المؤلفون: Debbie Robbrecht, Jean‐Jacques Grob, Oliver Bechter, Matteo Simonelli, Bernard Doger, Ivan Borbath, Marcus O. Butler, Tina Cheng, Patricia Martin Romano, Elvire Pons‐Tostivint, Massimo Di Nicola, Giuseppe Curigliano, Min‐Hee Ryu, Alejo Rodriguez‐Vida, Dirk Schadendorf, Elena Garralda, Giovanni Abbadessa, Brigitte Demers, Amele Amrate, Hong Wang, Joon Sang Lee, Robert Pomponio, Rui Wang

المصدر: Clinical and Translational Science, Vol 17, Iss 2, Pp n/a-n/a (2024)

مصطلحات موضوعية: Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270

الوصف: Abstract SAR439459, a ‘second‐generation’ human anti‐transforming growth factor‐beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti‐programmed cell death protein‐1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first‐in‐human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose‐escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose‐expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ‐pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune‐excluded’ to ‘immune‐infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1752-8054Test; https://doaj.org/toc/1752-8062Test

الوصول الحر: https://doaj.org/article/28412427e6174db093de8737922fa32aTest

المؤلفون: Monica Pierro, Capucine Baldini, Edouard Auclin, Hélène Vincent, Andreea Varga, Patricia Martin Romano, Perrine Vuagnat, Benjamin Besse, David Planchard, Antoine Hollebecque, Stéphane Champiat, Aurélien Marabelle, Jean-Marie Michot, Christophe Massard, Laura Mezquita

المصدر: Cancers, Vol 14, Iss 20, p 5078 (2022)

مصطلحات موضوعية: LIPI score, immune checkpoint inhibitors, older patients, neutrophils, aging, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Immunotherapy with immune checkpoint blockers (ICB) represents a valid therapeutic option in older patients for several solid cancer types. However, most of the data concerning efficacy and adverse events of ICB available are derived from younger and fitter patients. Reliable biomarkers are needed to better select the population that will benefit from ICB especially in older patients who may be at a higher risk of developing immune-related adverse events (irAEs) with a greater impact on their quality of life. The Lung Immune Prognostic Index (LIPI) is a score that combines pretreatment dNLR (neutrophils/[leukocytes − neutrophils]) and lactate dehydrogenase (LDH) and is correlated with outcomes in patients treated with ICB in non-small-cell lung cancer. We aimed to assess the impact of LIPI in ICB outcomes in a dedicated cohort of older patients. The primary objective was to study the prognostic role of LIPI score in patients aged 70 years or above in a real-life population treated with anti-programmed death-(ligand)1 (anti PD-(L)1). dNLR and LDH were collected in a prospective cohort of patients aged 70 years or above treated with PD-(L)1 inhibitors with metastatic disease between June 2014 and October 2017 at Gustave Roussy. LIPI categorizes the population into three different prognostic groups: good (dNLR ≤ 3 and LDH ≤ ULN—upper normal limit), intermediate (dNLR > 3 or LDH > ULN), and poor (dNLR > 3 and LDH > ULN). Anti PD-(L)1 benefit was analyzed according to overall survival (OS), progression free survival (PFS), and overall response rate (ORR) using RECIST v1.1. criteria. In the 191 older patients treated, most of them (95%) were ICB-naïve, and 160 (84%) had an ECOG performance status of 0–1 with a median age at ICB treatment of 77 (range, 70–93). The most common tumor types were melanoma (66%) and non-small-cell lung cancer (15%). The median follow-up duration was 18.8 months (95% CI 14.7–24.2). LIPI classified the population into three different groups: 38 (23%) patients had a good LIPI score, 84 (51%) had an intermediate LIPI score, and 43 (26%) had a poor LIPI score. The median OS was 20.7 months [95% CI, 12.6–not reached] compared to 11.2 months [95% CI, 8.41–22.2] and 4.7 months [95% CI, 2.2–11.3] in patients with a good, intermediate, and poor LIPI score, respectively (p = 0.0003). The median PFS was 9.2 months [95% CI, 6.2–18.1] in the good LIPI group, 7.2 months [95% CI, 5.4–13] in the intermediate LIPI group, and 3.9 months [95% CI, 2.3–8.2] in the poor LIPI group (p = 0.09). The rate of early death (OS < 3 months) was 37% in the poor LIPI group compared to 5% in the good LIPI group (

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/14/20/5078Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/b72f849c261a458c9ee024c736eaefd9Test

المؤلفون: Patricia Martin Romano, Eduardo Castanon, Antoine Hollebecque, Ludovic Lacroix, Nathalie Auger, Eric Angevin, Lambros Tselikas, Sami Ammari, Jean-Charles Soria, Christophe Massard

المصدر: Journal of Immunotherapy and Precision Oncology, Pp 152-155 (2019)

مصطلحات موضوعية: anti-epidermal growth factor receptor, cholangiocarcinoma, gene amplification, mesenchymal–epithelial transition factor, resistance, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Immunologic diseases. Allergy, RC581-607

الوصف: Mesenchymal–epithelial transition factor (MET) amplification has been suggested either as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been widely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment. A 60-year-old man presenting cholangiocarcinoma with EGFR amplification had a tumor response to anti-EGFR therapy. A new on-purpose tumor biopsy performed during tumor progression confirmed the known EGFR amplification as well as a new MET amplification. This clinical observation highlights the role of MET amplification as a mechanism of resistance to EGFR inhibitors.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2666-2345Test; https://doaj.org/toc/2590-017XTest

الوصول الحر: https://doaj.org/article/1642474e458b43f6bb34cbd5ae1dd354Test

المؤلفون: Capucine Baldini, Francois-Xavier Danlos, Andreea Varga, Matthieu Texier, Heloise Halse, Severine Mouraud, Lydie Cassard, Stéphane Champiat, Nicolas Signolle, Perrine Vuagnat, Patricia Martin-Romano, Jean-Marie Michot, Rastislav Bahleda, Anas Gazzah, Lisa Boselli, Delphine Bredel, Jonathan Grivel, Chifaou Mohamed-Djalim, Guillaume Escriou, Laetitia Grynszpan, Amelie Bigorgne, Saloomeh Rafie, Alae Abbassi, Vincent Ribrag, Sophie Postel-Vinay, Antoine Hollebecque, Sandrine Susini, Siham Farhane, Ludovic Lacroix, Aurelien Parpaleix, Salim Laghouati, Laurence Zitvogel, Julien Adam, Nathalie Chaput, Jean-Charles Soria, Christophe Massard, Aurelien Marabelle

المصدر: Journal of Experimental & Clinical Cancer Research, Vol 41, Iss 1, Pp 1-14 (2022)

مصطلحات موضوعية: Phase I, Dose escalation, Immunotherapy, Anti PD-1, Anti-angiogenic, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 — Prospectively registered.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-9966Test

الوصول الحر: https://doaj.org/article/cc022ab82e6e4fd69d684a17c4dfa3ffTest

المؤلفون: Damien Vasseur, Hela Sassi, Arnaud Bayle, Marco Tagliamento, Benjamin Besse, Christophe Marzac, Ahmadreza Arbab, Nathalie Auger, Sophie Cotteret, Mihaela Aldea, Félix Blanc-Durand, Arthur Géraud, Anas Gazzah, Yohann Loriot, Antoine Hollebecque, Patricia Martín-Romano, Maud Ngo-Camus, Claudio Nicotra, Santiago Ponce, Madona Sakkal, Olivier Caron, Cristina Smolenschi, Jean-Baptiste Micol, Antoine Italiano, Etienne Rouleau, Ludovic Lacroix

المصدر: Cells; Volume 11; Issue 12; Pages: 1901

مصطلحات موضوعية: cfDNA, liquid biopsy, next-generation sequencing, molecular tumor board, FDA-approved

الوصف: FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels’ size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.

وصف الملف: application/pdf

العلاقة: https://dx.doi.org/10.3390/cells11121901Test

الإتاحة: https://doi.org/10.3390/cells11121901Test

المؤلفون: Lauren Seknazi, Arthur Geraud, Vincent Goldschmidt, Capucine Baldini, Stéphane Champiat, Christophe Massard, Sophie Postel-Vinay, Aurelien Marabelle, Rastilav Bahleda, Antoine Hollebecque, Cristina Smolenschi, Anas Gazzah, Jean-Marie Michot, Patricia Martin-Romano, Aurore Vozy, Perrine Vuagnat, François-Xavier Danlos, Arnaud Bayle, Linda Mahjoubi, Barbara Pistilli, Yohann Loriot, Santiago Ponce-Aix, Kaissa Ouali

المصدر: Cancer Research. 83:P2-13

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Background: Breast cancer (BC) is the most frequent cancer and the second leading cause of cancer death for women. Although there is a need of new treatments to improve BC outcome, patients with BC are still under-represented in early phase trials, possibly because of the availability of numerous approved treatments and widely recruiting phase II and III trials. We aim to characterize the molecular profile, outcome and prognostic factors of patients with BC treated in a phase I trial at our institution. Methods: We retrospectively analyzed medical records of every BC patients treated consecutively in a phase I trial in the Early Drug Development Department (DITEP) at Gustave Roussy Cancer Center. Multivariate logistic regression models were used to determine the association between known prognostic factors such as ECOG, LDH or albumin levels, number of previous lines of treatment, metastatic sites and duration of treatment. When available, molecular profile was also reviewed. Results: Between April 1st 2008 and December 31th 2021, 4682 patients were enrolled and treated in a phase I trial in our department. Among them, 272 were treated for BC (5.8%): 271 women and 1 man, in 74 different trials. The median number of BC patients treated per year was 16.5 (min 1; max 33). Median time between consented date and C1D1 was 14 days (min 1; max 63). Median age at C1D1 was 50 years old (min 24; max 82). 5 patients (1.8%) were treated in an adjuvant setting (therapeutic vaccine) while all the others were metastatic. 12 patients (4.5%) had brain metastases and 127 patients (47.6%) had liver metastases. 186 patients (70%) had only 1 or 2 metastatic sites, and 81 (30%) had three or more sites. Triple negative was the most common subtype, representing 132 patients (48.5%), 125 (46%) were ER+ and 15 (5.5%) Her2+. Patients received a median number of 3 prior lines before enrollment (min 0; max 19). Overall, only 78 patients (28%) had a genetic testing: 30.7% had a germline BRCA1/2 mutation. 146 patients (54%) had a molecular profile (liquid biopsy or tissue sample) before their enrollment and among them 32,9% were oriented in a trial according to their specific profile. Regarding the type of treatments received: 21.7% were immunotherapy, 73.6% were targeted therapies (46.7% in monotherapy, 26.9% in different combinations with immunotherapy, chemotherapy, radiotherapy or endocrine treatments), 2.9% were chemotherapy and 1.8% endocrine therapy. The overall response rate was 11.1% (0.4% complete response, 10.7% partial response, 37.5% stable disease, 43.8% progressive disease and 7.6% not evaluable). Main reasons for discontinuation of treatment were: progressive disease (80.5%), toxicity (9.6%) and end of trial (6.6%). Median duration of treatment was 2 months (min 0; max 44), only 28.6% of patients were still treated after 3 months of trial and 10% at 6 months. At data cut off (June 21st 2022) median overall survival was 11 months. All patients had discontinued the trial by the time of the analysis: median number of lines of subsequent treatment was 2 (min 0; max 10) and 31 patients (11%) were enrolled in another phase I trial in our center. In a multivariate analysis, there was no prognostic factor associated with duration of treatment whether it was albumin (p=0.76) or LDH levels (p=0.68), ECOG (p=0.67), number of prior lines of treatment (p=0.79) or number of metastatic site (p=0.05). Conclusion: These results are consistent with prior published data as only few patients with BC are addressed for inclusion in a phase I trial, despite response rates and survival rates similar to other phase I patients. We did not find any specific factor associated with duration of treatment. It is likely that a thorough molecular profile could open more treatment options and access to phase I trials. Citation Format: Lauren Seknazi, Arthur Geraud, Vincent Goldschmidt, Capucine Baldini, Stéphane Champiat, Christophe Massard, Sophie Postel-Vinay, Aurelien Marabelle, Rastilav Bahleda, Antoine Hollebecque, Cristina Smolenschi, Anas Gazzah, Jean-Marie Michot, Patricia Martin-Romano, Aurore Vozy, Perrine Vuagnat, François-Xavier Danlos, Arnaud Bayle, Linda Mahjoubi, Barbara Pistilli, Yohann Loriot, Santiago Ponce-Aix, Kaissa Ouali. COBRA: Characteristics and Outcomes of patients with BReast cancer in phAse I trials at Gustave Roussy Cancer center [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-02.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::cf3c7ec9e4e98d11575b6815653da494Test
https://doi.org/10.1158/1538-7445.sabcs22-p2-13-02Test

المؤلفون: Jean‐Marie Michot, Cyril Quivoron, Clémentine Sarkozy, Alina Danu, Julien Lazarovici, Khalil Saleh, Yolla El‐Dakdouki, Vincent Goldschmidt, Camille Bigenwald, Matteo Dragani, Rastislav Bahleda, Capucine Baldini, Julia Arfi‐Rouche, Patricia Martin‐Romano, Lambros Tselikas, Anas Gazzah, Antoine Hollebecque, Ludovic Lacroix, David Ghez, Veronique Vergé, Christophe Marzac, Sophie Cotteret, Wassila Rahali, Jean‐Charles Soria, Christophe Massard, Olivier A. Bernard, Peggy Dartigues, Valérie Camara‐Clayette, Vincent Ribrag

المصدر: American Journal of Hematology. 98:645-657

مصطلحات موضوعية: Hematology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::83c09f85453cac881c334c43ddbe2644Test
https://doi.org/10.1002/ajh.26835Test

المؤلفون: Edouard Auclin, Perrine Vuagnat, Cristina Smolenschi, Julien Taieb, Jorge Adeva, Laetitia Nebot-Bral, Marta Garcia de Herreros, Rosario Vidal Tocino, Federico Longo-Muñoz, Yola El Dakdouki, Patricia Martín-Romano, Lydia Gaba, Tamara Saurí, Helena Oliveres, Eduardo Castañón, Rocio Garcia-Carbonero, Benjamin Besse, Christophe Massard, Laura Mezquita, Antoine Hollebecque

المصدر: Cancers; Volume 13; Issue 15; Pages: 3776

مصطلحات موضوعية: LIPI, dNLR, LDH, MSI-H, dMMR, immunotherapy, immune checkpoint inhibitors

الوصف: Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p < 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46–8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.

وصف الملف: application/pdf

العلاقة: Cancer Biomarkers; https://dx.doi.org/10.3390/cancers13153776Test

الإتاحة: https://doi.org/10.3390/cancers13153776Test

المؤلفون: Patricia Martin-Romano, Julien Adam, Jean-Yves Scoazec, Sébastien Gouy, Antonin Levy, Capucine Baldini, Stéphane Champiat, Jean-Charles Soria, Christophe Massard, Aurélien Marabelle, Eric Deutsch, Antoine Hollebecque

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: immunotherapy, radiation therapy, tumor response, immune microenvironment, anal squamous cell carcinoma, Immunologic diseases. