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1. Real-world prevalence, treatment and survival of 'high risk' early breast cancer, with mandatory testing of gBRCA1/2 mutation according to the OlympiA trial inclusion criteria: Data from a population-based registry

Author

Sylvain Ladoire, Ariane Mamguem Kamga, Loick Galland, Isabelle Desmoulins, Didier Mayeur, Courèche Kaderbhai, Silvia Mihaelia Ilie, Audrey Hennequin, Clementine Jankowski, Juliette Albuisson, Sophie Nambot, Charles Coutant, Laurent Arnould, Manon Reda, Caroline Truntzer, and Sandrine Dabakuyo

Subjects
Breast cancer, High risk, Olympia, BRCA, Adjuvant, Olaparib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: The results of the OlympiA study led to the approval of a PARP inhibitor (olaparib) as adjuvant treatment for early breast cancer (eBC) at high risk of relapse in patients with a germline BRCA1/2 mutation (gBRCAm). However, the proportion of patients in routine practice who meet the “high-risk” criteria applied in the OlympiA study, and for whom gBRCAm testing would now be mandatory, remains unknown. Patients and methods: In this population-based study, we use unique data from the French specialized Côte d'Or Breast and Gynecological Cancer Registry, to assess the real-life proportion, and long-term prognosis of patients treated for eBC between 2005 and 2015 with standard treatment, and at “high risk” of relapse according to the OlympiA trial criteria. Results: We included 3483 patients treated for HER2-negative eBC (N = 380 with ER-, and N = 3103 with ER + tumor). We found N = 62 (1.8 %) patients with gBRCA1/2 mutations. A total of 494 patients (14.2 %) were classified as “high risk” according to the Olympia criteria; 55 % with ER-tumors, and 9.1 % with ER + tumors, respectively. Despite more intensive systemic treatments in “high risk” patients, 10-year overall survival was much worse in these “high risk” patients compared to the others: 60.1 % vs 83.8 % in ER-tumors, and 55.4 % vs 84.1 % in ER + tumors. Our estimates of net survival show an even greater difference. Conclusion: This study provides real-life insights into the prevalence and prognosis of patients with high-risk eBC, in a context where the approval of adjuvant olaparib requires careful reorganization of care, so as not to overlook a patient with gBRCAm who could benefit from adjuvant olaparib.

Published
2024
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2. Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients

Author

Alexandre Le Marouille, Emma Petit, Courèche Kaderbhaï, Isabelle Desmoulins, Audrey Hennequin, Didier Mayeur, Jean-David Fumet, Sylvain Ladoire, Zoé Tharin, Siavoshe Ayati, Silvia Ilie, Bernard Royer, and Antonin Schmitt

Subjects
palbociclib, neutropenia, pharmacokinetic/pharmacodynamic, Pharmacy and materia medica, RS1-441
Abstract

Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L.

Published
2021
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3. Population Pharmacokinetics of Palbociclib in a Real-World Situation

Author

Bernard Royer, Courèche Kaderbhaï, Jean-David Fumet, Audrey Hennequin, Isabelle Desmoulins, Sylvain Ladoire, Siavoshe Ayati, Didier Mayeur, Sivia Ilie, and Antonin Schmitt

Subjects
palbociclib, population pharmacokinetics, real-world situation, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Palbociclib is an oral cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Its metabolism profile is associated with an important interpatient variability. We performed a population pharmacokinetics study of palbociclib in women routinely followed in a cancer center. One hundred and fifty-one samples were analyzed. The sampling times after administration ranged from 0.9 to 75 h and the samples were taken between 1 and 21 days after the beginning of the palbociclib cycle. Palbociclib was determined using a validated mass spectrometry method. The best model that described the concentrations was a one-compartment model with first-order absorption and an absorption lag time. Interindividual variability could only be estimated on the clearance and the first-order absorption. Creatinine clearance was found to be a significant covariate for the apparent clearance. No significant covariates could be observed with the first-order absorption. First-order absorption and absorption lag times were difficult to assess because of the constraints linked to the real-world setting due to the small number of samples used during the absorption process. However, palbociclib apparent clearance was satisfactorily estimated. Population pharmacokinetics (POP PK) with palbociclib could help to optimize dosing.

Published
2021
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4. MER4 endogenous retrovirus correlated with better efficacy of anti-PD1/PD-L1 therapy in non-small cell lung cancer

Author

Francois Ghiringhelli, Romain Boidot, Caroline Truntzer, Bertrand Routy, Philippe Joubert, Julie Lecuelle, Laure Favier, Cléa Fraisse, Aurélie Lagrange, Coureche Kaderbhai, and Sandy Chevrier

