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1. Use of circulating tumoral DNA to guide treatment for metastatic melanoma

Author

Audrey Vallée, Sandrine Charpentier, Guillaume Herbreteau, and Marc G. Denis

Subjects
Proto-Oncogene Proteins B-raf, 0301 basic medicine, Metastatic Cutaneous Melanoma, Genotype, Metastatic melanoma, Kaplan-Meier Estimate, medicine.disease_cause, Biomarkers, Pharmacological, Circulating Tumor DNA, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Neoplasm Metastasis, Melanoma, Genotyping, Pharmacology, Mutation, business.industry, medicine.disease, Minimal residual disease, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Molecular Medicine, business, DNA
Abstract

The management of metastatic cutaneous melanoma is conditioned by the identification of BRAF-activating mutations in tumor DNA. Tumor genotyping is usually performed on DNA extracted from tissue samples. However, these invasive samples are rarely repeated during follow-up, and their analysis requires a sample pre-treatment which may take several weeks. Circulating tumor DNA (ctDNA), released into blood by cancer cells, is a good alternative to tissue sampling. ctDNA is not subject to tumor heterogeneity, and can be analyzed rapidly, making possible the detection of mutations in emergency or in patients whose tumor cannot be sampled. ctDNA can also be analyzed repeatedly during follow-up, for postresection minimal residual disease assessment, for therapeutic response monitoring and for early relapse detection.

Published
2019
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2. Circulating Tumor DNA Early Kinetics Predict Response of Metastatic Melanoma to Anti-PD1 Immunotherapy: Validation Study

Author

Audrey Vallée, Amir Khammari, Brigitte Dréno, Anne-Chantal Knol, Guillaume Herbreteau, Emilie Varey, Marc G. Denis, Sandrine Théoleyre, Gaëlle Quéreux, Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Khammari, Amir

Subjects
0301 basic medicine, Oncology, Neuroblastoma RAS viral oncogene homolog, Cancer Research, medicine.medical_specialty, Metastatic melanoma, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Article, cell-free DNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, follow-up, melanoma, Digital polymerase chain reaction, anti-PD1, Anti pd1, circulating tumor DNA, criteria, business.industry, digital PCR, Melanoma, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, monitoring, 030104 developmental biology, Cell-free fetal DNA, Circulating tumor DNA, 030220 oncology & carcinogenesis, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, metastatic melanoma
Abstract

The ability of early (first weeks of treatment) ctDNA kinetics to identify primary resistance to anti-PD1 immunotherapies was evaluated with a validation cohort of 49 patients treated with anti‑PD1 for metastatic BRAF or NRAS-mutated melanoma, alone and pooled with the 53 patients from a previously described derivation cohort. BRAF or NRAS mutations were quantified on plasma DNA by digital PCR at baseline and after two or four weeks of treatment. ctDNA kinetics were interpreted according to pre-established biological response criteria. A biological progression (bP, i.e., a significant increase in ctDNA levels) at week two or week four was associated with a lack of benefit from anti-PD1 (4-month PFS = 0%, 1‑year OS = 13%, n = 12/102). Patients without initial bP had significantly better PFS and OS (4-month PFS = 78%, 1‑year OS = 73%, n = 26/102), as did patients whose ctDNA kinetics were not evaluable, due to low/undetectable baseline ctDNA (4-month PFS = 80%, 1‑year OS = 81%, n = 64/102). ctDNA detection at first-line anti-PD1 initiation was an independent prognostic factor for OS and PFS in multivariate analysis. Overall, early ctDNA quantitative monitoring may allow the detection of primary resistances of metastatic melanoma to anti-PD1 immunotherapies.

