90 results on '"Nina Radosevic‐Robin"'
Search Results
2. Supplementary Figure S1-S6 from Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis
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Bruno Robert, Christel Larbouret, André Pèlegrin, Jean-Max Pasquet, Dany Chalbos, Charles Theillet, Nina Radosevic-Robin, Marta Jarlier, Muriel Busson, Imade Aït-Arsa, Audrey Sirvent, Clément Chevalier, Stanislas du Manoir, Myriam Chentouf, and Wilhem Leconet
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Supplementary Figure 1. AXL, MER and TYRO-3 expression in Triple Negative Breast Cancer (TNBC) cell lines and PDXs by Western blot analysis. Supplementary Figure 2. AXL mRNA expression in a large dataset of breast cancer tumors. Supplementary Figure 3. The 100 genes most correlated with AXL expression in 254 basal-like breast cancers. Supplementary Figure 4. Effect of the anti-AXL monoclonal antibody 20G7-D9 on matrix degradation by breast cancer cell lines. Supplementary Figure 5. GAS6 regulates expression of EMT markers in TNBC - Western Blot quantifications. Supplementary Figure 6. E-cadherin expression in TNBC cell lines
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- 2023
3. Supplementary Table S1 from Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis
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Bruno Robert, Christel Larbouret, André Pèlegrin, Jean-Max Pasquet, Dany Chalbos, Charles Theillet, Nina Radosevic-Robin, Marta Jarlier, Muriel Busson, Imade Aït-Arsa, Audrey Sirvent, Clément Chevalier, Stanislas du Manoir, Myriam Chentouf, and Wilhem Leconet
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Suppl.Table 1: Analysis of the cellular localization, pathways and gene expression modification of the 100 genes most correlated with AXL expression in 254 basal-like breast cancers.
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- 2023
4. Data from Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis
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Bruno Robert, Christel Larbouret, André Pèlegrin, Jean-Max Pasquet, Dany Chalbos, Charles Theillet, Nina Radosevic-Robin, Marta Jarlier, Muriel Busson, Imade Aït-Arsa, Audrey Sirvent, Clément Chevalier, Stanislas du Manoir, Myriam Chentouf, and Wilhem Leconet
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Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6–dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation. Clin Cancer Res; 23(11); 2806–16. ©2016 AACR.
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- 2023
5. Pathologic Response to Neoadjuvant Sequential Chemoradiation Therapy in Locally Advanced Breast Cancer: Preliminary, Translational Results from the French Neo-APBI-01 Trial
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Nhu Hanh To, Isabelle Gabelle-Flandin, Thi My Hanh Luong, Gokoulakrichenane Loganadane, Nabila Ouidir, Chahrazed Boukhobza, Noémie Grellier, Camille Verry, Allan Thiolat, José L. Cohen, Nina Radosevic-Robin, and Yazid Belkacemi
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Cancer Research ,Oncology ,neoadjuvant ,radiotherapy ,triple negative breast cancer ,luminal B ,neutrophils-to-lymphocytes ratio ,tumor-infiltrating lymphocytes - Abstract
Background: Radiation therapy (RT), a novel approach to boost the anticancer immune response, has been progressively evaluated in the neoadjuvant setting in breast cancer (BC). Purpose: We aimed to evaluate immunity-related indicators of response to neoadjuvant chemoradiation therapy (NACRT) in BC for better treatment personalization. Patients and Methods: We analyzed data of the first 42 patients included in the randomized phase 2 Neo-APBI-01 trial comparing standard neoadjuvant chemotherapy (NACT) and NACRT regimen in locally advanced triple-negative (TN) and luminal B (LB) subtype BC. Clinicopathological parameters, blood counts and the derived parameters, total tumor-infiltrating lymphocytes (TILs) and their subpopulation, as well as TP53 mutation status, were assessed as predictors of response. Results: Twenty-one patients were equally assigned to each group. The pathologic complete response (pCR) was 33% and 38% in the NACT and NACRT groups, respectively, with a dose-response effect. Only one LB tumor reached pCR after NACRT. Numerous parameters associated with response were identified, which differed according to the assigned treatment. In the NACRT group, baseline hemoglobin of ≥13 g/dL and body mass index of
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- 2023
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6. Abstract P1-08-24: Platelet-to-lymphocyte ratio is worth using with tumor-infiltrating lymphocytes to predict good response to neoadjuvant chemotherapy in triple negative breast cancer: A study on 120 patients
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Nina Radosevic-Robin, Sejdi Lusho, Xavier Durando, Marie-Ange Mouret-Reynier, Myriam Kossai, Nathalie Lacrampe, Ioana Molnar, Frederique Penault-Llorca, and Catherine Abrial
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Cancer Research ,Oncology - Abstract
Introduction: Triple negative breast cancer (TNBC) is highly heterogeneous, but still most of the patients are treated by the anthracycline/taxane-based neoadjuvant therapy (NACT). Tumor-infiltrating lymphocytes (TILs) are a strong predictive and prognostic biomarker in TNBC, however not always available due to organizational and analytical issues. Peripheral blood counts, which reflect the systemic inflammatory/immune status, are easier to obtain than TILs. We investigated whether baseline white cell or platelet counts, as well as Neutrophil-to-Lymphocyte Ratio (NLR) or Platelet-to-Lymphocyte Ratio (PLR) could replace baseline TILs as predictive or prognostic biomarkers in a series of TNBC treated by standard NACT. Patients and methods: One hundred twenty patients uniformly treated by FEC/taxane NACT in a tertiary cancer care center were retrospectively analyzed. The presence of pathological complete response (pCR: ypT0/Tis, ypN0) or the presence of pCR and small residual disease (ypT0/Tis/T1ab, ypN0) were considered as good responses in data analysis. Baseline/pre-NACT blood count, NLR, PLR and TILs were evaluated as predictors of response, distant recurrence rate and distant recurrence-free survival (DRFS). TILs were assessed on breast tumor biopsies according to the recommendations of the International Immuno-Oncology Biomarker Working Group (www.tilsinbreastcancer.org). Results: TILs ≥30% and ≥1.5% were best predictors of pCR and distant recurrence risk, respectively (p=0.007, p=0.012). However, in this cohort, pCR status was not significantly associated with recurrence. Only the ensemble of patients with pCR and small residual disease had lower recurrence risk and longer survival DRFS (p=0.042, p=0.024, respectively) than the rest of the cohort (larger residual disease). The only parameter which could predict the pCR/small residual disease status was PLR: patients with values lower than 133.25 had significantly higher chance of reaching that status after NACT (p=0.045). However, no direct correlation could be established between baseline PLR and metastatic recurrence. No correlation either was found between TIL and individual blood counts, or between TILs and NLR or PLR. Conclusion: In this cohort, TILs retained their pCR predictive value, however PLR was better predictor of the ensemble of responses which had good outcome in terms of less distant recurrences or longer DRFS (pCR or small residual disease). Thus, baseline PLR is worth further, prospective investigation together with baseline TILs, as it might indicate a good TNBC response to NACT when TILs are unavailable. Citation Format: Nina Radosevic-Robin, Sejdi Lusho, Xavier Durando, Marie-Ange Mouret-Reynier, Myriam Kossai, Nathalie Lacrampe, Ioana Molnar, Frederique Penault-Llorca, Catherine Abrial. Platelet-to-lymphocyte ratio is worth using with tumor-infiltrating lymphocytes to predict good response to neoadjuvant chemotherapy in triple negative breast cancer: A study on 120 patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-24.
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- 2022
7. Nestin as a Prognostic Biomarker in High-grade Epithelial Ovarian Cancer Treated by Neoadjuvant Chemotherapy
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HUGO VEYSSIÈRE, GHASSAN ALDARAZI, IOANA MOLNAR, XAVIER DURANDO, and NINA RADOSEVIC-ROBIN
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Ovarian Neoplasms ,Cancer Research ,General Medicine ,Carcinoma, Ovarian Epithelial ,Prognosis ,Neoadjuvant Therapy ,Nestin ,Oncology ,Humans ,Female ,Prospective Studies ,Biomarkers ,Neoplasm Staging ,Retrospective Studies - Abstract
High-grade epithelial ovarian cancer (HGEOC) is a heterogeneous disease and among the deadliest types of cancer. It often acquires resistance to conventional chemotherapy and its prognosis remains highly poor. The tissue protein nestin, implicated in the assembly and disassembly of intermediate filaments, has been reported to be an unfavourable prognostic factor in several cancer types. We hypothesized that HGEOC progression is regulated by the proliferation of chemoresistant cancer stem cells, in which nestin might be implicated. This preliminary study aimed to evaluate nestin as a prognostic biomarker in HGEOC treated by neoadjuvant chemotherapy (NACT) followed by cytoreductive surgery.A retrospective study (2009-2019) was conducted on 92 patients with primary ovarian, fallopian tube or peritoneal HGEOC who underwent NACT followed by cytoreductive surgery. Nestin expression in tissue samples was semi-quantitatively evaluated defining nestin positivity for those with histochemical score ≥30. We then evaluated the prognostic value of nestin expression.The median progression-free survival was similar between nestin-positive (22 months) and nestin-negative (19 months) groups (p=0.57). Interestingly, the median overall survival was shorter for the nestin-positive group (48 vs. 67 months, respectively), however the difference did not reach statistical significance (p=0.43).Tissue nestin expression does not appear to be a relevant prognostic biomarker in HGEOC treated by NACT. However, we believe that prospective studies in larger cohorts should be conducted and evaluation of nestin in pre-NACT HGEOC samples needs to be explored.
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- 2022
8. WISP2/CCN5 Suppresses Vasculogenic Mimicry through Inhibition of YAP/TAZ Signaling in Breast Cancer Cells
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Nathalie Ferrand, Aude Fert, Romain Morichon, Nina Radosevic-Robin, Maurice Zaoui, Michèle Sabbah, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Cytométrie et Imagerie Saint-Antoine (CISA), Unité Mixte de Service d'Imagerie et de Cytométrie [CHU Saint-Antoine] (UMS LUMIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER
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WISP2/CCN5 ,vasculogenic mimicry ,breast cancer ,CYR61 ,YAP-TAZ signaling ,Cancer Research ,Oncology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology - Abstract
International audience; Vasculogenic mimicry (VM) formed by aggressive tumor cells to create vascular networks connected with the endothelial cells, plays an important role in breast cancer progression. WISP2 has been considered as a tumor suppressor protein; however, the relationship between WISP2 and VM formation remains unclear. We used the in vitro tube formation assay and in vivo immunohistochemical analysis in a mouse model, and human breast tumors were used to evaluate the effect of WISP2 on VM formation. Here we report that WISP2 acts as a potent inhibitor of VM formation in breast cancer. Enforced expression of WISP2 decreased network formation while knockdown of WISP2 increased VM. Mechanistically, WISP2 increased retention of oncogenic activators YAP/TAZ in cytoplasm, leading to decreased expression of the angiogenic factor CYR61. Studies using an in vivo mouse model and human breast tumors confirmed the in vitro cell lines data. In conclusion, our results indicate that WISP2 may play a critical role in VM and highlight the critical role of WISP2 as a tumor suppressor.
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- 2022
9. Author response for 'The immune microenvironment in patients with mismatch‐repair‐proficient oligometastatic colorectal cancer exposed to chemotherapy: the randomized MIROX GERCOR cohort study'
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null Marine Jary, null Wen‐Wei Liu, null Dongyao Yan, null Isaac Bai, null Andrea Muranyi, null Elise Colle, null Isabelle Brocheriou, null Anthony Turpin, null Nina Radosevic‐Robin, null Pierre Bourgoin, null Frédérique Penault‐Llorca, null Romain Cohen, null Dewi Vernerey, null Thierry André, null Christophe Borg, null Kandavel Shanmugam, and null Magali Svrcek
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- 2021
10. STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway
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Julie Gaston, Marion Pouillard, Vincent Jung, Laura Cheradame, Ida Chiara Guerrera, Mauro Modesti, Alain Schmitt, Vincent Goffin, Nina Radosevic-Robin, Stefano Cairo, Jean-Gabriel Judde, Nicolas Goudin, Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, XenTech [Évry], XenTech [Evry], Istituto di Ricerca Pediatrica [Padova, Italy] (IRP), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), and Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS)
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Genome instability ,Cancer Research ,DNA damage ,[SDV]Life Sciences [q-bio] ,Apoptosis ,Breast Neoplasms ,Biology ,Genomic Instability ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Genetics ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Gene silencing ,Animals ,Humans ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Innate immune system ,Cancer ,Membrane Proteins ,medicine.disease ,Prognosis ,Nucleotidyltransferases ,Xenograft Model Antitumor Assays ,eye diseases ,3. Good health ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Sting ,030220 oncology & carcinogenesis ,Stimulator of interferon genes ,Cancer research ,Female ,Neoplasm Recurrence, Local ,DNA Damage - Abstract
STING (Stimulator of Interferon Genes) is an endoplasmic reticulum-anchored adaptor of the innate immunity best known to trigger pro-inflammatory cytokine expression in response to pathogen infection. In cancer, this canonical pathway can be activated by intrinsic or drug-induced genomic instability, potentiating antitumor immune responses. Here we report that STING downregulation decreases cell survival and increases sensitivity to genotoxic treatment in a panel of breast cancer cell lines in a cell-autonomous manner. STING silencing impaired DNA Damage Response (53BP1) foci formation and increased DNA break accumulation. These newly identified properties were found to be independent of STING partner cGAS and of its canonical pro-inflammatory pathway. STING was shown to partially localize at the inner nuclear membrane in a variety of breast cancer cell models and clinical tumor samples. Interactomics analysis of nuclear STING identified several proteins of the DNA Damage Response, including the three proteins of the DNA-PK complex, further supporting a role of STING in the regulation of genomic stability. In breast and ovarian cancer patients that received adjuvant chemotherapy, high STING expression is associated with increased risk of relapse. In summary, this study highlights an alternative, non-canonical tumor-promoting role of STING that opposes its well-documented function in tumor immunosurveillance.
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- 2021
11. Refining patient selection for breast cancer immunotherapy: beyond PD-L1
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Myriam Kossai, Nina Radosevic-Robin, Frédérique Penault-Llorca, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, and COLO, Mouniati
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PD-L1 ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Breast Neoplasms ,Review ,Disease ,B7-H1 Antigen ,immune checkpoint inhibitors ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Immune system ,Artificial Intelligence ,Internal medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,medicine ,Humans ,Immunologic Factors ,Microbiome ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Patient Selection ,biomarkers ,Cancer ,Immunotherapy ,medicine.disease ,3. Good health ,Clinical trial ,[SDV] Life Sciences [q-bio] ,030220 oncology & carcinogenesis ,biology.protein ,Female ,business - Abstract
Therapies that modulate immune response to cancer, such as immune checkpoint inhibitors, began an intense development a few years ago; however, in breast cancer (BC), the results have been relatively disappointing so far. Finding biomarkers for better selection of BC patients for various immunotherapies remains a significant unmet medical need. At present, only tumour tissue programmed death-ligand 1 (PD-L1) and mismatch repair deficiency status are approved as theranostic biomarkers for programmed cell death-1 (PD-1)/PD-L1 inhibitors in BC. However, due to the complexity of tumour microenvironment (TME) and cancer response to immunomodulators, none of them is a perfect selector. Therefore, an intense quest is ongoing for complementary tumour- or host-related predictive biomarkers in breast immuno-oncology. Among the upcoming biomarkers, quantity, immunophenotype and spatial distribution of tumour-infiltrating lymphocytes and other TME cells as well as immune gene signatures emerge as most promising and are being increasingly tested in clinical trials. Biomarkers or strategies allowing dynamic assessment of BC response to immunotherapy, such as circulating/exosomal PD-L1, quantity of white/immune blood cell subpopulations and molecular imaging are particularly suitable for immunotreatment monitoring. Finally, host-related factors, such as microbiome and lifestyle, should also be taken into account when planning integration of immunomodulating therapies into BC management. As none of the biomarkers taken separately is accurate enough, the solution could come from composite biomarkers, which would combine clinical, molecular and immunological features of the disease, possibly powered by artificial intelligence., Highlights • At present, immune checkpoint inhibitors (ICIs) are the only approved immunotherapy drugs in BC. • Tumour PD-L1 and microsatellite status are current companion biomarkers for ICIs in BC; however, these need improvement. • Evaluation of tumour immune contexture and the dynamics of circulating immune cell counts are promising novel approaches. • Development of noninvasive monitoring and composite biomarkers will facilitate cancer immunotherapy, including in BC.
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- 2021
12. Recurrence biomarkers of triple negative breast cancer treated with neoadjuvant chemotherapy and anti-EGFR antibodies
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Michael F. Berger, Nina Radosevic-Robin, Yingjie Zhu, Emiliano Cocco, Lorenzo Ferrando, Maud Privat, Maurizio Scaltriti, Catherine Abrial, Helen Won, Jorge S. Reis-Filho, Flora Ponelle-Chachuat, Jean-Marc Nabholtz, Frédérique Penault-Llorca, Pier Selenica, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Memorial Sloane Kettering Cancer Center [New York], King Saud University [Riyadh] (KSU), AstraZeneca US [Waltham, USA], AstraZeneca [Cambridge, UK], and COLO, Mouniati
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[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,CXCR4 ,Article ,MHC Class II Gene ,Prognostic markers ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,MHC class I ,Cancer genomics ,medicine ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging ,Transcriptomics ,RC254-282 ,Triple-negative breast cancer ,Cancer ,030304 developmental biology ,0303 health sciences ,Chemotherapy ,biology ,business.industry ,fungi ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,3. Good health ,body regions ,[SDV] Life Sciences [q-bio] ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Tumour immunology ,Biomarker (medicine) ,Antibody ,business - Abstract
To find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways. Their TIL number before NAT in RR was very low (SOX2 and CXCR4. Our results indicate that high expression of cell cycle genes, combined with cold immunological phenotype, may predict strong TNBC resistance to NAT and rapid progression after it. This biomarker combination is worth validation in larger studies.
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- 2021
13. Neoadjuvant radiotherapy in triple-negative breast cancer: 'the past should not steal the present or hide the future'
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Nhu Hanh To, Nina Radosevic-Robin, and Yazid Belkacemi
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Oncology ,Radiology, Nuclear Medicine and imaging - Published
- 2021
14. Radiation therapy for triple-negative breast cancer: emerging role of microRNAs as biomarkers and radiosensitivity modifiers. A systematic review
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Nhu Hanh, To, Hoang Quy, Nguyen, Allan, Thiolat, Bisheng, Liu, José, Cohen, Nina, Radosevic-Robin, and Yazid, Belkacemi
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Gene Expression Regulation, Neoplastic ,MicroRNAs ,Biomarkers, Tumor ,Humans ,Triple Negative Breast Neoplasms ,Circulating MicroRNA ,Radiation Tolerance ,Biomarkers - Abstract
Radiation therapy (RT) for triple-negative breast cancer (TNBC) treatment is currently delivered in the adjuvant setting and is under investigation as a booster of neoadjuvant treatments. However, TNBC radioresistance remains an obstacle, so new biomarkers are needed to select patients for any integration of RT in the TNBC therapy sequence. MicroRNAs (miRs) are important regulators of gene expression, involved in cancer response to ionizing radiation (IR) and assessable by tumor tissue or liquid biopsy. This systematic review aimed to evaluate the relationships between miRs and response to radiation in TNBC, as well as their potential predictive and prognostic values.A thorough review of studies related to miRs and RT in TNBC was performed on PubMed, EMBASE, and Web of Science. We searched for original English articles that involved dysregulation of miRs in response to IR on TNBC-related preclinical and clinical studies. After a rigorous selection, 44 studies were chosen for further analysis.Thirty-five miRs were identified to be TNBC related, out of which 21 were downregulated, 13 upregulated, and 2 had a double-side expression in this cancer. Expression modulation of many of these miRs is radiosensitizing, among which miR-7, -27a, -34a, -122, and let-7 are most studied, still only in experimental models. The miRs reported as most influencing/reflecting TNBC response to IR are miR-7, -27a, -155, -205, -211, and -221, whereas miR-21, -33a, -139-5p, and -210 are associated with TNBC patient outcome after RT.miRs are emerging biomarkers and radiosensitizers in TNBC, worth further investigation. Dynamic assessment of circulating miRs could improve monitoring and TNBC RT efficacy, which are of particular interest in the neoadjuvant and the high-risk patients' settings.
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- 2021
15. XENOBREAST Trial: A prospective study of xenografts establishment from surgical specimens of patients with triple negative or luminal b breast cancer [version 3; peer review: 2 approved]
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Hugo Veyssière, Judith Passildas, Angeline Ginzac, Sejdi Lusho, Yannick Bidet, Ioana Molnar, Maureen Bernadach, Mathias Cavaille, Nina Radosevic-Robin, and Xavier Durando
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Science ,Medicine - Abstract
Introduction: Patient-derived xenografts (PDX) can be used to explore tumour pathophysiology and could be useful to better understand therapeutic response in breast cancer. PDX from mammary tumours are usually made from metastatic tumours. Thus, PDX from primary mammary tumours or after neoadjuvant treatment are still rare. This study aims to assess the feasibility to establish xenografts from tumour samples of patients with triple negative or luminal B breast cancer in neoadjuvant, adjuvant or metastatic setting. Methods: XENOBREAST is a single-centre and prospective study. This feasibility pilot trial aims to produce xenografts from tumour samples of patients with triple negative or luminal B breast cancer. Patient enrolment is expected to take 3 years: 85 patients will be enrolled and followed for 28 months. Additional blood samples will be taken as part of the study. Surgical specimens from post-NAC surgery, primary surgery or surgical excision of the metastases will be collected to establish PDX. Histomolecular characteristics of the established PDX will be investigated and compared with the initial histomolecular profile of the collected tumours to ensure that they are well-established. Ethics and dissemination: XENOBREAST belongs to category 2 interventional research on the human person. This study has been approved by the Sud Méditerranée IV – Montpellier ethics committee. It is conducted notably in accordance with the Declaration of Helsinki and General Data Protection Regulation (GDPR). Study data and findings will be published in peer-reviewed medical journals. We also plan to present the study and all data at national congresses and conferences. Registration: ClinicalTrials.gov ID NCT04133077; registered on October 21, 2019.
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- 2021
16. Tumour-infiltrating lymphocytes in non-invasive breast cancer: A systematic review and meta-analysis
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Elisa Agostinetto, Evandro de Azambuja, Nina Radosevic-Robin, Maria Alice Franzoi, Roberto Salgado, Rafael Caparica, Marcello Ceppi, Karen Willard-Gallo, Sherene Loi, Frédérique Penault-Llorca, Marco Bruzzone, Université libre de Bruxelles (ULB), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), IRCCS Ospedale Policlinico San Martino [Genoa, Italy], Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Peter MacCallum Cancer Centre [Melbourne, Australie], and COLO, Mouniati
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Oncology ,medicine.medical_specialty ,Receptor, ErbB-2 ,[SDV]Life Sciences [q-bio] ,“Local recurrence” ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,“Tumour infiltrating lymphocytes” ,Medicine ,Humans ,030212 general & internal medicine ,Chirurgie ,RC254-282 ,ComputingMilieux_MISCELLANEOUS ,“Non-invasive breast cancer” ,business.industry ,Carcinoma in situ ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,General Medicine ,Odds ratio ,medicine.disease ,Prognosis ,Confidence interval ,3. Good health ,[SDV] Life Sciences [q-bio] ,030220 oncology & carcinogenesis ,Meta-analysis ,Biomarker (medicine) ,Surgery ,Female ,Original Article ,Neoplasm Recurrence, Local ,business - Abstract
Background: The role of tumour infiltrating lymphocytes (TILs) as a biomarker in non-invasive breast cancer is unclear. This meta-analysis assessed the prognostic impact of TIL levels in patients with non-invasive breast cancer. Methods: Systematic literature search was performed to identify studies assessing local recurrence in patients with non-invasive breast cancer according to TIL levels (high vs. low). Subgroup analyses per local recurrence (invasive and non-invasive) were performed. Secondary objectives were the association between TIL levels and non-invasive breast cancer subtypes, age, grade and necrosis. Odds ratios (ORs) and 95% confidence intervals (CI) were extracted from each study and a pooled analysis was conducted with random-effect model. Results: Seven studies (N = 3437) were included in the present meta-analysis. High-TILs were associated with a higher likelihood of local recurrence (invasive or non-invasive, N = 2941; OR 2.05; 95%CI, 1.03–4.08; p = 0.042), although with a lower likelihood of invasive local recurrence (N = 1722; OR 0.69; 95%CI, 0.49–0.99; p = 0.042). High-TIL levels were associated with triple-negative (OR 3.84; 95%CI, 2.23–6.61; p < 0.001) and HER2-positive (OR 6.27; 95%CI, 4.93–7.97; p < 0.001) subtypes, high grade (OR 5.15; 95%CI, 3.69–7.19; p < 0.001) and necrosis (OR 3.09; 95%CI, 2.33–4.10; p < 0.001). Conclusions: High-TIL levels were associated with more aggressive tumours, a higher likelihood of local recurrence (invasive or non-invasive) but a lower likelihood of invasive local recurrence in patients with non-invasive breast cancer., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2021
17. Anti-tumoral activity of the Pan-HER (Sym013) antibody mixture in gemcitabine-resistant pancreatic cancer models
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Emilia, Rabia, Véronique, Garambois, Julie, Hubert, Marine, Bruciamacchie, Nelly, Pirot, Hélène, Delpech, Morgane, Broyon, Charles, Theillet, Pierre-Emmanuel, Colombo, Nadia, Vie, Diego, Tosi, Celine, Gongora, Lakhdar, Khellaf, Marta, Jarlier, Nina, Radosevic-Robin, Thierry, Chardès, André, Pèlegrin, and Christel, Larbouret
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Antimetabolites, Antineoplastic ,Receptor, ErbB-3 ,Receptor, ErbB-2 ,EGFR ,pancreatic cancer ,gemcitabine ,Mice, Nude ,chemoresistance ,Deoxycytidine ,Xenograft Model Antitumor Assays ,Gemcitabine ,Antibodies ,Tumor Burden ,ErbB Receptors ,Pancreatic Neoplasms ,Pan-Her ,Drug Resistance, Neoplasm ,HER3 ,Cell Line, Tumor ,Report ,HER2 ,Animals ,Humans ,Female ,Cell Proliferation - Abstract
Chemoresistance, particularly to gemcitabine, is a major challenge in pancreatic cancer. The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptors 2 and 3 (HER2, HER3) are expressed in many tumors, and they are relevant therapeutic targets due to their synergistic interaction to promote tumor aggressiveness and therapeutic resistance. Cocktails of antibodies directed against different targets are a promising strategy to overcome these processes. Here, we found by immunohistochemistry that these three receptors were co-expressed in 11% of patients with pancreatic adenocarcinoma. We then developed gemcitabine-resistant pancreatic cancer cell models (SW-1990-GR and BxPC3-GR) and one patient-derived xenograft (PDX2846-GR) by successive exposure to increasing doses of gemcitabine. We showed that expression of EGFR, HER2 and HER3 was increased in these gemcitabine-resistant pancreatic cancer models, and that an antibody mixture against all three receptors inhibited tumor growth in mice and downregulated HER receptors. Finally, we demonstrated that the Pan-HER and gemcitabine combination has an additive effect in vitro and in mice xenografted with the gemcitabine-sensitive or resistant pancreatic models. The mixture of anti-EGFR, HER2 and HER3 antibodies is a good candidate therapeutic approach for gemcitabine-sensitive and -resistant pancreatic cancer.
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- 2021
18. Abstract P5-12-09: The ≥5% cut-off reveals tumor PD-L1 positivity as potential selection biomarker for patient enrollment into the trials evaluating anti-PD-1 or anti-PD-L1 agents in neoadjuvant treatment of triple negative breast cancer
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Nina Radosevic-Robin, Catherine Abrial, Wilfrid Finck, Camille Poirier, J Passildas, Frédérique Penault-Llorca, Fabrice Kwiatkowski, and Xavier Durando
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Cancer ,Pembrolizumab ,medicine.disease ,Breast cancer ,Atezolizumab ,Internal medicine ,PD-L1 ,medicine ,biology.protein ,Biomarker (medicine) ,Stage (cooking) ,business ,Triple-negative breast cancer - Abstract
Background: Durable responses of triple negative breast cancer (TNBC) to pembrolizumab (anti-PD-1) or atezolizumab (anti-PD-L1) have been reported in the metastatic setting. Moreover, it is currently being hypothesized that immune checkpoint inhibitors might be more effective in the neoadjuvant setting, due to better preserved anti-tumor immunity in early TN disease. However, biomarkers predictive of response to anti-PD-1 or anti-PD-L1 agents, as well as biomarker-based strategies for testing those drugs in the neoadjuvant setting are still lacking. We evaluated PD-L1 protein expression and the composition of tumor-infiltrating lymphocytes (TILs) in untreated TNBC, in order to get a better insight into the TNBC sub-population(s) which would be suitable for neoadjuvant anti-PD-1 or anti-PD-L1 therapy evaluation. Methods: TNBC patients consecutively treated at the Jean Perrin Comprehensive Cancer Centre (Clermont-Ferrand, France), from 01/01/2010 to 12/31/2014, were included. FFPE tumor tissues were assessed for PD-L1 expression by immunohistochemical (IHC) laboratory-developed test (clone 28-8, Abcam), in tumor cells (tPD-L1) and in TILs. Positivity cut-offs evaluated were ≥1%, ≥5% and ≥10%. The amount CD8+, CD4+, FoxP3+ or PD-1+ TILs was determined by counting those cells, detected by IHC methods, within 5 consecutive HPFs (x400), from tumor invasive front toward tumor center. Clinical disease stage was determined using the TNM system. Results: One hundred and two TNBCs were assessed. There were 28.4%, 23.5% or 16.7% tPD-L1-positive cases (cs), for cut-offs ≥1%, ≥5% or ≥10%, respectively. Similarly, 32.4%, 15.7% or 5.9% of cs were positive for PD-L1 in TILs, using the same cut-offs. With ≥5% as cut-off, positivity for tPD-L1 significantly correlated with the amount of CD8+ (p=0.023), FoxP3+ (p=0.0036) or PD-1+ TILs (p=0.043). The same cut-off, applied to TILs, revealed significant correlations between PD-L1 positivity and the amount of each CD8+, CD4+ or PD-1+ TILs (p=0.025, 0.039 and 0.0042, respectively). Interestingly, when the ≥5% cut-off was used, tumors of T2 size were most frequently tPD-L1+ (11/41 cs, 26.8%), compared with the T1 (3/35 cs, 8.6%) and T3+T4 (3/18 cases, 16.7%) (p=0.04). With regards to TILs, with the ≥5% cut-off, the PD-L1+ cases belonged exclusively to the T1+T2 group (15/76), whereas the T3+T4 group was PD-L1-negative (0/18 cs). Other two cut-offs revealed only occasional correlations. Conclusion: This single-center, real-world TNBC cohort contained a high number of smaller tumors (T1-T2). The IHC-based PD-L1 assessment, with ≥5% as the positivity cut-off, revealed that approximately 1/4 of TNBC could be candidates for neoadjuvant anti-PD-1/anti-PD-L1 approaches. Combined with the amount of CD8+ and PD-1+ TILs, tumor PD-L1 positivity might make an easy-to-use composite biomarker for the 1st-level patient selection for PD-1 or PD-L1 inhibitors in neoadjuvant TNBC treatment. The 2nd level could exploit, for example, the assessment of mutation burden in tumors with low tPD-L1 or amount of CD8+ or PD-1+ TILs. Such tumors might be more frequent among larger TNBC (T3-T4). Citation Format: Finck W, Passildas J, Poirier C, Kwiatkowski F, Abrial C, Durando X, Penault-Llorca F, Radosevic-Robin N. The ≥5% cut-off reveals tumor PD-L1 positivity as potential selection biomarker for patient enrollment into the trials evaluating anti-PD-1 or anti-PD-L1 agents in neoadjuvant treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-09.
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- 2019
19. Platelet-to-Lymphocyte Ratio Is Associated With Favorable Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer: A Study on 120 Patients
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Sejdi Lusho, Xavier Durando, Marie-Ange Mouret-Reynier, Myriam Kossai, Nathalie Lacrampe, Ioana Molnar, Frederique Penault-Llorca, Nina Radosevic-Robin, Catherine Abrial, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Division de Recherche Clinique, Délégation Recherche Clinique et Innovation, Centre de Lutte contre le Cancer, Centre Jean PERRIN, 58 rue Montalembert, 63011 Clermont-Ferrand Cedex1, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre d'investigation Clinique, UMR501, 63011 CLERMONT-FERRAND (CIC), Université Clermont Auvergne (UCA), Département d'oncologie médicale, Centre Jean PERRIN, 63011 Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département d'anatomopathologie, Centre Jean PERRIN, Clermont-Ferrand, France, and LUSHO, Sejdi
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Anthracycline ,medicine.medical_treatment ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease ,03 medical and health sciences ,pathologic complete response (pCR) ,0302 clinical medicine ,peripheral blood counts ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,triple negative breast cancer (TNBC) ,Internal medicine ,Medicine ,platelet-to-lymphocyte ratio (PLR) ,Neoadjuvant therapy ,Triple-negative breast cancer ,RC254-282 ,Original Research ,Chemotherapy ,tumor-infiltrating lymphocytes (TILs) ,Taxane ,business.industry ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,distant recurrence ,business ,neoadjuvant chemotherapy - Abstract
IntroductionTriple negative breast cancer (TNBC) is highly heterogeneous, but still most of the patients are treated by the anthracycline/taxane-based neoadjuvant therapy (NACT). Tumor-infiltrating lymphocytes (TILs) are a strong predictive and prognostic biomarker in TNBC, however are not always available. Peripheral blood counts, which reflect the systemic inflammatory/immune status, are easier to obtain than TILs. We investigated whether baseline white cell or platelet counts, as well as, Neutrophil-to-Lymphocyte Ratio (NLR) or Platelet-to-Lymphocyte Ratio (PLR) could replace baseline TILs as predictive or prognostic biomarkers in a series of TNBC treated by standard NACT.Patients and MethodsOne hundred twenty patients uniformly treated by FEC/taxane NACT in a tertiary cancer care center were retrospectively analyzed. The presence of pathological complete response (pCR: ypT0/Tis, ypN0) or the presence of pCR and/small residual disease (ypT0/Tis/T1ab, ypN0) were considered as good responses in data analysis. Baseline/pre-NACT blood count, NLR, PLR and TILs were evaluated as predictors of response, distant recurrence rate and distant recurrence-free survival (DRFS).ResultsTILs ≥30% and ≥1.5% were best predictors of pCR and distant recurrence risk, respectively (p = 0.007, p = 0.012). However, in this cohort, pCR status was not significantly associated with recurrence. Only the ensemble of patients with pCR and small residual disease had lower recurrence risk and longer survival DRFS (p = 0.042, p = 0.024, respectively) than the rest of the cohort (larger residual disease). The only parameter which could predict the pCR/small residual disease status was PLR: patients with values lower than 133.25 had significantly higher chance of reaching that status after NACT (p = 0.045). However, no direct correlation could be established between baseline PLR and metastatic recurrence. No correlation either was found between TIL and individual blood counts, or between TILs and NLR or PLR.ConclusionIn this cohort, TILs retained their pCR predictive value; however PLR was a better predictor of the ensemble of responses which had good outcome in terms of less distant recurrences or longer DRFS (pCR or small residual disease). Thus, baseline PLR is worth further, prospective investigation together with baseline TILs, as it might indicate a good TNBC response to NACT when TILs are unavailable.