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Endogenous retroviruses (ERVs) are highly expressed in various cancer types and are associated with increased innate immune response and better efficacy of antiprogrammed death-1/ligand-1 (anti-PD1/PD-L1)-directed immune checkpoint inhibitors (ICI) in preclinical models. However, their role in human non-small cell lung cancer (NSCLC) remains unknown.Methods We conducted a retrospective study of patients receiving ICI for advanced NSCLC in two independent cohorts. ERV expression was determined by RNA sequencing. The primary endpoint was progression-free survival (PFS) under ICI. The secondary endpoint was overall survival (OS) from ICI initiation. We studied expression of 6205 ERVs. Multivariate Cox regression model with lasso penalty was estimated on the training set to select ERVs significantly associated with survival. The predictive power of these ERVs was compared with that of previously described transcriptomic signatures.Results We studied two independent cohorts of 89 and 70 patients, used as training and validation sets. Clinicopathological characteristics included 75% of patients with non-squamous NSCLC. We selected four ERVs significantly associated with PFS. Only high MER4 ERV was associated with better PFS and OS in both cohorts. From a biological point of view, high MER4 expression is associated with higher infiltration of eosinophils and inflammatory gene signatures, while low MER4 expression is associated with enrichment in metabolism and proliferation signatures. Adding MER4 to previously described transcriptomic signatures of response to ICI improved their predictive power.Conclusions MER4 ERV expression is useful to stratify risk and predict PFS and OS in patients treated with ICI for NSCLC. It also improves the predictive power of other known transcriptomic signatures.

Published
2022
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5. A Real-World Study of Patients with Advanced Non-squamous Non-small Cell Lung Cancer with EGFR Exon 20 Insertion: Clinical Characteristics and Outcomes

Author

Nicolas Girard, Eric Pichon, David Planchard, Didier Debieuvre, Radj Gervais, Gaëlle Chenuc, Pascale Dubray-Longeras, J. Otto, Eric Dansin, Hervé Lena, Anne Madroszyk, Maurice Pérol, Thomas Filleron, Xavier Quantin, Lise Bosquet, Gaëtane Simon, Coureche Kaderbhai, Sophie Cousin, Sandrine Hiret, Christelle Clément-Duchêne, Christos Chouaid, and Roland Schott

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Population, Exon, Carcinoma, Non-Small-Cell Lung, Internal medicine, medicine, Humans, Pharmacology (medical), Epidermal growth factor receptor, education, Lung cancer, Protein Kinase Inhibitors, education.field_of_study, biology, Performance status, business.industry, Incidence (epidemiology), Combination chemotherapy, Exons, Immunotherapy, Middle Aged, medicine.disease, ErbB Receptors, Mutation, biology.protein, Female, business
Abstract

In Europe, few data regarding the characteristics of EGFR exon 20 insertion (20ins) mutations in non-small cell lung cancer (NSCLC) are available. Using a large real-world cohort, we assessed the incidence, characteristics, and outcomes of patients with non-squamous (nsq) NSCLC harboring EGFR exon 20ins. The Epidemio-Strategy and Medical Economics advanced and metastatic lung cancer data platform including advanced/metastatic nsqNSCLC patients from January 2015 was analyzed (cut-off date: June 30, 2020). Characteristics, epidermal growth factor receptor (EGFR) mutation and other mutations, treatment patterns, and clinical outcomes were assessed for patients harboring EGFR exon 20ins, common EGFR mutations, other EGFR mutations, and wild-type EGFR. Survival parameters were estimated by the Kaplan-Meier method in these four groups. Out of 9435 nsqNSCLC patients tested for EGFR, 1549 (16.4%) had a mutation, including 61 with EGFR exon 20ins (3.9% of all mutated EGFR). These 61 patients had a mean age of 63.6 years, were mostly female (68.9%) and non-smokers (55.7%), with de novo stage IV disease (73.8%) and performance status 0–1 (76.9%). Almost all patients (95.1%) with exon 20ins received systemic therapy (median, three lines). First-line systemic treatments consisted mainly of combination chemotherapy (70.7%), single-agent EGFR tyrosine kinase inhibitors (10.3%), and single-agent immunotherapy (5.2%). After a median follow-up of 25.0 (95% confidence interval [CI] 22.3–32.4) months, the median real-world overall survival was 24.3 (19.1–32.6) months in patients with exon 20ins compared to 35.4 (95% CI 32.6–37.5) in patients with common EGFR mutation (n = 1049) (p = 0.049) and 19.6 (95% CI 18.6–20.5) in patients with wild-type EGFR (n = 7866) (p = 0.2). This large national study in nsqNSCLC patients confirms that EGFR exon 20ins is a rare condition (0.6%). The prognosis associated with exon 20ins appears to be in line with that of wild-type EGFR, but worse than common EGFR mutations, highlighting the need for advancements for this rare population.

Published
2021
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6. Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients

Author

Siavoshe Ayati, Antonin Schmitt, Alexandre Le Marouille, Bernard Royer, Audrey Hennequin, Emma Petit, Sylvain Ladoire, Coureche Kaderbhai, Jean-David Fumet, Didier Mayeur, Silvia Ilie, Zoé Tharin, and Isabelle Desmoulins

Subjects
Volume of distribution, medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, palbociclib, business.industry, Population, Pharmaceutical Science, Renal function, Neutropenia, Palbociclib, medicine.disease, Gastroenterology, Article, RS1-441, Pharmacy and materia medica, Pharmacokinetics, Therapeutic drug monitoring, Internal medicine, Pharmacodynamics, medicine, neutropenia, pharmacokinetic/pharmacodynamic, education, business
Abstract

Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L, 29.6% IIV), Slope (0.0011 L/µg, 28.8% IIV), Mean Transit Time (MTT, 5.29 days, 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L.