Published
2021
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3. Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

Author

Anne-Laure Bidaud, Eric Dannaoui, Guillaume Herbreteau, and Patrick Schwarz

Subjects
0301 basic medicine, Microbiology (medical), Drug, Antifungal, medicine.drug_class, media_common.quotation_subject, 030106 microbiology, agar diffusion assay, Plant Science, Review, Bioinformatics, 03 medical and health sciences, In vivo, time-kill curves, Medicine, In patient, gradient concentration strip, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, media_common, business.industry, Broth microdilution, checkerboard, antifungal resistance, In vitro, Clinical trial, 030104 developmental biology, antifungal combination, lcsh:Biology (General), Checkerboard, business
Abstract

Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

Published
2021

4. Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab

Author

Denis Moro-Sibilot, Guillaume Herbreteau, Olivier Molinier, José Hureaux, Patrick Merle, Jeannick Madelaine, Audrey Rabeau, J. Otto, Florian Guisier, Clarisse Audigier-Valette, Lionel Uwer, Valérie Gounant, Aldo Renault, Marc G. Denis, Laurent Greillier, Jean-Louis Pujol, Alexandra Langlais, Franck Morin, Pierre-Jean Souquet, Delphine Carmier, Centre hospitalier universitaire de Nantes (CHU Nantes), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Assistance Publique - Hôpitaux de Marseille (APHM), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Grenoble, Service de pneumologie, oncologie thoracique et soins intensifs respiratoires [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier de Pau, Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Herrada, Anthony, and Hôpital Charles Nicolle [Rouen]-CHU Rouen

Subjects
Oncology, atezolizumab, medicine.medical_specialty, medicine.medical_treatment, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Atezolizumab, Internal medicine, medicine, RB1, Progression-free survival, TP53, 030304 developmental biology, 0303 health sciences, Chemotherapy, Mutation, business.industry, lcsh:R, SCLC, General Medicine, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, ctDNA, NOTCH, 3. Good health, Clinical trial, 030220 oncology & carcinogenesis, Non small cell, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, mutation, business
Abstract

Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. Methods: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. Results: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49, 65.3%) and RB1 (25/49, 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. Conclusion: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.

Published
2020
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5. Circulating Tumour DNA Is an Independent Prognostic Biomarker for Survival in Metastatic BRAF or NRAS-Mutated Melanoma Patients

Author

Emilie Varey, Guillaume Herbreteau, Brigitte Dréno, Audrey Vallée, Anne-Chantal Knol, Sandrine Théoleyre, Gaëlle Quéreux, Amir Khammari, Cécile Frenard, Paul Hofman, Marc G. Denis, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Dupuis, Christine

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], NRAS, medicine.disease_cause, lcsh:RC254-282, BRAF, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, melanoma, Prognostic biomarker, Progression-free survival, Stage (cooking), neoplasms, Univariate analysis, Mutation, business.industry, Melanoma, circulating tumour DNA, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, [SDV] Life Sciences [q-bio], 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, prognosis, mutation, business, DNA
Abstract

Circulating tumour DNA (ctDNA) can be used to identify gene alterations. The purpose of this study was to determine whether the detection of ctDNA, based on the identification of BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma. In total, 68 BRAF or NRAS-mutated stage IV or unresectable stage III metastatic cutaneous melanoma patients were included and tested for the presence of BRAF and NRAS mutations in circulating DNA before treatment initiation, using the Cobas BRAF/NRAS Mutation Test (Roche). The expected mutation was detected in the plasma of 34/68 patients (50% sensitivity). ctDNA detection was associated with AJCC stage, along with the number and nature of metastases. ctDNA was less frequently detected in NRAS-mutated than in BRAF-mutated melanoma (36% and 66%, respectively). At initiation of first-line treatment, ctDNA detection was associated with poor prognosis in Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis (log-rank: p = 0.002 and p &lt, 0.0001, respectively). In multivariate analysis, ctDNA detection was an independent factor of poor prognosis in OS, after adjustment for AJCC stage, number and nature of metastases and gender (HR = 4.384, 95% CI: (1.308, 14.699), p = 0.017).

Published
2020
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6. Efficient treatment of a metastatic melanoma patient with a combination of BRAF and MEK inhibitors based on circulating tumor DNA analysis: a case report

Author

Audrey Vallée, Anne-Chantal Knol, Guillaume Herbreteau, Mélanie Saint-Jean, Brigitte Dréno, Sandrine Théoleyre, Marc G. Denis, Gaëlle Quéreux, Amir Khammari, Bernardo, Elizabeth, Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Immuno-Dermatologie [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Biochimie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Clinical and translational research in skin cancer ( CRCINA - Département INCIT - Equipe 2 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre d’Investigation Clinique de Nantes ( CIC Nantes ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
0301 basic medicine, Pathology, Skin Neoplasms, lcsh:Medicine, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Neoplasm Metastasis, Melanoma, lcsh:QH301-705.5, Mutation, MEK inhibitor, General Medicine, Middle Aged, Treatment efficacy, 3. Good health, Treatment Outcome, Circulating tumor DNA, 030220 oncology & carcinogenesis, Female, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Metastatic melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, BRAF, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Case report, Humans, Poor performance status, lcsh:Science (General), Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase Kinases, business.industry, lcsh:R, medicine.disease, 030104 developmental biology, chemistry, lcsh:Biology (General), Cancer research, business, Tomography, X-Ray Computed, DNA, lcsh:Q1-390
Abstract

International audience; BACKGROUND:Fixed tissues are the standard samples used in routine practice for molecular testing. But sometimes tissues are lacking or difficult to obtain. In these cases, circulating tumor DNA released from tumor cells can be used as an alternative source of tumor DNA.CASE PRESENTATION:We present the case of a 63-year-old Caucasian woman with a metastatic melanoma and a very poor performance status. A plasma sample was tested and the BRAF p.V600E mutation was detected. Based on this result, a treatment combining a BRAF inhibitor and a MEK inhibitor was immediately started. This patient achieved a complete response. In addition, by repeating the plasma test, we could obtain a precise kinetic of release of mutated BRAF DNA in plasma.CONCLUSIONS:We report here for the first time the efficient treatment of a metastatic melanoma patient on the basis of circulating tumor DNA analysis. This urgent treatment provided a dramatic response in a patient with a very poor initial condition. The kinetic data most likely reflect treatment efficacy.

Published
2017
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7. RASmutation leading to acquired resistance to dabrafenib and trametinib therapy in a multiplemyeloma patient harboring BRAF mutation

Author

Philippe Moreau, Steven Le Gouill, Baptiste Le Calvez, Olivier Theisen, Nicolas Blin, Guillaume Herbreteau, Françoise Kraeber-Bodéré, Thomas Gastinne, Benoit Tessoulin, Chloé Antier, Céline Bossard, Yannick Le Bris, Cyrille Touzeau, Marie C. Béné, Viviane Dubruille, Bastien Jamet, Beatrice Mahe, Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Hématologie Biologique [Hôpital Hôtel-Dieu, Nantes], Hôpital Hôtel-Dieu [Nantes] (Centre Hospitalier Universitaire de Nantes), Département de Biochimie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Nord Laennec [CHU Nantes], Service de Médecine Nucléaire [Nantes], Hôpital Laennec, Imaging and Longitudinal Investigations to Ameliorate Decision-making [Nantes] (ILIAD), Site de Recherche Intégrée sur le Cancer [Nantes] (SIRIC), Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Pathologie [CHU Nantes], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Nuclear Oncology (CRCINA-ÉQUIPE 13), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Neuroblastoma RAS viral oncogene homolog, endocrine system diseases, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Targeted therapy, BRAF, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, dabrafenib, neoplasms, Multiple myeloma, 030304 developmental biology, Trametinib, 0303 health sciences, trametinib, Bortezomib, business.industry, Daratumumab, Dabrafenib, Pomalidomide, medicine.disease, digestive system diseases, 3. Good health, multiple myeloma, 030220 oncology & carcinogenesis, Cancer research, business, medicine.drug, RAS
Abstract