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- 2021
20. Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy
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Virginia Bluthgen, Morgane Masson, Mathieu Rouanne, Julie Massé, Frank Aboubakar, Ithar Gataa, Myriam Kossai, Edouard Auclin, Laura Mezquita, Lizza E.L. Hendriks, David Planchard, Caroline Caramella, Pierre Alemany, Jean-Pierre Pignon, Anas Gazzah, Nina Radosevic-Robin, Sylvestre Le Moulec, Benjamin Besse, Julien Adam, Caroline Rossoni, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Pulmonologie, and MUMC+: MA Med Staf Spec Longziekten (9)
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Immune checkpoint inhibitor ,NSCLC ,Prognostic ,Tumor-infiltrating lymphocytes ,03 medical and health sciences ,Nonesmall cell lung cancer ,Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Lung cancer ,Immune Checkpoint Inhibitors ,Aged ,Retrospective Studies ,Chemotherapy ,Performance status ,business.industry ,Hazard ratio ,hemic and immune systems ,Retrospective cohort study ,TIL ,Middle Aged ,medicine.disease ,Progression-Free Survival ,030104 developmental biology ,Nivolumab ,030220 oncology & carcinogenesis ,Cohort ,Adenocarcinoma ,Female ,France ,Immunotherapy ,business ,Biomarkers - Abstract
Background: The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC.Methods: This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as >= 10% density. The primary end-point was overall survival (OS).Results: Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status
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- 2021
21. INSTIGO Trial: Evaluation of a Plasma Protein Profile as a Predictive Biomarker for Metastatic Relapse of Triple Negative Breast Cancer
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Hugo Veyssière, Sejdi Lusho, Ioana Molnar, Myriam Kossai, Maureen Bernadach, Catherine Abrial, Yannick Bidet, Nina Radosevic-Robin, Xavier Durando, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), and Veyssère, Hugo
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Study Protocol ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Biopsy ,medicine ,Prospective cohort study ,TILs ,predictive biomarker ,Triple-negative breast cancer ,RC254-282 ,RNA signature ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ctDNA ,medicine.disease ,Blood proteins ,3. Good health ,Radiation therapy ,030104 developmental biology ,metastatic relapse ,030220 oncology & carcinogenesis ,triple negative breast cancer ,Biomarker (medicine) ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,blood cells ,business ,plasma proteins - Abstract
BackgroundTriple negative breast cancer (TNBC) accounts for 10-20% of breast cancers but has no specific therapy. While TNBC may be more sensitive to chemotherapy than other types of breast cancer, it has a poor prognosis. Most TNBC relapses occur during the five years following treatment, however predictive biomarkers of metastatic relapse are still lacking. High tumour-infiltrating lymphocytes (TILs) levels before and after neo-adjuvant chemotherapy (NAC) are associated with lower relapse risk and longer survival but TILs assessment is highly error-prone and still not introduced into the clinic. Therefore, having reliable biomarker of relapse, but easier to assess, remains essential for TNBC management. Searching for such biomarkers among serum/plasma proteins, circulating tumoral DNA (ctDNA) and blood cells appear relevant.MethodsThis single-centre and prospective study aims to discover predictive biomarkers of TNBC relapse and particularly focuses on plasma proteins. Blood samples will be taken at diagnosis, on the day of first-line or post-NAC surgery, on the day of radiotherapy start, then 6 months and one year after radiotherapy. A blood sample will be taken at the time of metastatic relapse diagnosis. Blood samples will be used for circulating protein quantification, blood cell counts and circulating tumour DNA quantification. A tumour RNA signature, based on the analysis of the RNA expression of 6 genes, will also be tested from the initial biopsy taken routinely. In NAC patients, TILs quantity will be assessed on TNBC pre-treatment biopsy and surgical specimen.Ethics and DisseminationINSTIGO belongs to category 2 interventional research on humans. This study has been approved by the SUD-EST IV ethics committee and is conducted in accordance with the Declaration of Helsinki and General Data Protection Regulation (GDPR). Study findings will be published in peer-reviewed medical journals.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04438681.
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- 2021
22. Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox
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Nik Hauser, Meinrad Mannhart, Frédérique Penault-Llorca, Sibylle Loibl, Joerg Heil, Oreste Gentilini, Tibor Kovacs, Christoph Tausch, Michael Gnant, Andreas R. Günthert, Evandro de Azambuja, Katja Pinker, Giuseppe Curigliano, Icro Meattini, Nina Radosevic-Robin, Peter Dubsky, Petra Steyerova, Isabel T. Rubio, Maria João Cardoso, Walter P. Weber, Mona Knotek-Roggenbauerc, Philip Poortmans, Carsten Denkert, Henry Mark Kuerer, Michael Knauer, Marie Jeanne T.F.D. Vrancken Peeters, Mathilde Ritter, Tanja Spanic, Fatima Cardoso, Susan J. Knox, Patrizia Sager, Giacomo Montagna, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)
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medicine.medical_specialty ,Consensus ,Delphi Technique ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Clinical Decision-Making ,Delphi method ,MEDLINE ,Antineoplastic Agents ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mastectomy, Segmental ,Medical Oncology ,Systemic therapy ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine ,Humans ,030212 general & internal medicine ,Stage (cooking) ,Intensive care medicine ,Neoadjuvant therapy ,Neoplasm Staging ,business.industry ,medicine.disease ,Neoadjuvant Therapy ,3. Good health ,Clinical trial ,Treatment Outcome ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,Human medicine ,business ,Mastectomy - Abstract
International audience; Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.
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- 2021
23. STING Promotes Breast Cancer Cell Survival by an Inflammatory-Independent Nuclear Pathway Enhancing the DNA Damage Response
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Laura Cheradame, Stefano Cairo, Vincent Jung, Alain Schmitt, Jean-Gabriel Judde, Julie Gaston, Vincent Goffin, Mauro Modesti, Ida Chiara Guerrera, Nina Radosevic-Robin, and Marion Pouillard
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Sting ,Immune system ,Innate immune system ,DNA damage ,DNA repair ,Stimulator of interferon genes ,Cancer cell ,Cancer research ,Gene silencing ,Biology ,eye diseases - Abstract
STING (Stimulator of Interferon Genes) is a well-known endoplasmic reticulum-anchored adaptor of the innate immunity that triggers the expression of inflammatory cytokines in response to pathogen infection. In cancer cells, this pro-inflammatory pathway can be activated by genomic DNA damage potentiating antitumor immune responses. Here we report that STING promotes cancer cell survival and resistance to genotoxic treatment in a cell-autonomous manner. Mechanistically, we show that STING partly localizes at the inner nuclear membrane in various breast cancer cell lines and clinical tumor samples, and interacts with several proteins of the DNA damage response (DDR). STING overexpression enhances the amount of chromatin-bound DNA-dependent Protein Kinase (DNA-PK) complex, while STING silencing impairs DDR foci formation and DNA repair efficacy. Importantly, this function of STING is independent of its canonical pro-inflammatory pathway. This study highlights a previously unappreciated cell-autonomous tumor-promoting mechanism of STING that opposes its well-documented role in tumor immunosurveillance.Graphical abstract
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- 2020
24. PERCEPTION Trial protocol: Comparison of predictive and prognostic capacities of neutrophil, lymphocyte, and platelet counts and tumor-infiltrating lymphocytes in triple negative breast cancer
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Hugo Veyssière, Mathilde Gay-Bellile, Yannick Bidet, Catherine Abrial, Nathalie Lacrampe, Nina Radosevic-Robin, Myriam Kossai, Sejdi Lusho, Maureen Bernadach, Mathias Cavaillé, Ioana Molnar, Xavier Durando, LUSHO, Sejdi, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Division de Recherche Clinique, Délégation Recherche Clinique et Innovation, Centre de Lutte contre le Cancer, Centre Jean PERRIN, 58 rue Montalembert, 63011 Clermont-Ferrand Cedex1, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre d'investigation Clinique, UMR501, 63011 CLERMONT-FERRAND (CIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département d'oncologie médicale, Centre Jean PERRIN, 63011 Clermont-Ferrand, Centre Jean Perrin, Département d'anatomie et de cytologie pathologiques., and Centre Jean Perrin, Département d'oncogénétique
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Adult ,Blood Platelets ,Oncology ,medicine.medical_specialty ,Adolescent ,Neutrophils ,Lymphocyte ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease ,Young Adult ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Breast cancer ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Predictive Value of Tests ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Cytotoxic T cell ,Lymphocyte Count ,Lymphocytes ,030212 general & internal medicine ,Triple-negative breast cancer ,ComputingMilieux_MISCELLANEOUS ,Platelet Count ,Tumor-infiltrating lymphocytes ,business.industry ,Cancer ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,3. Good health ,Clinical trial ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Background Triple negative breast cancer affects 10% to 20% of all women diagnosed with breast cancer. Due to its characteristics, treatment strategies are limited and metastatic recurrences are common in the first 5 years after treatment. However, not all patients affected by this disease develop metastases. Tumor-infiltrating lymphocytes have shown to be reliable predictive biomarkers of treatment response and metastatic recurrences. However, we need to develop simpler and faster ways to predict response to cytotoxic treatment and the possibility of eventual cancer relapse by identifying new biomarkers. Recently, new studies are emerging, suggesting a predictive role of circulating blood cells in different types of cancer. In this study, we will assess the correlation between tumor-infiltrating lymphocytes and different elements of the blood count in patients diagnosed with triple negative breast cancer. Methods The main objective of this study is to evaluate the correlation between the peripheral neutrophil-to-lymphocyte ratio and the amount of tumor-infiltrating lymphocytes, assessed in triple negative breast cancer patients at diagnosis. Secondary objectives include evaluation of the correlation between tumor-infiltrating lymphocytes at diagnosis and the baseline absolute neutrophil, lymphocyte, and platelet counts, as well as the platelet-to-lymphocyte ratio. The triple negative breast cancer patients will be enrolled in the PERCEPTION trial during the first year after the treatment completion. Two supplementary blood tests, at 12 months after the end of treatment and at the time of the first metastatic recurrence, will be performed. Discussion The discovery of new prognostic and predictive biomarkers is crucial for triple negative breast cancer. We set up the PERCEPTION clinical trial in order to evaluate certain blood counts as early biomarkers and to assess their correlation with tumor-infiltrating lymphocytes. Demonstration of comparative predictive and/or prognostic capacities of peripheral blood counts and tumor-infiltrating lymphocytes would allow introduction of the former as simple and cheap biomarkers in triple negative breast cancer patient management. Trial registration The PERCEPTION study has been registered in the French National Agency of Medical Security registry on the 2nd of July 2019 under the number 2019-A01861-56 and in the ClinicalTrials.org registry under the number NCT04068623.
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- 2020
25. [18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer
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Sébastien Schmitt, E. Jouberton, Marie Roy, Yann Bouvet, Aurélie Maisonial-Besset, Jean-Michel Chezal, Nina Radosevic-Robin, Elisabeth Miot-Noirault, Florent Cachin, Emmanuel Chautard, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Zionexa [Aubière], and COLO, Mouniati
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lcsh:Medical physics. Medical radiology. Nuclear medicine ,medicine.medical_treatment ,lcsh:R895-920 ,PET imaging ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,chemotherapy ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Phospholipid scrambling ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,In vivo ,Medicine ,Radiology, Nuclear Medicine and imaging ,Triple-negative breast cancer ,Original Research ,Chemotherapy ,Tumor hypoxia ,business.industry ,[18F]ML-10 ,apoptosis ,triple negative breast cancer ,3. Good health ,in vivo ,Paclitaxel ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,business ,FMISO - Abstract
Purpose Pathological complete response to the neoadjuvant therapy (NAT) for triple negative breast cancer (TNBC) is predictive of prolonged patient survival. Methods for early evaluation of NAT efficiency are still needed, in order to rapidly adjust the therapeutic strategy in case of initial non-response. One option for this is molecular imaging of apoptosis induced by chemotherapy. Therefore, we investigated the capacity of [18F]ML-10 PET imaging, an apoptosis radiotracer, to detect tumor cell apoptosis and early predict the therapeutic response of human TNBC. Results Initially, the induction of apoptosis by different therapies was quantified. We confirmed, in vitro, that paclitaxel or epirubicin, the fundamental cytotoxic drugs for breast cancer, induce apoptosis in TNBC cell lines. Exposure of TNBC models MDA-MB-231 and MDA-MB-468 to these drugs induced a significant increase (p < 0.01) of the apoptotic hallmarks: DNA fragmentation, membrane phospholipid scrambling, and PARP activation. Secondarily, apoptotic fraction was compared to the intracellular accumulation of the radiotracer. [18F]ML-10 accumulated in the apoptotic cells after 72 h of treatment by paclitaxel in vitro; this accumulation positively correlated with the apoptotic fraction. In vivo, [18F]ML-10 was rapidly cleared from the nontarget organs and mainly eliminated by the kidneys. Comparison of the in vivo [18F]FDG, [18F]FMISO, and [18F]ML-10 uptakes revealed that the tumor accumulation of [18F]ML-10 was directly related to the tumor hypoxia level. Finally, after the in vivo treatment of TNBC murine xenografts by paclitaxel, apoptosis was well induced, as demonstrated by the cleaved caspase-3 levels; however, no significant increase of [18F]ML-10 accumulation in the tumors was observed, either on day 3 or day 6 after the end of the treatment. Conclusions These results highlighted that PET imaging using [18F]ML-10 allows the visualization of apoptotic cells in TNBC models. Nevertheless, the increase of the chemotherapy-induced apoptotic response when using paclitaxel could not be assessed using this radiotracer in our mouse model.
