalenc, A Mailliez, T L'Haridon, P Cottu, S Abadie-Lacourtoisie, B You, M Mousseau, J Dauba, F Del Piano, I Desmoulins, F Coussy, N Madranges, J Grenier, F C Bidard, C Proudhon, G MacGrogan, C Orsini, M Pulido, A Gonçalves (2016 Apr 8)

A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO : 812-8 : DOI : 10.1093/annonc/mdw067 En savoir plus
Résumé

Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone.

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Francesca Riva, Oleksii I Dronov, Dmytro I Khomenko, Florence Huguet, Christophe Louvet, Pascale Mariani, Marc-Henri Stern, Olivier Lantz, Charlotte Proudhon, Jean-Yves Pierga, Francois-Clement Bidard (2016 Feb 10)

Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer.

Molecular oncology : 481-93 : DOI : 10.1016/j.molonc.2016.01.006 En savoir plus
Résumé

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using « liquid biopsies » at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy.

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Année de publication : 2015

C Helissey, F Berger, P Cottu, V Diéras, L Mignot, V Servois, C Bouleuc, B Asselain, S Pelissier, I Vaucher, J Y Pierga, F C Bidard (2015 Feb 22)

Circulating tumor cell thresholds and survival scores in advanced metastatic breast cancer: the observational step of the CirCe01 phase III trial.

Cancer letters : 213-8 : DOI : 10.1016/j.canlet.2015.02.010 En savoir plus
Résumé

The clinical validity of circulating tumor cell (CTC) count changes during chemotherapy in metastatic breast cancer patients has been validated, but its clinical utility remains to be demonstrated. We report here the non-randomized run-in phase of the CirCe01 trial which was designed to evaluate CTC changes and thresholds to other palliative prognostic scores and establish CTC thresholds to be used in the randomized part of the study. CTC count (CellSearch®) and other prognostic parameters (serum albumin level, lymphocyte level, LDH level, prognostic inflammatory and nutritional index (PINI) and Barbot’s score) were assessed in 56 metastatic breast cancer patients before the first cycle of third line chemotherapy. Early changes of CTC count were correlated with treatment outcome. Independent prognostic markers in multivariate analysis were: low serum albumin (HR = 11.1), poor performance status (HR = 3.8), ≥5 CTC/7.5 ml (HR = 3.8) and triple negative subtype (HER2+ and hormone positive vs triple negative: both HR = 0.2). Among patients with ≥5 CTC/7.5 ml at baseline, a composite criteria (<5 CTC/7.5 ml or relative decrease ≥-70% of the baseline CTC count) showed better prognostication for PFS (p=0.002).

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