International audience; Multiple myeloma (MM) is still considered incurable and new therapeutic approaches are therefore needed. Deep-sequencing analysis revealed the presence of BRAF mutations in up to 15% of patients. The clinical experience of BRAF-targeted therapy in myeloma patients harboring BRAF mutation is still limited. We here report the case of a patient with penta-refractory (bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab) MM with extramedullary BRAF-mutated disease that achieved clinical response to dual BRAF and MEK inhibition. At the time of disease progression, gene sequencing analysis of the tumor at the time of progression demonstrated a clonal evolution with emergence of aNRAS mutation and persistence of BRAF and TP53 mutations. Backtracking of the NRAS mutation was performed by digital polymerase chain reaction on the baseline biopsy and identified the pre-existence of the NRAS at a subclonal level. This observation is the first report of acquired NRAS mutation leading to resistance to dual BRAF/MEK inhibitors in MM. These data suggest that a systematic search for RAS mutations using highly sensitive techniques should be performed before considering targeted therapy in relapsed myeloma with BRAF mutation.

Published
2020
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8. Prospective evaluation of two screening methods for molecular testing of metastatic melanoma: Diagnostic performance of BRAF V600E immunohistochemistry and of a NRAS-BRAF fully automated real-time PCR-based assay

Author

Audrey Vallée, Guillaume Herbreteau, Marie Denis-Musquer, Marc G. Denis, Sandrine Théoleyre, and Céline Bossard

Subjects
0301 basic medicine, Oncology, Neuroblastoma RAS viral oncogene homolog, Melanomas, Male, endocrine system diseases, DNA Mutational Analysis, Gene Identification and Analysis, Artificial Gene Amplification and Extension, Polymerase Chain Reaction, GTP Phosphohydrolases, 0302 clinical medicine, Sequencing techniques, Medicine and Health Sciences, Missense mutation, Digital polymerase chain reaction, DNA sequencing, Prospective Studies, Neoplasm Metastasis, Melanoma, Sanger sequencing, Multidisciplinary, Immunohistochemistry, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), symbols, Medicine, Female, Research Article, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Substitution Mutation, Concordance, Science, Mutation, Missense, Research and Analysis Methods, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Genetics, Humans, Molecular Biology Techniques, neoplasms, Mutation Detection, Molecular Biology, Immunohistochemistry Techniques, Aged, business.industry, Dideoxy DNA sequencing, Biology and Life Sciences, Cancers and Neoplasms, Membrane Proteins, medicine.disease, digestive system diseases, Histochemistry and Cytochemistry Techniques, 030104 developmental biology, Amino Acid Substitution, Mutation, Immunologic Techniques, business, V600E
Abstract

Screening for theranostic biomarkers is mandatory for the therapeutic management of cutaneous melanoma. BRAF and NRAS genes must be tested in routine clinical practice. The methods used to identify these alterations must be sensitive to detect mutant alleles in a background of wild type alleles, and specific to identify the correct mutation. They should not require too much material, since in some cases the available samples are small biopsies. Finally, they should also be quick enough to allow a rapid therapeutic management of patients. Sixty five consecutive formalin-fixed paraffin-embedded (FFPE) melanoma samples were prospectively tested for BRAF mutations with the VE1 (anti-BRAF V600E) antibody and for both BRAF and NRAS mutations with the Idylla NRAS-BRAF-EGFR S492R Mutation Assay cartridges. Results were compared to our routine laboratory practice, allele specific amplification and/or Sanger sequencing and discordant cases confirmed by digital PCR. Excluding discordant by-design-mutations, system failures and DNA quantity or quality failures, BRAF IHC demonstrated an overall concordance of 89% for BRAF V600E mutation detection, the Idylla system gave a concordance of 100% for BRAF mutation detection and of 92.1% for NRAS mutation detection when compared to our reference. When discrepancies were observed, all routine results were confirmed by digital PCR. Finally, BRAF IHC positive predictive value (PPV) was of 82% and negative predictive value (NPV) of 92%. The Idylla cartridges showed a PPV and NPV of both 100% for BRAF mutation detection and a PPV and NPV of 100% and 87% respectively, for NRAS mutation detection. In conclusion, BRAF V600E immunohistochemistry is efficient for detecting the V600E mutation, but negative cases should be further evaluated by molecular approaches for other BRAF mutations. Since 3 NRAS mutations have not been detected by the Idylla NRAS-BRAF-EGFR S492R Mutation Assay, these cartridges should not be used as a substitute for traditional molecular methods in the conventional patient therapeutic care process without the expertise needed to have a critical view of the produced results.