Published
2021

7. Seroprevalence of SARs-CoV-2 among the staff and patients of a French cancer centre after first lockdown: the canSEROcov study

Author

Laurent Arnould, Julie Vincent, Elise Ballot, Vincent Goussot, Cléa Fraisse, Charles Coutant, Anne-Laure Simonet-Lamm, Jean-David Fumet, Emilie Redersdorff, Nathalie Bremaud, Siavoshe Ayati, Adele Cueff, François Ghiringhelli, Sylvie Zanetta, Caroline Truntzer, Silvia Ilie, Didier Mayeur, Roxana Hanu, Bruno Coudert, Alice Hervieu, Sylvain Ladoire, Aurélie Lagrange, Aurélie Bertaut, Nils Martin, Coureche Kaderbhai, Leila Bengrine-Lefevre, Irina Mazilu, Laure Favier, Isabelle Desmoulins, Rémi Palmier, and Audrey Hennequin

Subjects
0301 basic medicine, Male, Cancer Research, Serology, 0302 clinical medicine, Hygiene, Seroepidemiologic Studies, Epidemiology, Medicine, Prospective cohort study, Child, media_common, Original Research, Aged, 80 and over, serodiagnosis, seroprevalence, Social distance, Middle Aged, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Carrier State, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, media_common.quotation_subject, Health Personnel, SARS-COV-2, Cancer Care Facilities, Asymptomatic, COVID-19 Serological Testing, staff, 03 medical and health sciences, Young Adult, Seroprevalence, Humans, Antibody, Aged, business.industry, healthcare workers, Cancer, COVID-19, cancer center, Cancer patients, medicine.disease, Personnel, Hospital, 030104 developmental biology, Family medicine, business
Abstract

Background In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection. Methods After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown. Findings A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients. Interpretation We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.

Published
2021

8. Biologie moléculaire des carcinomes bronchiques : standards actuels et perspectives

Author

Zoé Tharin, François Ghiringhelli, and Coureche Kaderbhai

Subjects
03 medical and health sciences, Medical Laboratory Technology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Biochemistry (medical), 030212 general & internal medicine, Analytical Chemistry
Abstract

Resume Le carcinome bronchique est un probleme majeur de sante publique avec 1,8 million de nouveaux cas par an et represente la premiere cause de mortalite par cancer dans le monde. Dans ce travail, nous nous interessons uniquement aux carcinomes bronchiques non a petite cellule de type adenocarcinomes dans la mesure ou, a l’heure actuelle, ils representent le seul type histologique pouvant presenter des alterations moleculaires actionnables d’un point de vue therapeutique. Plusieurs mutations ou rearrangements geniques sont a rechercher de maniere systematique au diagnostic d’adenocarcinome bronchique localement avance ou metastatique, a savoir : EGFR (Epidermal Growth Factor Receptor), ALK (Anaplastic Lymphoma Kinase), RO S 1 (ROS1 proto-oncogene receptor tyrosine kinase), KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), B Raf et HER2 (human epidermal growth factor receptor 2). La presence de ces anomalies offre dans un certain nombre des cas, la possibilite d’acceder a une therapie ciblee par inhibiteur de tyrosine kinase, dont l’efficacite s’est averee superieure aux doublets de chimiotherapie classiques.

Published
2018
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9. 109P Real-world evaluation of pembrolizumab monotherapy for PD-L1 positive (TPS>50%) metastatic NSCLC in France

Author

Maurice Pérol, Christos Chouaid, Xavier Quantin, Coureche Kaderbhai, C. Audigier Valette, D. Couch, Thomas Burke, Hervé Lena, M. Santorelli, E. Nguyen, L. Bensimon, C. Fabre, C. Courtinard, and Thomas Filleron

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, business.industry, Internal medicine, Medicine, Pembrolizumab, business, PD-L1 Positive
Published
2021
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10. EGFR Exon 20 insertion: Prognostic and predictive values in advanced non-small cell lung cancer, a real-world study

Author

Xavier Quantin, Pascale Dubray-Longeras, Nicolas Girard, Eric Dansin, Eric Pichon, Gaëtane Simon, Anne-Laure Martin, David Planchard, Didier Debieuvre, Sandrine Hiret, Christos Chouaid, Josiane Otto, Thomas Filleron, Radj Gervais, Roland Schott, Christelle Clément-Duchêne, Anne Madroszyk, Coureche Kaderbhai, Sophie Cousin, and Maurice Pérol

Subjects
Cancer Research, Exon, Oncology, Egfr mutation, business.industry, Cancer research, Medicine, Non small cell, business, Lung cancer, medicine.disease, Predictive value
Abstract

9062 Background: In Europe, 10-15% of non-squamous non-small cell lung cancer (nsqNSCLC) have EGFR mutations of which 5-12% are an Exon 20 insertion (20ins). Methods: Analysis of Epidemio-Strategy and Medical Economics (ESME) Advanced and Metastatic Lung cancer (AMLC) Data Platform (NCT03848052), a multicenter real-life database using a supervised, retrospective data collection process. The database includes 13737 advanced nsqNSCLC treated from January 2015 at participating centres. The cut-off date for patient follow-up for this analysis was June 30, 2020. The aim of the study was to assess real-world patient characteristics, treatment patterns and clinical outcomes of advanced nsqNSCLC EGFR 20ins. Overall survival (OS) of EGFR cohorts (20ins, 19del/L858R without 20ins, other EGFR mutations) and EGFR wild-type/not tested cohort were assessed. Results: 1549 (11.3%) nsqNSCLC had an EGFR mutation, 61 (3.9%) of whom being an EGFR 20ins. These 61 patients (pts) are mainly female (68.9%), non-smoker (55.7%), with de novo stage IIIB/IV disease (78.6%), PS 0-1 (76.9%). Median age was 68.0 years (q1-q3: 54-74). PD-L1 status was assessed in 34 (55.7%) pts, mainly (n = 20) before first line and 22 (64.7%) had negative result. Most (63.9%) pts had EGFR 20ins positive result available before first line. Almost all pts (95.1%, n = 58) received a systemic therapy with a median number of 3 (q1-q3: 1-4) lines. In first line setting, 74% of the pts received chemotherapy (mainly chemotherapy combination), 13.7% received EGFR TKI (mainly as monotherapy) and 8.6% received immunotherapy only. Median treatment duration for pts treated with CarboPem (n = 19), CisplatinPem (n = 16) and CarboTaxol (n = 6) were 4.7 (q1-q3: 2.6-6.6), 7.4 (q1-q3: 5.0-12.8) and 3.3 (q1-q3: 2.8-3.8) months, respectively. For afatinib (n = 3), erlotinib (n = 2) and gefitinib (n = 1), median treatment durations were 1.6 (q1-q3: 0.5-2.8); 1.8 (q1-q3: 1.4-2.1) and 2.3 months, respectively. After a median follow up of 36.3 (95%CI: 34.1-39.8) months, median OS was 24.3 (95%CI: 19.1-32.6) months; 1 and 2-years OS rates were 82.5% (95%CI: 69.7-90.2) and 52.6% (95%CI: 37.3-65.9), respectively. For pts with 19del/L858R without 20ins (n = 1049) and those with other EGFR mutations (n = 439) median OS were 35.4 (95%CI: 32.6-37.5) and 41.7 (95%CI: 31.9-53.5), respectively compared to 20.7 (95%CI: 20.0-21.8] months for pts EGFR wild type/not tested (n = 12188). Conclusions: This large, national real-world analysis based on medical chart data’s confirm that EGFR 20ins is a rare disease (0.4% of advanced nsqNSCLC). Currently available EGFR TKIs appear to have low efficacy and response to chemotherapy seems identical to that of EGFR wild-type/not tested pts. Prognosis for NSCLC pts with EGFR 20ins mutations was in line with that of EGFR wild type/not tested but worse than common EGFR mutations highlighting the need for advancements for this rare population.

Published
2021
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11. 110P Real-world evaluation of pembrolizumab monotherapy for previously treated PD-L1 positive (TPS>1%) advanced NSCLC in France

Author

Maurice Pérol, G. Chenuc, Nicolas Girard, C. Courtinard, Gaëtane Simon, Thomas Burke, Thomas Filleron, A-L. Martin, Didier Debieuvre, Xavier Quantin, L. Bensimon, Radj Gervais, Christos Chouaid, Matthieu Carton, Roland Schott, C. Audigier Valette, M. Santorelli, Coureche Kaderbhai, and Hervé Lena

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, Pembrolizumab, business, Previously treated, PD-L1 Positive
Published
2021
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12. The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer

Author

Zoé Tharin, François Ghiringhelli, and Coureche Kaderbhai

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Immune checkpoint inhibitors, Review, lcsh:RC254-282, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Lung cancer, Exome, business.industry, Surrogate endpoint, biomarkers, Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), Immunohistochemistry, immunotherapy, business
Abstract

Immune checkpoint inhibitors radically changed the treatment of patients with non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies when used as monotherapy. The assessment of Program Death Ligand-1 (PD-L1) tumor expression by immunohistochemistry is used to select potential responder patients, but this not an optimal marker since it does not predict the absence of anti PD-1 efficacy. Despite this shortcoming, PD-L1 remains the gold standard biomarker in many studies and the only biomarker available for clinicians. In addition to histological markers, transcriptomic and exome analyses have revealed potential biomarkers requiring further confirmation. Recently, tumor mutational burden has emerged as a good surrogate marker of outcome. In this review we will detail current knowledge on DNA and RNA related biomarkers.