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- 2020
26. XENOBREAST Trial: A prospective study of xenografts establishment from surgical specimens of patients with triple negative or luminal b breast cancer
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Hugo Veyssière, Sejdi Lusho, Judith Passildas, Mathias Cavaillé, Angeline Ginzac, Nina Radosevic-Robin, Ioana Molnar, Xavier Durando, Yannick Bidet, Maureen Bernadach, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, and COLO, Mouniati
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Oncology ,0301 basic medicine ,medicine.medical_specialty ,Luminal B breast cancer ,viruses ,[SDV]Life Sciences [q-bio] ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,General Biochemistry, Genetics and Molecular Biology ,Metastatic tumours ,Study Protocol ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Neoadjuvant treatment ,Internal medicine ,Humans ,Medicine ,Triple negative breast cancer ,Prospective Studies ,General Pharmacology, Toxicology and Pharmaceutics ,Prospective cohort study ,Triple negative ,Triple-negative breast cancer ,ComputingMilieux_MISCELLANEOUS ,Luminal B Breast Cancer ,General Immunology and Microbiology ,Patient-Derived Xenografts ,business.industry ,Ethics committee ,virus diseases ,Articles ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Neoadjuvant Therapy ,digestive system diseases ,3. Good health ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,030220 oncology & carcinogenesis ,Interventional research ,Heterografts ,Female ,business ,030217 neurology & neurosurgery - Abstract
Introduction: Patient-derived xenografts (PDX) can be used to explore tumour pathophysiology and could be useful to better understand therapeutic response in breast cancer. PDX from mammary tumours are usually made from metastatic tumours. Thus, PDX from primitive mammary tumours or after neoadjuvant treatment are still rare. This study aims to assess the feasibility to establish xenografts from tumour samples of patients with triple negative or luminal B breast cancer in neoadjuvant, adjuvant or metastatic setting. Methods: XENOBREAST is a single-centre and prospective study. This feasibility pilot trial aims to produce xenografts from tumour samples of patients with triple negative or luminal B breast cancer. Patient enrolment is expected to take 3 years: 85 patients will be enrolled and followed for 28 months. Additional blood samples will be taken as part of the study. Surgical specimens from post-NAC surgery, primary surgery or surgical excision of the metastases will be collected to establish PDX. Histomolecular characteristics of the established PDX will be investigated and compared with the initial histomolecular profile of the collected tumours to ensure that they are well-established. Ethics and dissemination: XENOBREAST belongs to category 2 interventional research on the human person. This study has been approved by the Sud Méditerranée IV – Montpellier ethics committee. It is conducted notably in accordance with the Declaration of Helsinki and General Data Protection Regulation (GDPR). Study data and findings will be published in peer-reviewed medical journals. We also plan to present the study and all data at national congresses and conferences. Registration: ClinicalTrials.gov ID NCT04133077; registered on October 21, 2019.
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- 2020
27. EP1225 How the conformity of surgical practice with the national guidelines improved the quality of management of ovarian granulosa cell tumors (GCT)? A TMRG and GINECO group study
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J-M Classe, Fabrice Lecuru, C. Pomel, Elsa Kalbacher, Nina Radosevic-Robin, Sebastien Gouy, Nicolas Chopin, M Angeles-Fite, T. de La Motte Rouge, Dominique Berton-Rigaud, H Bonsang Kitzis, C. Lefeuvre-Plesse, Patricia Pautier, F Guyon, Magali Provansal, Anne Floquet, C. Lenck, R. Ramanah, Eric Leblanc, Frédéric Selle, E Lambaudies, Isabelle Treilleux, S. Martin, Frédéric Beurrier, P Meus, I.L. Ray-Coquard, A. Lesoin, Florence Joly, and C Martinez Gomez
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medicine.medical_specialty ,Hysterectomy ,Ovarian Granulosa Cell ,business.industry ,medicine.medical_treatment ,Gold standard ,Retrospective cohort study ,Endometrium ,Curettage ,Surgery ,Omentectomy ,medicine.anatomical_structure ,medicine ,Radical surgery ,business - Abstract
Introduction/Background Surgery is the cornerstone of ovarian Granulosa Cell Tumor (GCT). Complete resection with adequate staging is the gold standard in 1st line setting. The aim of this study is to assess the impact of an appropriate surgery according to the guidelines. Methodology This is a nationwide five-year retrospective study, including 463 patients (of the 639 included patients) with a definitive diagnosis of GCT between 2011 and 2016. Medical and surgical practices were analyzed for conformity. Conformity to guidelines was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysteretomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsy and peritoneal cytology) according to the FIGO classification. Results Median age at diagnosis was 49 years old (range 10–89). The median size of tumor was 94 mm (range 5–400). Radical surgery was performed in 240 patients (51,8%), while a fertility-sparing surgery was performed in 98 cases (21,2%). A complete surgical staging was performed in only 76 cases (16,4%). 289 (62.4%) patients received an evaluation of the endometrium (hysterectomy or endometrial curettage). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (29,6%) and not assessable in 48 cases (10,4%) respectively. A statistically significant improvement in the surgical management was observed among patients treated after 2012 compared to those treated before 2012. This Improvement included: endometrial evaluation (p=0,026), tumour rupture rate during surgery (p=0,010) and the global compliance of the surgery (p Conclusion Staging surgery provides a better assessment and an appropriate treatment of this rare tumors. According to this study, the implementation of a national network and guidelines dedicated to rare gynaecologic tumors seems to significantly improve the surgical management of the patients with GCT. Disclosure Nothing to disclose.
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- 2019
28. Abstract P2-09-29: Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes
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Maurizio Scaltriti, Emiliano Cocco, Frédérique Penault-Llorca, Maud Privat, Catherine Abrial, and Nina Radosevic-Robin
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,Cetuximab ,Tumor-infiltrating lymphocytes ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Breast cancer ,Internal medicine ,medicine ,biology.protein ,Panitumumab ,PTEN ,business ,Neoadjuvant therapy ,Triple-negative breast cancer ,medicine.drug - Abstract
Background: Epidermal growth factor receptor (EGFR) is expressed in ˜50% of triple negative breast cancer (TNBC) and has been proposed as a therapeutic target in this disease. However, trials testing EGFR blockade in TNBC failed to show significant clinical benefit. Probable reasons for such results were patient selection based on EGFR expression and the enrollment of heavily pretreated metastatic patients. Our team has conducted two neoadjuvant trials testing the activity of the anti-EGFR antibodies panitumumab (PTB) and cetuximab (CTX) combined with chemotherapy in locally advanced TNBC. Biomarkers predictive of pathological complete response (pCR) were the level of tumor cell EGFR protein expression and tumor-infiltrating lymphocytes' (TILs) profile (PMIDs 24827135, 26649807). The PTB-treated pts had a higher pCR rate (47%) than the CTX-treated pts (24%), but also a twice higher relapse rate, after 5 years of follow-up. Here we report results of genomic and TILs studies, performed in order to reveal possible determinants of recurrences in those trials. Methods: Tumor tissues sampled before and after neoadjuvant therapy (NAT) have been analyzed by next generation sequencing (NGS) using a targeted exome panel (MSK-IMPACT) of 410 cancer-related genes. Gene expression was evaluated by Affymetrix arrays. TIL density was assessed on pre-NAT samples according to Salgado et al, 2014 (PMID 25214542). The correlation between response, recurrences, genomic and TIL findings was analyzed in a case-by-case fashion. Results: Sixteen tumors that achieved pCR (PTB: 11, CTX: 5) and 23 non-pCR tumors (PTB: 11, CTX: 12) have been analyzed. For 14 non-pCR tumors (PTB: 6, CTX: 8) data have been obtained both from the pre-NAT and the post-NAT sample. Among those tumors, 6 recurred within 2 years after surgery (PTMB: 3, CTX: 3) and assays are on-going on several others that relapsed. Several genomic aberrations that potentially played a causative role in opposing to therapy were identified. We observed multiple mutations in the PI3K pathway in several non-pCR or relapsing pts. Interestingly, in a residual tumor (RT) of a non-pCR patient we found 3 different activating mutations in PIK3CA and one in PTEN. Another example of genomic selection induced by pharmacological pressure is the emergence of a HRAS G12S mutation in a RT after CTX. Additional novel findings include in-frame mutations and deletions in ARID1B and PARP1 amplification in non-pCR pts. Most of the tumors which recurred had ≤10% TILs (9/13) and only 4/13 had ≥30%. Among the tumors with a post-NAT RT but without recurrence, 17/33 had ≤10% TILs and 16/33 ≥30%. No particular link between TIL density and mutation pattern was observed. Conclusions: This is an example of a case-by-case approach where we captured the intrinsic inter-tumor heterogeneity, which is likely responsible for the different responses to EGFR-targeting in TNBC. Genes/pathways candidate of resistance to therapy are currently being validated. Citation Format: Radosevic-Robin N, Cocco E, Privat M, Abrial C, Penault-Llorca F, Scaltriti M. Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-29.
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- 2018
29. Abstract P4-15-03: Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS)
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L Tixier-Deves, Anne Cayre, M.M. Dauplat, Nina Radosevic-Robin, Catherine Abrial, B Bayol, Fabrice Kwiatkowski, Frédérique Penault-Llorca, and D. Azria
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Oncology ,In situ ,Cancer Research ,medicine.medical_specialty ,Tumor-infiltrating lymphocytes ,business.industry ,Luma ,Cancer ,Histology ,medicine.disease ,Breast cancer ,Internal medicine ,Cohort ,medicine ,Biomarker (medicine) ,skin and connective tissue diseases ,business - Abstract
Background: Numerous studies have shown important impact of tumor-infiltrating lymphocytes (TILs) on natural or therapeutically-modified evolution of invasive breast cancer (IBC), however knowledge about TIL role in breast ductal carcinoma in situ (DCIS) is still limited. Because of the lack of reliable prognostic parameters, DCIS treatment is much less personalized than IBC therapy. BONBIS is a phase 3 French multicenter randomized trial designed to compare 2 schemes of adjuvant radiotherapy (adjRT) for DCIS (Azria et al, ASCO meeting 2011, TPS 131). It is accompanied by a translational study of DCIS pathobiology, aimed to discover predictive or prognostic biomarkers. Here we present results of TIL density (TIL-d) assessment, its correlation with pathobiology of the lesions and preliminary clues for further biomarker search in this DCIS cohort. Methods: Formalin-fixed, paraffin-embedded DCIS surgical specimens, obtained before adjRT, were prospectively collected and centrally reviewed for histology (architectural pattern, nuclear grade, proliferation, presence of necrosis), receptor status (ER, PR, HER2) and TIL-d. TIL-d was assessed on H&E-stained DCIS sections and reported as percentage of the DCIS specialized stroma area occupied by lymphocytes, lympho-plasmocytes and plasmocytes. Tumors were classified using the St Gallen 2011 criteria for IBC (PMID 21709140). For purpose of this study, the HER2+ category included all cases with HER2 protein expression scored 2+ and 3+, irrespective of the ERBB2 amplification status. Results: TIL-d was assessed in 495 cases, with distribution as follows: 0-4% TILs (D1): 85.5% (n=423); 5-9% TILs (D2): 9.3% (n=46); ≥10% TILs (D3): 5.2% (n=26). Molecular subclasses of those cases were: luminal A (LumA): 39% (n=192); luminal B (LumB): 25.5% (n=126), HER2+: 28.5% (n=141) and triple-negative (TN): 7% (n=33). TIL-d significantly correlated with molecular subclass: ≥5% TILs (D2) were found in 39.4% (13/33) TN, 22.7% (32/141) HER2+, 18.2% (23/126) LumB and only in 1% (2/192) LumA cases (p Citation Format: Bayol B, Tixier-Deves L, Dauplat M, Kwiatkowski F, Cayre A, Abrial C, Azria D, Penault-Llorca F, Radosevic-Robin N. Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-03.
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- 2018
30. 444P Prevalence of NTRK1/2/3 fusions in dMMR/MSI metastatic colorectal cancer
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Anne Cayre, Frédérique Penault-Llorca, Magali Svrcek, Léo Mas, Raphael Colle, Nina Radosevic-Robin, T. Andre, Pierre Bourgoin, and Régis Cohen
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Oncology ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Internal medicine ,Medicine ,Hematology ,business ,medicine.disease - Published
- 2021
31. Abstract 2038: A non-canonical, cell-autonomous STING function protects breast cancer cells from intrinsic and genotoxic-induced DNA instability
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Marion Pouillard, Ida Chiara Guerrera, Laura Cheradame, Vincent Jung, Nina Radosevic-Robin, Vincent Goffin, Jean-Gabriel Judde, Mauro Modesti, Julie Gaston, Stefano Cairo, and Alain Schmitt
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Cancer Research ,business.industry ,medicine.medical_treatment ,Cell ,Cancer ,medicine.disease ,medicine.disease_cause ,eye diseases ,Sting ,Immune system ,medicine.anatomical_structure ,Oncology ,Cancer immunotherapy ,Cancer cell ,Cancer research ,medicine ,Ovarian cancer ,business ,Carcinogenesis - Abstract
Several studies have recently indicated the activation of the immune system against tumor cells as well as the targeting of cancer cell DNA damage repair mechanisms as effective strategies to target tumor growth. STING is a well-known DNA sensor of innate immunity mostly characterized as a transmembrane protein of various cytoplasmic organelles that senses cytosolic DNA as a danger signal and triggers inflammatory responses. A current cancer immunotherapy strategy relies on the use of STING agonists to boost the patient's immune system through a cytokine-mediated recruitment of immune cells that infiltrate and kill tumor cells. However, the role of the STING pathway in cancer is far to be fully understood as there is otherwise accumulating evidence that activation of the cGAS-STING pathway can have a deleterious outcome. We recently showed that genotoxic treatment of breast cancer PDXs and cell lines triggered the STING pathway. Genetic inhibition of this pathway in MCF7 cells increased genotoxic treatment efficacy by promoting cell death and delaying cell colony regrowth, indicating that STING pathway intrinsically promotes cell resistance to treatment. In this study, we show that STING silencing decreased cell viability in a panel of classical or PDX-derived breast cancer cell lines irrespective of their ER status and of the genotoxic treatment received. Cell fractionation indicates that part of the STING pool intrinsically resides in the nucleus of various malignant and non-malignant cells. Fluorescence and electron microscopy show that STING partly resides at the inner membrane of the nucleus, and mass-spectrometry analysis revealed that STING interacts with core proteins of the non-homologous end joining (NHEJ) DNA damage repair (DDR) complex. STING promotes NEHJ-related protein assembly with chromatin, and its silencing decreases DDR and cell viability, while STING overexpression protects cancer cells from genotoxic treatment. STING involvement in DDR is independent of the classical STING-TBK1-IFN inflammatory response, thus identifying a new functional pathway for STING. STING nuclear localization was confirmed in a panel of breast cancer patient-derived xenografts and in surgical samples from breast cancer patients that received neoadjuvant chemotherapy. Evaluation of the impact of STING expression on patient outcome via the Kaplan Meier plotter show that overall STING expression level is positively correlated with favorable outcome in breast cancer patients, however high STING expression in breast and ovarian cancer patients treated with adjuvant chemotherapy is associated with poor prognosis. These findings place STING at the crossroad of DDR and immune surveillance, two major pathways for tumorigenesis and tumor survival. Citation Format: Laura Cheradame, Ida Chiara Guerrera, Julie Gaston, Alain Schmitt, Vincent Jung, Marion Pouillard, Nina Radosevic-Robin, Mauro Modesti, Jean-Gabriel Judde, Vincent Goffin, Stefano Cairo. A non-canonical, cell-autonomous STING function protects breast cancer cells from intrinsic and genotoxic-induced DNA instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2038.
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- 2021
32. Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC)
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Frédérique Penault-Llorca, Romain Cohen, Anne Cayre, Thierry André, Raphael Colle, Pierre Bourgoin, Nina Radosevic-Robin, and Magali Svrcek
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Cancer Research ,biology ,Colorectal cancer ,Kinase ,business.industry ,Cell ,medicine.disease ,Tropomyosin ,digestive system diseases ,medicine.anatomical_structure ,Oncology ,Trk receptor ,medicine ,Cancer research ,biology.protein ,DNA mismatch repair ,Receptor ,business ,neoplasms ,Neurotrophin - Abstract
e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.
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- 2021
33. Ki67 assessment in breast cancer: an update
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Nina Radosevic-Robin, Frédérique Penault-Llorca, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), and Université d'Auvergne - Clermont-Ferrand I (UdA)
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Pathology and Forensic Medicine ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Neoadjuvant treatment ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,guidelines ,Ki67 antigen ,skin and connective tissue diseases ,Gynecology ,business.industry ,Cancer ,prediction ,medicine.disease ,Neoadjuvant Therapy ,3. Good health ,Ki-67 Antigen ,030104 developmental biology ,030220 oncology & carcinogenesis ,recommendations ,immunohistochemistry ,Ki67 index ,prognosis ,business ,Ki67 - Abstract
International audience; Although immunohistochemical detection of the Ki67 antigen has been used for many years to assess cancer proliferation, this marker is still not recommended for routine use in clinical management of breast cancer. The major reason for this situation is a lack of a standardised procedure for Ki67 assessment as well as persistence of several issues of debate with regards to the Ki67 assay interpretation and the marker's clinical utility. Nowadays Ki67 assessment is principally used for estimation of prognosis and guiding the decision on adjuvant treatment choice, as well as for prediction of response to neoadjuvant treatment in ER+/HER2- breast cancer. In ER-/HER2+ and ER-/HER2- tumours, high post-neoadjuvant Ki67 index is associated with unfavourable prognosis. We review here the elements impacting analytical validity of the Ki67 immunohistochemical assay, the evidence of its clinical utility and the current recommendations for its use in breast cancer management.
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- 2017
34. Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group
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Shahinaz Bedri, Karen Willard-Gallo, Sunil R. Lakhani, Stefan Michiels, Jan Budczies, Nina Radosevic-Robin, Zuzana Kos, Michael Untch, S Rim Kim, Giuseppe Viale, Barbara Ingold Heppner, Bruno Valentin Sinn, Stephen B. Fox, Roberto Salgado, Nicolas Sirtaine, Peter Sinn, Toralf Reimer, Sandra Demaria, Stephan Wienert, Anita Bane, Sandra A O'Toole, David L. Rimm, Zsuzsanna Bago-Horvath, Carsten Denkert, Matthias Christgen, Ewa Chmielik, Dongxia Gao, Frédérique Penault-Llorca, Giuseppe Floris, Sibylle Loibl, Sherene Loi, Gunter von Minckwitz, Audrey Poterie, Stuart J. Schnitt, Hans Kreipe, Koen Van de Vijver, Sunil V. Badve, Roland de Wind, Jane E. Brock, Cecile Colpaert, Gert Van den Eynden, Peter A. Fasching, Giancarlo Pruneri, and Frederick Klauschen
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0301 basic medicine ,Oncology ,Pathology ,medicine.medical_specialty ,Intraclass correlation ,Concordance ,Breast Neoplasms ,Pathology and Forensic Medicine ,Surgical pathology ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Image Interpretation, Computer-Assisted ,medicine ,Humans ,Pathology, Clinical ,Clinical pathology ,business.industry ,medicine.disease ,Confidence interval ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,business - Abstract
Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for
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- 2016
35. MA25.03 Tumor-Infiltrating Lymphocytes (TIL) and Outcomes with Immunotherapy (ICI) or Chemotherapy in Advanced NSCLC (aNSCLC) Patients
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I. Gataa, F. Aboubakar, Myriam Kossai, Caroline Caramella, J. Massé, M. Masson, M.V. Bluthgen, Benjamin Besse, J.P. Pignon, Julien Adam, David Planchard, Mathieu Rouanne, Laura Mezquita, C. Rossoni, Lizza E.L. Hendriks, Edouard Auclin, Nina Radosevic-Robin, A. Gazzah, and S. Le Moulec
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Pulmonary and Respiratory Medicine ,Chemotherapy ,Oncology ,business.industry ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,medicine ,Cancer research ,Immunotherapy ,business - Published
- 2019
36. The French national network dedicated to rare gynecological cancers diagnosis and management could improve the quality of surgery in daily practice of granulosa cell tumors. A TMRG and GINECO group Study
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Patricia Pautier, Carlos Martínez-Gómez, Florence Joly, I.L. Ray-Coquard, H Bonsang-Kitzis, Nina Radosevic-Robin, Fabrice Lecuru, Christophe Pomel, Magali Provansal, Frédéric Beurrier, Eric Lambaudie, F Guyon, Elsa Kalbacher, P Méeus, C. Chakiba, Anne Floquet, T. de la Motte Rouge, Frédéric Selle, C. Lefeuvre-Plesse, A. Lesoin, Martina Aida Angeles, C. Lenck, R. Ramanah, Isabelle Treilleux, Sebastien Gouy, Dominique Berton, S. Martin, J-M Classe, Eric Leblanc, Nicolas Chopin, Centre Léon Bérard [Lyon], ASSOCIATION POUR LA MISE EN VALEUR DES ETANGS DU PERIGORD, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Residual Tumor & Response to Treatment Laboratory (RT2Lab) - Translational Research Department, Institut Curie, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Department of Surgical Oncology Centre Oscar Lambret, U155, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Surgical Oncology Centre Jean Perrin, U773, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-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)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Bergonié [Bordeaux], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Gynecologic and Oncologic Surgery Hopital Européen Georges Pompidou, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Collège de France (CdF (institution))-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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0301 basic medicine ,Adult ,medicine.medical_specialty ,Adolescent ,National network ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Gynecologic Surgical Procedures ,Rare Diseases ,Recurrence ,Sex cord stromal tumor ,Medicine ,Humans ,Stage (cooking) ,Radical surgery ,Child ,Pathological ,Aged ,Granulosa Cell Tumor ,Neoplasm Staging ,Retrospective Studies ,Aged, 80 and over ,Ovarian Neoplasms ,Hysterectomy ,business.industry ,Medical record ,Obstetrics and Gynecology ,Rare cancer ,Middle Aged ,Granulosa cell tumors ,3. Good health ,Surgery ,Omentectomy ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,France ,Guideline Adherence ,business ,Sex Cord-Stromal Tumor - Abstract
The French national rare gynecological tumor network has been established to improve the quality of care through offering expertise in double reading histological diagnosis, reviewing cases and guiding management of these tumors through specialized multidisciplinary tumor boards and online clinical guidelines (www.ovaire-rare.com). The aim of this study is to evaluate the impact of the development and implementation of this network by assessing the conformity of medical practice with the guidelines concerning the granulosa cell tumors (GCTs).This is a French nationwide study, including 463 patients (out of the 639 identified patients) with a definitive diagnosis of GCT between 2011 and 2016. Surgical practices were analyzed for conformity with the current guidelines (www.ovaire-rare.org). Medical records, surgical and pathological reports were systematically analyzed. Total conformity was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysterectomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsies and peritoneal cytology) according to the FIGO stage. Partial conformity referred to a conservative or radical surgery without surgical staging and non-conformity was defined as a non-optimal surgery as recommended by the guidelines.Median age at diagnosis was 49 years old (range 10-89). The median size of tumor was 94 mm (range 5-400). Radical surgery was performed in 240 patients (52%); while a fertility-sparing surgery was performed in 98 cases (21%). A surgical staging was performed in 76 cases (16%) and an evaluation of the endometrium in 289 cases (62%). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (30%) and not assessable in 48 cases (10%). A statistically significant difference for compliance was observed in restaging surgery (p 0,001), radical surgery (p = 0,017) and the period (before or after) of the implementation of the network (p 0,001). Survival analyses did not allow us to demonstrate a significant difference in overall survival nor in PFS although there was a trend in favor of optimal surgery compared to incomplete/non optimal surgery.Surgical management's conformity to the guidelines increases over time from 2011 to 2016. According to this study, the implementation of a national network dedicated to rare gynecologic tumors seems to significantly improve the surgical management of the patients with ovarian granulosa cell tumors.
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- 2019
37. Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance
- Author
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Jaafar Bennouna, Christelle De La Fouchardiere, Simon Pernot, Trevor Stanbury, Jean-Baptiste Bachet, Thibault Voron, Florence Castan, Emmanuelle Samalin, Olivier Bouché, Christophe Borg, Cécile Badoual, Sophie Gourgou, Nina Radosevic-Robin, Eric Tartour, Frédérique Penault-Llorca, Magali Terme, François Ghiringhelli, David Malka, Valérie Boige, Eric Francois, Julien Taieb, Elie Marcheteau, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire [AP-HP Hôpital Européen Georges Pompidou] (Service de Biochimie), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Rôle des cellules dendritiques dans la régulation des effecteurs de l'immunité antitumorale, Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomopathologie, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER-UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, Centre Hospitalier Universitaire de Reims (CHU Reims), Service de pneumologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de biostatistiques en Oncologie, CRLC Val d'Aurelle, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de gastroenterologie [CHU HEGP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Kaplan-Meier Estimate ,Peripheral blood mononuclear cell ,Gastroenterology ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Stomach Neoplasms ,Surgical oncology ,Internal medicine ,medicine ,Humans ,Pathological ,ComputingMilieux_MISCELLANEOUS ,Aged ,Aged, 80 and over ,business.industry ,FOXP3 ,General Medicine ,Middle Aged ,Prognosis ,3. Good health ,Killer Cells, Natural ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear ,Biomarker (medicine) ,Female ,030211 gastroenterology & hepatology ,business ,CD8 - Abstract
The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. Circulating natural killer (NK) cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56+ cells (NK), CD8+, and FoxP3+ (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4+ and CD8+ T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8+ T cells, but not NK or FoxP3+ cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21–0.92]; p = 0.02). The prognostic value of CD8+ TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18–0.96]; p = 0.039). Diffuse/mixed-type AGC has lower rates of CD8+ TILs and circulating NK cells and Tregs than the intestinal type. This “cold tumor” phenotype may be associated with a worse outcome.
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- 2019
38. An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer
- Author
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Laura Bourillon, Céline Bourgier, Christel Larbouret, Nadège Gaborit, Pierre-Emmanuel Colombo, Alexandre Zampieri, Nina Radosevic-Robin, Charles Theillet, Eva Llès, Thierry Chardès, Hélène Delpech, Véronique Garambois, André Pèlegrin, Marta Jarlier, Béatrice Orsetti, D. Azria, Charline Ogier, 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS), This work was supported by the program 'Investissement d’Avenir' (grant agreement: Labex MabImprove, ANR-10-LABX-53-01, A. Pèlegrin), by INSERM Transfert (CoPoC grant HER3ADC, T. Chardès) and the SIRIC Montpellier Cancer (SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553, T. Chardès)., ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), Chardès, Thierry, and Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID
- Subjects
Cancer Research ,Immunoconjugates ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Cell ,pancreatic cancer ,Antibodies, Monoclonal, Murine-Derived ,Mice ,0302 clinical medicine ,Pancreatic tumor ,Phosphorylation ,skin and connective tissue diseases ,irradiation ,Chemistry ,Chemoradiotherapy ,Cell cycle ,3. Good health ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,HER3/ErbB3 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Oligopeptides ,Carcinoma, Pancreatic Ductal ,STAT3 Transcription Factor ,Radiosensitizer ,Antibody-drug conjugate ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Cell Survival ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Immunologic Factors ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Cell Proliferation ,monomethylauristatin ,medicine.disease ,Xenograft Model Antitumor Assays ,[SDV.BIO] Life Sciences [q-bio]/Biotechnology ,Radiation therapy ,Pancreatic Neoplasms ,body regions ,ADC ,Apoptosis ,Cancer research - Abstract
International audience; Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemo- and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the non-ligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC. This article is protected by copyright. All rights reserved.
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- 2019
39. Characterisation of gut, lung, and upper airways microbiota in patients with non-small cell lung carcinoma: Study protocol for case-control observational trial
- Author
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Rea Bingula, Jean-Yves Berthon, Marie-Paule Vasson, Emilie Thivat, Annick Bernalier-Donadille, Edith Filaire, Fabrice Kwiatkowski, Nina Radosevic-Robin, and Marc Filaire
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0301 basic medicine ,Adult ,Lung Neoplasms ,Gut flora ,chemotherapy ,digestive system ,immune response ,03 medical and health sciences ,Feces ,0302 clinical medicine ,Immune system ,Immunity ,Study Protocol Clinical Trial ,Carcinoma, Non-Small-Cell Lung ,gut-lung axis ,Carcinoma ,Medicine ,Humans ,Saliva ,non-small cell lung cancer ,Aged ,Lung ,biology ,business.industry ,Microbiota ,digestive, oral, and skin physiology ,Case-control study ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,biology.organism_classification ,Neoadjuvant Therapy ,3. Good health ,Gastrointestinal Microbiome ,Immunity, Humoral ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Case-Control Studies ,Immunology ,business ,tumour microenvironment ,Bronchoalveolar Lavage Fluid ,Research Article - Abstract
Background: Several studies have confirmed the important role of the gut microbiota in the regulation of immune functions and its correlation with different diseases, including cancer. While brain-gut and liver-gut axes have already been demonstrated, the existence of a lung-gut axis has been suggested more recently, with the idea that changes in the gut microbiota could affect the lung microbiota, and vice versa. Likewise, the close connection between gut microbiota and cancer of proximal sites (intestines, kidneys, liver, etc.) is already well established. However, little is known whether there is a similar relation when looking at world's number one cause of death from cancer—lung cancer. Objective: Firstly, this study aims to characterise the gut, lung, and upper airways (UAs) microbiota in patients with non-small cell lung cancer (NSCLC) treated with surgery or neoadjuvant chemotherapy plus surgery. Secondly, it aims to evaluate a chemotherapy effect on site-specific microbiota and its influence on immune profile. To our knowledge, this is the 1st study that will analyse multi-site microbiota in NSCLC patients along with site-specific immune response. Methods: The study is a case-controlled observational trial. Forty NSCLC patients will be divided into 2 groups depending on their anamnesis: Pchir, patients eligible for surgery, or Pct-chir, patients eligible for neoadjuvant chemotherapy plus surgery. Composition of the UAs (saliva), gut (faeces), and lung microbiota (from broncho-alveolar lavage fluid (BALF) and 3 lung pieces: “healthy” tissue distal to tumour, peritumoural tissue and tumour itself) will be analysed in both groups. Immune properties will be evaluated on the local (evaluation of the tumour immune cell infiltrate, tumour classification and properties, immune cell phenotyping in BALF; human neutrophil protein (HNP) 1–3, β-defensin 2, and calprotectin in faeces) and systemic level (blood cytokine and immune cell profile). Short-chain fatty acids (SCFAs) (major products of bacterial fermentation with an effect on immune system) will be dosed in faecal samples. Other factors such as nutrition and smoking status will be recorded for each patient. We hypothesise that smoking status and tumour type/grade will be major factors influencing both microbiota and immune/inflammatory profile of all sampling sites. Furthermore, due to non-selectivity, the same effect is expected from chemotherapy.
- Published
- 2018
40. Tumor mutational burden in non-small cell lung cancer—the pathologist’s point of view
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Frédérique Penault-Llorca and Nina Radosevic-Robin
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Cell ,non-small cell lung cancer (NSCLC) ,Immunotherapy ,Pembrolizumab ,Mini-Review ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,medicine ,ROS1 ,Personalized medicine ,Non small cell ,business ,Lung cancer - Abstract
In non-small cell lung cancer (NSCLC), the pathologist has contributed to the development of personalized medicine from the determination of the right histological type to EGFR and ALK/ROS1 molecular screening for targeted therapies. With the development of immunotherapies, pathologists intervene forefront with programmed death-ligand 1 (PD-L1) immunohistochemical testing, companion test for pembrolizumab monotherapy, first line and complementary test to the other programmed cell death-1 (PD-1) PD-L1 inhibitors. Recently, tumor mutational burden has emerged as a promising tool to evaluate sensitivity to immunotherapy (IO). The pathologist has a crucial role in the setting of tumor mutational burden (TMB) testing for the selection and the preparation of the sample for high throughput molecular analysis, and in the first steps of the next-generation sequencing (NGS) workflow.
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- 2018
41. Combination of phosphotidylinositol-3-kinase targeting with cetuximab and irradiation: A preclinical study on an orthotopic xenograft model of head and neck cancer
- Author
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Gérard Milano, Alexandre Bozec, Mathieu Gautier, Hedi Ben Yahia, Nina Radosevic-Robin, Serge Marcie, Emmanuel Chamorey, Frédérique Penault-Llorca, and Nathalie Ebran
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0301 basic medicine ,Oncology ,MAPK/ERK pathway ,medicine.medical_specialty ,Buparlisib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Growth factor receptor ,Internal medicine ,medicine ,neoplasms ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cetuximab ,business.industry ,Head and neck cancer ,medicine.disease ,Head and neck squamous-cell carcinoma ,digestive system diseases ,3. Good health ,030104 developmental biology ,Otorhinolaryngology ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Background The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). Methods We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice. Results Compared with control, the BKM120-cetuximab and the BKM120-cetuximab-RT combinations led to the highest tumor inhibition (p < .001). The highest inhibitory effect of treatments on cell proliferation, mitogen-activated protein kinase (MAPK) and PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways were found with the BKM120-cetuximab association. The association of BKM120 and cetuximab with RT inhibited RT-induced activation of the MAPK pathway. Conclusion These results can serve as a preclinical rationale for innovative treatments combining PI3K inhibition with anti-EGFR therapies and irradiation in patients with HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck, 2016
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- 2016
42. Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer
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N. Chalabi, K.E. Benmammar, V. Servent, Sharif Kullab, Xavier Durando, I. van Praagh, Anne Cayre, Fabrice Kwiatkowski, Y-J Bignon, Nina Radosevic-Robin, M.M. Dauplat, Catherine Abrial, J.P. Jacquin, J-M Nabholtz, Frédérique Penault-Llorca, Ph. Chollet, Marie-Ange Mouret-Reynier, and M.R.K. Bahadoor
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Cetuximab ,business.industry ,medicine.medical_treatment ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Docetaxel ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,Panitumumab ,Combined Modality Therapy ,business ,Neoadjuvant therapy ,Triple-negative breast cancer ,medicine.drug - Abstract
Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy.
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- 2015
43. Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer
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Gérard Milano, Marco Merlano, Cristiana Lo Nigro, Anne Sudaka, Martino Monteverde, Nina Radosevic-Robin, Alexandre Bozec, Frédérique Penault-Llorca, Nicolas Toussan, Nathalie Ebran, and Marie-Christine Etienne-Grimaldi
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cetuximab ,business.industry ,medicine.disease ,Head and neck squamous-cell carcinoma ,Temsirolimus ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Otorhinolaryngology ,Tumor progression ,030220 oncology & carcinogenesis ,Internal medicine ,Sirolimus ,medicine ,Cancer research ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,medicine.drug ,EGFR inhibitors - Abstract
Objectives/Hypothesis Recent preclinical and clinical studies on head and neck squamous cell carcinoma (HNSCC) revealed synergistic effects when combining anti-EGFR agents with conventional chemotherapeutic drugs. Activation of the PI3-kinase/AKT/mTOR signaling pathway has been identified as an important mechanism implicated in tumor progression and resistance to EGFR inhibitors. The aim of this study was to investigate the effects of combining the mTOR inhibitor temsirolimus (Tem) with the anti-EGFR agent cetuximab (Cet) and conventional chemotherapeutic drugs (cisplatin and fluorouracil (C/F)) on an orthotopic model of HNSCC. Study Design Preclinical in vivo study. Methods We evaluated the anti-tumor efficacy (measured tumor volume) of Tem, Cet, and C/F, administered alone or in combination. Investigations were performed using a human HNSCC cell line, CAL33, injected into the mouth floor of nude mice. Results As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced almost complete tumor growth arrest (P = 0.001). Tem significantly enhanced the impact of the Cet-C/F combination on tumor growth (P < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labeling), MAPK (pP42/44 labeling), and PI3K/AKT/mTOR (pS6R labeling) signaling pathways were found with the Tem-Cet association. Conclusion In this orthotopic HNSCC model, the combination of Tem with Cet produced synergistic effects on tumor growth. These results were corroborated by a strong inhibition of both MAPK and PI3K-mTOR signaling pathways. Level of Evidence N/A. Laryngoscope, 126:E156–E163, 2016
- Published
- 2015
44. Immunological signature meta-analysis across lung cancer cohorts within the NanoString Clinical Transcriptional Atlas Group (CTAG) associated with patient outcome and history
- Author
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Diane Damotte, M. Cumberbatch, P Morel, Sarah Warren, Karen Leroy, M. Duruisseaux, A. Brindel, M. Bhagat, Frédérique Penault-Llorca, J. Lopez, J. Reeves, SuFey Ong, Nina Radosevic-Robin, and François Goldwasser
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Tumor biology ,Hematology ,Gene signature ,medicine.disease ,Internal medicine ,Meta-analysis ,T cell subset ,Overall survival ,Medicine ,Progression-free survival ,business ,Lung cancer ,Objective response ,health care economics and organizations - Abstract
Background With the approval of anti-PD1 blocking antibodies in a growing number of indications, understanding the mechanisms responsible for potentiating response to these agents has been a critical avenue of research. However, most studies rely on the use of single cohorts and are relatively limited in their scope, thus limited their utility. Methods We created a consortium of investigators who share clinical and accompanying transcriptional data collected on the NanoString® nCounter® platform from patients treated with single agent immunotherapy to facilitate biomarker research. In this study, we apply a meta-analysis to a combined cohort of 4 lung cancer studies (n = 150) to identify transcriptional correlates of response to identify patients who are likely to experience clinical benefit. Results RNA was profiled with the NanoString IO360 and IO360 beta gene expression panels, and 43 signatures that describe facets of the immune response, tumor biology, and the tumor microenvironment were calculated. Included in these signatures is the Tumor Inflammation Signature (TIS), an investigational 18 gene signature of a suppressed adaptive immune response which enriches for clinical response to pembrolizumab. These signatures, as well as genes of interest identified in a given cohort, were compared to objective response, overall survival, or progression free survival across the cohorts. We confirm previously reported association of TIS with patient outcome and identify immune cell subsets that are also associated with response. In addition, we examine differences between patients with distinct mutational backgrounds, smoking histories, or histological classifications, as well as differences attributable to biopsy location. Conclusion This multi-cohort study allows for the development of multi-variate predictors of response to anti-PD1 monotherapy using a single research assay to transcriptionally profile the tumors. We can generate robust predictions from real-world cohorts, which may lead to the development of improved diagnostic assays to guide treatment decisions. Legal entity responsible for the study NanoString Technologies. Funding NanoString Technologies. Disclosure N. Radosevic-Robin: Research grant / Funding (institution): NanoString Technologies. J. Reeves: Full / Part-time employment: NanoString Technologies. K. Leroy: Research grant / Funding (self): NanoString Technologies. M. Duruisseaux: Research grant / Funding (self): NanoString Technologies. P. Morel: Full / Part-time employment: NanoString Technologies. M. Bhagat: Research grant / Funding (institution): NanoString Technologies. F. Penault-Llorca: Advisory / Consultancy, Research grant / Funding (institution): NanoString Technologies. D. Damotte: Research grant / Funding (institution): NanoString Technologies. F. Goldwasser: Research grant / Funding (institution): NanoString Technologies. A. Brindel: Research grant / Funding (institution): NanoString Technologies. M. Cumberbatch: Research grant / Funding (institution): NanoString Technologies. S. Ong: Full / Part-time employment: NanoString Technologies. J. Lopez: Research grant / Funding (institution): NanoString Technologies. S. Warren: Full / Part-time employment: NanoString Technologies.
- Published
- 2019
45. Détection de la maladie résiduelle du sarcome d’Ewing dans le tissu ovarien et testiculaire par une méthode sensible et spécifique
- Author
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Chaput L, Nina Radosevic-Robin, Kanold J, Andrei Tchirkov, Hanae Pons-Rejraji, Florence Brugnon, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] ,[SDV.BA]Life Sciences [q-bio]/Animal biology ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2018
46. Assessment of a sensitive and specific method to detect ewing sarcoma minimal residual disease inn testicular and ovarian tissue by RT-qPCR (2018)
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Chaput L, Greze V, Halle P, Tchirkov, A., Veronese L, Nina Radosevic-Robin, Pereira B, Lejeune H, Durand, P., Martin G, Cremeau As, Canis M, Florence Brugnon, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), COLO, Mouniati, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2018
47. Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer?
- Author
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N. Chalabi, Jean-Marc Nabholtz, Sharif Kullab, Xavier Durando, Kheir-Eddine Benmammar, Marie-Ange Mouret-Reynier, Nina Radosevic-Robin, Philippe Chollet, Catherine Abrial, Mohun Bahadoor, Qian Wang-Lopez, and Frédérique Penault-Llorca
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Receptor, ErbB-2 ,medicine.medical_treatment ,Breast Neoplasms ,Breast cancer ,In vivo ,Internal medicine ,Evaluation methods ,Biomarkers, Tumor ,Humans ,Medicine ,Breast ,Pathological ,Neoadjuvant therapy ,Complete response ,business.industry ,Surrogate endpoint ,Hematology ,Prognosis ,medicine.disease ,Neoadjuvant Therapy ,Treatment Outcome ,Immunohistochemistry ,Female ,business - Abstract
Breast cancer is heterogeneous in clinical, morphological, immunohistochemical and biological features, as reflected by several different prognostic subgroups. Neoadjuvant approaches are currently used for the "in vivo" efficacy assessment of treatments. Pathological complete response (pCR) has been reported as a reliable predictive factor of survival in that setting. However, pCR remains a subject of controversy in terms of definition and its evaluation methods. In addition, its predictive value for patient outcome in various breast cancer biological subtypes has been under debate. In this review, we will present the existing definitions of pCR, the impact of its evaluation methods on its rate and the assessment of its predictive value for patient outcome in the molecular subtypes of breast cancer (luminal A and B, Triple Negative and HER2-positive).
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- 2015
48. Pathology of Breast Cancer
- Author
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Nina Radosevic-Robin and Frédérique Penault-Llorca
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Oncology ,medicine.medical_specialty ,Pathology ,Surgical margin ,business.industry ,medicine.medical_treatment ,Cancer ,Pathology Report ,medicine.disease ,Malignancy ,Breast cancer ,Internal medicine ,Epidemiology of cancer ,medicine ,Stage (cooking) ,business ,Neoadjuvant therapy - Abstract
The pathologist is involved at various steps in the management of patients with breast cancer, beginning with the confirmation of malignancy and ending with the establishment of prognostic and predictive markers. A close collaboration between surgeons and pathologists is mandatory for proper diagnostics of breast cancer, especially during frozen section analysis, gross tumour examination and evaluation of response to neoadjuvant therapy. The pathology report must contain the histological characteristics of the tumour, the classical prognostic and theranostic markers (stage, receptor profile) as well as the surgical margin status. More recently, prognostic parameters obtained by gene expression analysis may complete the report.
- Published
- 2017
49. Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis
- Author
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Imade Ait-Arsa, Muriel Busson, André Pèlegrin, Christel Larbouret, Nina Radosevic-Robin, Jean-Max Pasquet, Dany Chalbos, Audrey Sirvent, Clément Chevalier, Charles Theillet, Marta Jarlier, Wilhem Leconet, Bruno Robert, Stanislas du Manoir, Myriam Chentouf, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), Institute of Mathematical Statistics and Actuarial Science [Bern] (IMSV), University of Bern, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunociblage des Tumeurs et Ingenierie des Anticorps, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Cancer Research ,Cell signaling ,Epithelial-Mesenchymal Transition ,Triple Negative Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Triple-negative breast cancer ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,AXL receptor tyrosine kinase ,GAS6 ,Receptor Protein-Tyrosine Kinases ,Bone metastasis ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Axl Receptor Tyrosine Kinase ,Antibodies, Anti-Idiotypic ,3. Good health ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,Cancer research ,Heterografts ,Female ,Signal Transduction - Abstract
Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC). Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways. Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6–dependent cell signaling implicated in EMT and in cell migration/invasion. Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation. Clin Cancer Res; 23(11); 2806–16. ©2016 AACR.
- Published
- 2017
50. A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability
- Author
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David G. Cox, Daniel Birnbaum, Qing Wang, Pascal Finetti, Frédéric Hollande, Emmanuelle Despras, François Bertucci, Emmanuelle Ruiz, Joël Lachuer, Christelle Chassot, Frédérique Fauvet, Pierre Saintigny, Roxane M. Pommier, Julie Caramel, Arnaud M. Vigneron, Anne Wierinckx, Nina Radosevic-Robin, Frédérique Penault-Llorca, Emmanuelle Charafe-Jauffret, Julien Wicinski, Emilie Thomas, Mojgan Devouassoux-Shisheboran, Stéphane Ansieau, Christiane Pinatel, Olivier Cabaud, Alain Puisieux, Anne-Pierre Morel, Jean-Luc Jauffret, Valérie Combaret, Jérôme Guitton, Caroline Moyret-Lalle, Agnès Tissier, Christophe Ginestier, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomo-Pathologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Synergie Lyon Cancer [Lyon], Laboratoire de Génétique de la Radiosensibilité (LGR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), clinique Phenicia, Service d'Oncologie Médicale, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), ProfileXpert, Université de Lyon, Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-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 Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Melbourne, Cancérologie expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Arts et Métiers ParisTech d'Angers - Procédés Matériaux Durabilité ( LAMPA - PMD ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Oncologie Moléculaire, Oncovirologie et Biothérapies, Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Laboratoire de Génétique de la Radiosensibilité ( LGR ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire de Toxicologie ( ISPB ), Université de Lyon-Université de Lyon, Hunan Institute of Science and Technology, Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Equipe 6, Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), equipe 2, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -labex DEVweCAN, Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Synergie Lyon Cancer [Lyon], Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Genome instability ,Pathology ,Cellular differentiation ,[SDV]Life Sciences [q-bio] ,Fluorescent Antibody Technique ,medicine.disease_cause ,Malignant transformation ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,Mice, Inbred NOD ,Chromosome instability ,Aged, 80 and over ,Stem Cells ,Cell Differentiation ,General Medicine ,Middle Aged ,Flow Cytometry ,3. Good health ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Female ,Stem cell ,Adult ,Chromatin Immunoprecipitation ,medicine.medical_specialty ,Adolescent ,DNA damage ,Immunoblotting ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Real-Time Polymerase Chain Reaction ,Genomic Instability ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Mammary Glands, Human ,Aged ,Gene Expression Profiling ,Carcinoma ,Zinc Finger E-box-Binding Homeobox 1 ,Epithelial Cells ,Sequence Analysis, DNA ,030104 developmental biology ,Tissue Array Analysis ,Methionine Sulfoxide Reductases ,Cancer research ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species ,Carcinogenesis ,DNA Damage - Abstract
International audience; Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
- Published
- 2017
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