Published
2019

9. Persistent deficiency of circulating mucosal-associated invariant T (MAIT) cells in ANCA-associated vasculitis

Author

Jerome Martin, Cécile Braudeau, Régis Josien, Caroline Hémont, Karine Amouriaux, Nina Salabert, Antoine Néel, Marie Rimbert, Guillaume Herbreteau, Mohamed Hamidou, Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire d’Immunologie [CHU Nantes] (Centre d’Immunomonitorage Nantes Atlantique - CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Faculté de Médecine - Université de Nantes, A grant from the Direction de la Recherche Clinique et de l’Innovation (DRCI), CHU Nantes (#BRD/09/06), the CIMNA was supported by the IMBIO-DC program supported by the 'Region des Pays de la Loire'., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], and ANR: ANR11-LABX-0016-01

Subjects
Adult, Male, 0301 basic medicine, Immunology, MAIT cells, Innate lymphoid cells, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Mucosal associated invariant T cell, Lymphocyte Activation, Peripheral blood mononuclear cell, Mucosal-Associated Invariant T Cells, Immunophenotyping, Flow cytometry, Pathogenesis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, T-Lymphocyte Subsets, medicine, Humans, Immunology and Allergy, Lymphocyte Count, Aged, Innate immunity, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Innate immune system, medicine.diagnostic_test, ANCA, business.industry, Innate lymphoid cell, Middle Aged, medicine.disease, Immunity, Innate, 3. Good health, Phenotype, 030104 developmental biology, Case-Control Studies, Cytokines, Female, Microscopic polyangiitis, business, Granulomatosis with polyangiitis, ANCA-Associated vasculitis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience; Objective: Mucosal associated invariant T cells (MAIT) and innate lymphoid cells (ILCs) have immuno-regulatory functions at mucosal sites and have been involved in various inflammatory and autoimmune diseases. The aim of this study was to assess their frequencies in blood in ANCA-associated vasculitis (AAV).Methods: The frequencies and function of MAIT cells, ILCs, gdT, iNKT, NK cells were analyzed by flow cytometry on PBMC of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) without any treatment, in acute (AP) and remission phase (RP) and compared with healthy controls (HC).Results: The frequencies of MAIT cells were strongly decreased in GPA and MPA in AP compared to HC, both in never treated and in relapsing patients and independently of patient age. This was associated with an activated phenotype of patient MAIT cells, as shown by increased expression of CD69 and IFNg. MAIT cells remained decreased during RP in AAV patients. The frequencies of iNKT and gdT cells were unaffected compared to HC, whereas those of NK cells were slightly reduced during AP in MPA. We also observed a significant decrease in frequencies of total ILCs with decreased ILC2 and ILC3 and increased ILC1 during AP in both GPA and MPA compared to HC. These frequencies normalized during RP. Interestingly , we observed a significant correlation between the frequency of total ILCs and BVAS.Conclusion: We show for the first time that AAV are associated with a major decrease and an activated phenotype of blood MAIT cell. These features persisted during remission suggesting a role for MAIT cells in the pathogenesis of AAV.

Published
2016
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10. Circulating free tumor DNA in non-small cell lung cancer (NSCLC): clinical application and future perspectives

Author

Guillaume Herbreteau, Nicola Normanno, Audrey Vallée, Paul Hofman, Marc G. Denis, and Sandrine Charpentier

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, business.industry, non-small cell lung cancer (NSCLC), Review Article, medicine.disease, Minimal residual disease, Response to treatment, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, chemistry, Circulating tumor DNA, Egfr mutation, 030220 oncology & carcinogenesis, medicine, Cancer research, Routine clinical practice, Non small cell, business, DNA
Abstract

Major advances in the treatment of non-small cell lung cancer (NSCLC) patients have been obtained during the last decade. Molecular testing of tumor samples is therefore mandatory in routine clinical practice. Tumor DNA is also present as cell-free molecules in blood, which is therefore a very useful and convenient source of tumor DNA. In this review, we discuss pre-analytical and analytical aspects of circulating tumor DNA (ctDNA) analysis. We also describe the use of ctDNA analysis in routine clinical practice, and discuss the potential use of ctDNA monitoring both to identify minimal residual disease and as a potential tool to early identify patients’ response to treatment.

Published
2019

11. Quantitative monitoring of circulating tumor DNA predicts response of cutaneous metastatic melanoma to anti-PD1 immunotherapy

Author

Audrey Vallée, Marc G. Denis, Emilie Varey, Amir Khammari, Guillaume Herbreteau, Sandrine Théoleyre, Gaëlle Quéreux, Brigitte Dréno, Anne-Chantal Knol, Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire de Biochimie et Plateforme de Génétique Moléculaire des Cancers [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Clinical and translational research in skin cancer ( CRCINA - Département INCIT - Equipe 2 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre d’Investigation Clinique de Nantes ( CIC Nantes ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Metastatic melanoma, Somatic cell, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, cell-free DNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Digital polymerase chain reaction, anti-PD1, circulating tumor DNA, business.industry, digital PCR, Melanoma, Immunotherapy, medicine.disease, 3. Good health, 030104 developmental biology, Cell-free fetal DNA, Circulating tumor DNA, 030220 oncology & carcinogenesis, business, Progressive disease, Research Paper, metastatic melanoma
Abstract

International audience; Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy.

Published
2018
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12. Circulating tumour DNA: analytical aspects and clinical applications for metastatic melanoma patients

Author

Guillaume Herbreteau, Marc G. Denis, Sandrine Théoleyre, Gaëlle Quéreux, Audrey Vallée, Amir Khammari, Brigitte Dréno, and Anne-Chantal Knol

Subjects
0301 basic medicine, Proto-Oncogene Proteins B-raf, Metastatic melanoma, DNA Mutational Analysis, Polymerase Chain Reaction, Circulating Tumor DNA, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Biomarkers, Tumor, Humans, Neoplasm Metastasis, Gene, Genotyping, Melanoma, Tumor marker, Blood Specimen Collection, business.industry, General Medicine, medicine.disease, Neoplastic Cells, Circulating, Primary tumor, 3. Good health, 030104 developmental biology, chemistry, Blood Preservation, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, business, DNA, Blood Chemical Analysis
Abstract

The management of metastatic melanoma has evolved since the onset of treatments with BRAF inhibitors. In order to predict which patients are likely to respond to these treatments, the therapeutic strategy is now conditioned by the search for the activating mutations of the BRAF gene. Tumor genotyping is routinely performed from DNA extracted from tissue or cellular specimens from the primary tumor, metastases, or neoplastic effusions. Due to their invasiveness, these specimens are rarely repeated during the management. In addition, the analysis of the tumor material requires a pretreatment of the sample (formalin fixation, paraffin inclusion, preparation of tissue sections) and may take up to several weeks, making emergency treatment with BRAF inhibitors impossible. Circulating tumor DNA (ctDNA), released by cancer cells in the blood stream, appears as an alternative to tissue sampling. The pre-analytical conditions are now well defined, and several technological approaches can be used to demonstrate the desired molecular alterations. ctDNA is less affected by tumor heterogeneity, can be collected in a minimally invasive manner and analyzed rapidly. Furthermore, ctDNA can be repeatedly analyzed during follow-up, which makes it possible to envisage its use as a specific tumor marker, in order to monitor the response to the treatment and to detect treatment failure.

Published
2017

13. Treatment of a NSCLC patient with osimertinib based on the detection of the EGFR T790M resistance mutation in cerebrospinal fluid

Author

Audrey Vallée, Guillaume Herbreteau, Hélène Senellart, Marc G. Denis, Ingrid Masson, and Sandrine Théoleyre

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Cancer Research, Pathology, medicine.medical_specialty, business.industry, EGFR T790M, Resistance mutation, medicine.disease, 03 medical and health sciences, ErbB Receptors, 030104 developmental biology, 0302 clinical medicine, Meningeal carcinomatosis, Cerebrospinal fluid, Text mining, Oncology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Cancer research, Medicine, Osimertinib, business
Published
2017
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14. Clinical significance of BRAF mutation status in circulating tumor DNA of metastatic melanoma patients at baseline

Author

Anne Chantal Knol, Amir Khammari, Guillaume Herbreteau, Anabelle Brocard, Audrey Vallée, Brigitte Dréno, Sandrine Théoleyre, Gaëlle Quéreux, Emilie Varey, Aurélie Gaultier, Jean-Michel Nguyen, Lucie Peuvrel, Mélanie Saint-Jean, Marc G. Denis, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), SEB-PIMESP, Centre hospitalier universitaire de Nantes (CHU Nantes), CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Adult, Male, Proto-Oncogene Proteins B-raf, 0301 basic medicine, Pathology, medicine.medical_specialty, plasma DNA, overall survival, Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Biology, medicine.disease_cause, Biochemistry, S100 protein, Circulating Tumor DNA, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Clinical significance, Neoplasm Metastasis, Melanoma, Molecular Biology, Aged, Mutation, L-Lactate Dehydrogenase, S100 Proteins, Cancer, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, BRAF mutation, chemistry, Circulating tumor DNA, 030220 oncology & carcinogenesis, Cancer research, Female, France, DNA, metastatic melanoma
Abstract

International audience; Circulating tumor DNA is a promising non-invasive tool for cancer monitoring. The main objective of our work was to investigate the relationship between mutant BRAF DNA in plasma and clinical response. Thirty-eight stage IV patients with a V600 mutated BRAF melanoma were included prior to any treatment. DNA was extracted from plasma and mutant DNA was detected using the amplification-refractory mutation system method. Before the beginning of any treatment, the corresponding BRAF mutation was detected in 29 of the 38 tested plasma samples (76.3% positive per cent agreement). We observed a strong correlation between the presence of circulating mutated DNA and overall survival (OS; P=.02), and with the number of metastatic sites (P=.01). The presence of circulating mutated DNA was also strongly correlated with serum LDH activity (P

Published
2016
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15. Rapid clearance of circulating tumor DNA during treatment with AZD9291 of a lung cancer patient presenting the resistance EGFR T790M mutation

Author

Laurent Tessonnier, Audrey Vallée, Guillaume Herbreteau, Sandrine Théoleyre, Clarisse Audigier-Valette, Marc G. Denis, and Julien Merrien

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, business.industry, EGFR T790M, DNA, Neoplasm, medicine.disease, Neoplastic Cells, Circulating, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Circulating tumor DNA, 030220 oncology & carcinogenesis, Internal medicine, Carcinoma, Non-Small-Cell Lung, Mutation (genetic algorithm), medicine, Humans, Lung cancer, business
Published
2015

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