Published
2018

13. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

Author

Caroline Flament, Christophe Klein, Gladys Ferrere, Laura Mondragón, Coureche Kaderbhai, Meriem Messaoudene, Bertrand Routy, B. Escudier, Hira Rizvi, Jordi Remon Masip, Lisa Derosa, Gérard Zalcman, Nicolas Jacquelot, Conrad Rauber, Kristina Iribarren, François Ghiringhelli, Nathalie Galleron, Nicolas Pons, Romain Daillère, Jean-Charles Soria, Matthew D. Hellmann, Marine Fidelle, Eric Deutsch, Vichnou Poirier-Colame, Laura Mezquita, Benoit Quinquis, Corentin Richard, Bo Qu, Aurélie Fluckiger, Patrick Gonin, Céline Clémenson, Yohann Loriot, Paule Opolon, Connie P.M. Duong, Laurence Zitvogel, Maria Paula Roberti, C. Naltet, Bernhard Ryffel, Guido Kroemer, Laurence Albiges, Veronique Minard-Colin, Alexander M.M. Eggermont, Maryam Tidjani Alou, Florence Levenez, Didier Raoult, François Goldwasser, Solenn Brosseau, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Institut Gustave Roussy (IGR), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Université Sorbonne Paris Cité (USPC), Sorbonne Université (SU), Laboratoire de Mecanique des Fluides et d'Acoustique (LMFA), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), UMR 996 - DHU Hépatinov, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie et de Technologies de Saclay (IBITECS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service d'Oncologie Thoracique [ Bichat], Hôpital Bichat - Claude Bernard-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Université Paris-Saclay, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Migrations internationales, espaces et sociétés (MIGRINTER UMR 7301), Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Radiothérapie moléculaire (UMR 1030), Département de radiothérapie [Gustave Roussy], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncologie génito-urinaire, 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Dpt of Women's and Children's Health [Stockholm], Karolinska University Hospital [Stockholm], Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Gustave Roussy Course of Excellence in Oncology-Fondation Philanthropia, McGill University Townsend hematology research fellowship award, Ligue contre le Cancer (equipe labelisee), Agence Nationale de la Recherche (ANR)-Projets blancs, ANR under the frame of E-Rare-2 (ERA-Net for Research on Rare Diseases), Association pour la recherche sur le cancer (ARC), Canceropole Ile-de-France, Institut National du Cancer (INCa), Institut Universitaire de France, Fondation pour la Recherche Medicale (FRM), European Research Council (ERC), LeDucq Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), Paris Alliance of Cancer Research Institutes (PACRI), philanthropia, European Project: 257144,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,ARTFORCE(2011), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Bichat - Claude Bernard-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Plateforme histo-cyto-pathologies (PHCP), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INRA US1367 MetaGenoPolis, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Immunologie et embryologie moléculaires (IEM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Paris Descartes - Paris 5 (UPD5), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy ( IGR ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), MetaGénoPolis, Institut National de Recherche Agronomique, Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme histo-cyto-pathologies ( PHCP ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Unité de radiothérapie moléculaire ( UMR 1030 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Karolinska University Hospital Solna, Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institute, Centre de Recherche des Cordeliers (CRC), and Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Receptors, CXCR3, medicine.drug_class, T-Lymphocytes, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, Antibiotics, CCR9, [SDV.CAN]Life Sciences [q-bio]/Cancer, CXCR3, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Feces, Mice, Receptors, CCR, 03 medical and health sciences, 0302 clinical medicine, Verrucomicrobia, Neoplasms, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, biology, Antibodies, Monoclonal, Cancer, Immunotherapy, Fecal Microbiota Transplantation, medicine.disease, biology.organism_classification, Interleukin-12, Anti-Bacterial Agents, Gastrointestinal Microbiome, 3. Good health, Blockade, 030104 developmental biology, 030220 oncology & carcinogenesis, CD4 Antigens, Immunology, biology.protein, Metagenome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Akkermansia muciniphila
Abstract

Good bacteria help fight cancer Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32

Published
2018
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14. Immune classifications with cytotoxic CD8+ and Th17 infiltrates are predictors of clinical prognosis in glioblastoma

Author

Julie Vincent, Walid Farah, Emeric Limagne, Valentin Derangère, François Ghiringhelli, Aurélie Bertaut, Coureche Kaderbhai, Caroline Truntzer, Marie Hélene Aubriot-Lorton, Romain Boidot, Rachid Madkouri, Sylvain Ladoire, Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Épidémiologie / biostatistiques - Département d’Information Médicale (DIM), CGFL, Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] (CLIPP), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [CHU de Dijon], Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] ( CLIPP ), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies ( FEMTO-ST ), Université de Technologie de Belfort-Montbeliard ( UTBM ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ) -Université de Technologie de Belfort-Montbeliard ( UTBM ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ) -Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] ( ICMUB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Bourgogne Franche-Comté ( UBFC ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), and Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Angiogenesis, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, CD8+ T cells, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, medicine, Immunology and Allergy, Cytotoxic T cell, RC254-282, Th17 T cells, business.industry, glioblastoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, FOXP3, RC581-607, immune infiltrate, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Immunohistochemistry, Immunologic diseases. Allergy, business, CD163, CD8
Abstract

IF 7.719; International audience; Background: Interest is growing on immune cells involvement in central nervous system tumors such as glioblastoma. Even if a few reports highlighted that immune classifications could have a prognostic value, no paradigm has been clearly yet established on large and homogeneous cohorts. The aim of our study was to analyze the prognostic role of the in situ immune response of cytotoxic T cells (i.e., CD8(+)), Foxp3 cells, Th17 and tumor-associated macrophages in glioblastoma on two independent large and homogeneous cohorts.Methods: We worked on two large homogenous cohorts of patients having glioblastoma who underwent standard radiochemotherapy. The first cohort of 186 patients was analyzed using IHC procedures (CD8(+), IL-17A, FoxP3 and CD163) of surgery pieces. We next worked with transcriptomic data available online and used metagene strategy analysis for the second cohort of 525 patients.Results: Cytotoxic CD8(+) lymphocytes and Foxp3 cells were associated with a good prognosis, while Th17 were associated with a poor clinical outcome. These data were confirmed with transcriptomic analysis. Moreover, we showed for the first time a strong link between angiogenesis and Th17 metagenes expressions in glioblastoma.Conclusions: Our study shows that glioblastoma bearing patients can be classified on the immune infiltrate aspects. Beyond this prognostic role of immune biomarkers, subsequent classifications could definitely help clinicians to handle targeted therapy administration and immunotherapeutic interventions.

Published
2017
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15. Taxane rechallenge during metastatic disease in HER-2 negative breast cancer patients: Clinical activity, tolerance and survival results

Author

Manon Réda, Anaïs Fouquier, Isabelle Desmoulins, Didier Mayeur, Courèche Kaderbhai, Silvia Ilie, Audrey Hennequin, Bruno Coudert, Aurélie Bertaut, and Sylvain Ladoire

Subjects
Breast cancer, Metastatic cancer, Paclitaxel, Chemotherapy, Rechallenge, Taxanes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Taxanes are major drugs for metastatic breast cancer (MBC) treatment, and are generally well tolerated, making them attractive for therapeutic reintroduction (rechallenge) during metastatic course. In view of the paucity of current literature, we questioned the usefulness of taxane rechallenge in a population of patients previously treated with taxanes in a metastatic setting. Methods: From the local database of a French cancer center, we retrospectively identified 756 patients diagnosed with ER+/HER2-, or triple negative MBC, and treated between 2008 and 2021. Among them, 58 patients (7.8%) were rechallenged with taxanes. Clinical characteristics, response rates, and survival were retrospectively evaluated and compared to patients who received taxanes only once. Results: Compared to non-rechallenged population, patients treated with taxane rechallenge were significantly younger, with better general status, and received more treatment. First taxane exposure led to better tumor response and was more frequently discontinued for reasons other than progression, compared to the non-rechallenged population. Taxane rechallenge led to an objective response rate of 27.6%, and a clinical benefit rate of 46.6%, with a median progression-free survival (PFS) of 5.7 months, and a median overall survival (OS) of 11.6 months. We also found a PFS2/PFS1 ratio >1.3 in 55.2% of the rechallenge population. Conclusion: Although only a minority of MBC patients are concerned, taxane rechallenge appears to be a pragmatic option with an acceptable tolerance, and good efficacy, especially when these drugs have shown clinical activity earlier in the disease course, and/or have been stopped for reasons other than progression.

Published
2023
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16. P1.01-116 Early Immune-Related Adverse Events Under PD-1/PD-L1 Inhibitors Predict Better Progression-Free Survival in NSCLC

Author

Coureche Kaderbhai, Pierre Saintigny, S. Ortiz-Cuaran, S. Chabaud, E.M. Neidhardt, J. Fumet, F. Ghiringhelli, Bénédicte Mastroianni, Maurice Pérol, Valérie Paulus, M. Boussageon, V. Avrillon, A. Swalduz, Jérôme Fayette, and David Pérol

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, biology, business.industry, Immune system, Internal medicine, PD-L1, medicine, biology.protein, Progression-free survival, Adverse effect, business
Published
2019
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17. Antibiotic Use Does Not Appear to Influence Response to Nivolumab

Author

Anne Aarnink, Aurélie Lagrange, Jean David Fumet, Emeric Limagne, François Ghiringhelli, Coureche Kaderbhai, Romain Boidot, Corentin Richard, Pascal Foucher, Laure Favier, Bruno Coudert, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Service de chirurgie cardio-vasculaire et thoracique (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon )

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Lung Neoplasms, Time Factors, medicine.medical_treatment, Antibiotics, Kaplan-Meier Estimate, NSCLC, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Risk Factors, Carcinoma, Non-Small-Cell Lung, Response rate (survey), Aged, 80 and over, Antibodies, Monoclonal, General Medicine, Middle Aged, 3. Good health, Anti-Bacterial Agents, Nivolumab, Treatment Outcome, 030220 oncology & carcinogenesis, Female, France, medicine.medical_specialty, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, microbiota, Humans, Lung cancer, Aged, Proportional Hazards Models, Retrospective Studies, Chi-Square Distribution, Proportional hazards model, business.industry, Retrospective cohort study, Immunotherapy, medicine.disease, 030104 developmental biology, Polypharmacy, business, Chi-squared distribution
Abstract

International audience; Background: Microbiota is known to influence response to anticancer immunotherapy. We examined whether antibiotic usage could impact nivolumab efficacy in patients treated for non-small-cell lung cancer (NSCLC). Patients and Methods: Seventy-four patients with NSCLC were included in this retrospective study. They received nivolumab between 2015 and 2016 (3 mg/kg i.v. q2w). The association between RECIST response and antibiotic usage was determined using Chi-square and Cox proportional hazard model. Results: A total of 17, 21 and 36 patients experienced response, stable disease and progression disease under nivolumab. Only 15 (20.3%) patients were exposed to antibiotic medication in the 3 months before the first nivolumab injection or during treatment. We found a similar response rate for the two populations, without impact of antibiotic exposure (Chi-square test p= 0.75). Moreover, we observed no impact of antibiotic medication on progression-free survival under nivolumab (log-rank test, p= 0.72). Conclusion: Microbiota modification induced by antibiotics does not appear to affect the efficacy of nivolumab in patients with NSCLC.

Published
2017
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18. Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma

Author

Valentin Derangère, Klaus Luc Mourier, François Ghiringhelli, Bruno Chauffert, Caroline Truntzer, Rachid Madkouri, Wahlid Farah, Julie Vincent, Aurélie Bertaut, Coureche Kaderbhai, Marie Hélene Aubriot-Lorton, Romain Boidot, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] ( CLIPP ), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies ( FEMTO-ST ), Université de Technologie de Belfort-Montbeliard ( UTBM ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ) -Université de Technologie de Belfort-Montbeliard ( UTBM ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ) -Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] ( ICMUB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Service de Pathologie [CHU de Dijon], Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] (CLIPP), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer (U866) (LNC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
0301 basic medicine, Oncology, Male, Vascular Endothelial Growth Factor A, genetic structures, Neutrophils, medicine.medical_treatment, Angiogenesis Inhibitors, Biomarkers, Pharmacological, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Leukocyte Count, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Granulocyte Colony-Stimulating Factor, Endothelial Growth-Factor, prognostic factor, Neoadjuvant therapy, Randomized Controlled Trials as Topic, Neovascularization, Pathologic, Brain Neoplasms, Colony-Stimulating Factor, Age Factors, Chemoradiotherapy, Middle Aged, Prognosis, Neoadjuvant Therapy, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, To-Lymphocyte Ratio, Absolute neutrophil count, Female, medicine.drug, medicine.medical_specialty, Bevacizumab, Malignant Glioma, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, bevacizumab, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, Humans, Pretreatment Neutrophil, Karnofsky Performance Status, Single-Agent Bevacizumab, Retrospective Studies, Newly-Diagnosed Glioblastoma, Recurrent Glioblastoma, business.industry, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Gene Expression Profiling, glioblastoma, Cancer, Retrospective cohort study, Lomustine, medicine.disease, Phase-Ii Trial, eye diseases, Surgery, Irinotecan, 030104 developmental biology, prognosistic factor, Brain-Tumors, sense organs, Clinical Research Paper, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

// Aurelie Bertaut 1 , Caroline Truntzer 2 , Rachid Madkouri 3 , Coureche Guillaume Kaderbhai 4 , Valentin Derangere 5 , Julie Vincent 4 , Bruno Chauffert 6 , Marie Helene Aubriot-Lorton 7 , Wahlid Farah 3 , Klaus Luc Mourier 3 , Romain Boidot 5,8 and Francois Ghiringhelli 4,5,8,9 1 Biostatistics unit Georges Francois Leclerc Cancer Center, Dijon, France 2 CLIPP, Research Center, University of Burgundy, Dijon, France 3 Department of Neurosurgery, CHU, Dijon, France 4 Department of Medical Oncology, Georges Francois Leclerc Cancer Center, Dijon, France 5 Platform of Transfer in Cancer Biology Genetic and histology, Georges Francois Leclerc Cancer Center, Dijon, France 6 Department of Medical Oncology, University Hospital Amiens, Amiens, France 7 Department of Pathology, CHU, Dijon, France 8 INSERM U866, Dijon, France 9 University of Bourgogne Franche-Comte, Dijon, France Correspondence to: Francois Ghiringhelli, email: // Keywords : glioblastoma, bevacizumab, prognostic factor Received : April 11, 2016 Accepted : July 10, 2016 Published : July 28, 2016 Abstract Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence ( N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm 3 . Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression , the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.

Published
2016
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19. Molecular intrinsic subtypes, genomic, and immune landscapes of BRCA-proficient but HRD-high ER-positive/HER2-negative early breast cancers

Author

Elise Ballot, Loïck Galland, Hugo Mananet, Romain Boidot, Laurent Arnould, Isabelle Desmoulins, Didier Mayeur, Courèche Kaderbhai, Silvia Ilie, Audrey Hennequin, Anthony Bergeron, Valentin Derangère, François Ghiringhelli, Caroline Truntzer, and Sylvain Ladoire

Subjects
Early breast cancer, ER-positive breast cancer, BRCA, Exome, NGS, HRD score, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Purpose The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. We hypothesized that ER + /HER2- early breast tumors without BRCA 1/2 mutation could have high HRD score and aimed to describe their genomic, transcriptomic, and immune landscapes. Patients and methods In this study, we reported BRCA 1/2 mutational status, HRD score, and mutational signature 3 (S3) expression, in all early breast cancer (eBC) subtypes from the TCGA database, with a particular focus in ER + /HER2-. In this subtype, bioinformatics analyses of tumor transcriptomic, immune profile, and mutational landscape were performed, according to HRD status. Overall survival (OS), progression free-interval (PFI), and variables associated with outcome were also evaluated. Results Among the 928 tumor samples analyzed, 46 harbored BRCA 1/2 mutations, and 606 were ER + /HER2- (of which 24 were BRCA 1/2 mutated). We found a subset of BRCA-proficient ER + /HER2— eBC, with high HRD score. These tumors displayed significantly different immune, mutational, and tumor molecular signatures landscapes, compared to BRCA-mutated and BRCA-proficient HRD-low tumors. Outcome did not significantly differ between these 3 groups, but biological factors associated with survival are not the same across the 3 entities. Conclusion This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation.

Published
2022
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20. P2.03b-037 Prognostic Impact of 1st-Line Treatment and Molecular Testing in Advanced NSCLC in France - Results of the IFCT-PREDICT.amm Study

Author

Arnaud Scherpereel, Fabrice Barlesi, Franck Morin, Marie Wislez, Denis Moro-Sibilot, Eric Dansin, Elisabeth Quoix, Patrick Merle, Alexandra Langlais, Anne Madroszyk, Gérard Zalcman, Sandrine Hiret, P. Missy, Elizabeth Fabre, Pierre-Jean Souquet, Sylvie Friard, Coureche Kaderbhai, Michael Duruisseaux, Hervé Lena, Virginie Westeel, Julien Mazieres, Catherine Daniel, and Jacques Cadranel

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, business.industry, Internal medicine, Medicine, Line (text file), business
Published
2017
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21. Response to first-line chemotherapy regimen to predict efficacy of nivolumab in lung cancer

Author

François Ghiringhelli, Pierre Saintigny, Bruno Coudert, Jean David Fumet, Emeric Limagne, Anne Aarnink, Corentin Richard, Coureche Kaderbhai, Aurélie Lagrange, Laure Favier, Pascal Foucher, Maurice Pérol, Sandra Ortiz-Cuaran, and Paul Hofman

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.drug_class, Monoclonal antibody, medicine.disease, 03 medical and health sciences, Regimen, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Medicine, Nivolumab, First line chemotherapy, business, Lung cancer
Abstract

3026 Background: Nivolumab is a monoclonal antibody, targeting PD-1 receptor and demonstrating durable clinical benefit in 20% of metastatic NSCLC patients in second and further treatment lines. The expression of one of the PD-1 ligand, PD-L1 assessed by IHC is associated with better outcome. However, robust predictive markers of efficacy are lacking. Methods: 115 pts with stage IV NSCLC (42 squamous, 73 adenocarcinoma) were included in this retrospective study in 4 different institutions. They received nivolumab (3 mg/kg IV Q2W) after at least one line of systemic platinum-based chemotherapy. Response to first line chemotherapy and to nivolumab (RECIST 1.1) was determined on CT scan by two physicians. Association between best response to first-line regimen and PFS, OS or response to nivolumab was determined using both Chi2 and Cox analysis. Results: 46 (40%), 44 (38%) and 25 (22%) patients experimented PR, SD and PD to first-line platinum-based chemotherapy. 25 (22%), 34 (29.5%), 56 (48.5%) experimented PR, SD and PD to nivolumab. 59.5% (53/89) of patients who experimented clinical benefit (SD+PR) to first-line also experimented clinical benefit to nivolumab while only 20% (5/25) of patients with PD as best response to chemotherapy experimented clinical benefit to nivolumab (Chi2 test p = 0.002). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Cox uni and multivariate models included age, histology and performance status underlined that patients with clinical benefit from chemotherapy had improved PFS with nivolumab (P = 0.002) (median PFS on nivolumab regimen of 4.9, 3.3 and 1.8 months for patients with PR, SD and PD to first-line, respectively). Similar results were obtained for OS (P = 0.03). Conclusions: Our data suggest that response to first-line chemotherapy may be a good surrogate marker of response, PFS and OS to post-platinum nivolumab in metastatic NSCLC.

Published
2017
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22. Efficacy of platinum-based chemotherapy in metastatic breast cancer and HRD biomarkers: utility of exome sequencing

Author

Loïck Galland, Elise Ballot, Hugo Mananet, Romain Boidot, Julie Lecuelle, Juliette Albuisson, Laurent Arnould, Isabelle Desmoulins, Didier Mayeur, Courèche Kaderbhai, Silvia Ilie, Audrey Hennequin, Anthony Bergeron, Valentin Derangère, François Ghiringhelli, Caroline Truntzer, and Sylvain Ladoire

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Metastatic breast cancer (MBC) is frequently managed by platinum-based chemotherapy during the disease course. The real benefit of these treatments is uncertain at advanced stages of the disease and in non-triple-negative subtypes. Since homologous recombination deficiency (HRD) could inform about tumor sensitivity to DNA-damaging agents, we aimed to determine biomarkers of genomic instability, and their link with platinum efficacy. In this single-center study, we report BRCA1/2 mutational status, HRD score and signature 3 levels, all obtained by tumor exome sequencing, in 86 patients with various subtypes of MBC and who received platinum-based chemotherapy. Overall response rate, disease control rate, PFS and PFS2/PFS1 ratio were evaluated to assess platinum-based chemotherapy efficacy. Among the 86 tumor samples analyzed, 7 harbored BRCA1/2 mutations. We found a subset of BRCA-proficient MBC with high HRD score or high S3 levels, comparable to BRCA-mutated tumors. However, these patients with high HRD score or high S3 tumor level do not seem to benefit more from platinum-based chemotherapy than the others, in terms of response rates and/or PFS, regardless of BC molecular subtype. By multivariate analysis, only the absence of liver metastases was independently associated with significantly better PFS on platinum-based chemotherapy. However, some of our exploratory analyses reveal that certain methods, when optimized, seem to associate with platinum benefit. Tumor exome sequencing methodology for quantifying HRD has to be approached systematically, and further validated and standardized prior to its clinical use. Further studies are warranted to confirm these results to guide platinum use in MBC.

Published
2022
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23. Blood baseline neutrophil count to predict bevacizumab efficacy in glioblastoma

Author

Romain Boidot, Aurélie Bertaut, Coureche Kaderbhai, Julie Vincent, Bruno Chauffert, François Ghiringhelli, and Rachid Madkouri

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Bevacizumab, business.industry, medicine.disease, Internal medicine, Cohort, medicine, Absolute neutrophil count, business, medicine.drug, Glioblastoma
Abstract

2024Background: Bevacizumab is frequently used at recurrence of glioblastoma. However, no biomarker could predict its efficacy. Methods: Exploratory cohort consisted in all patients treated with St...

Published
2016
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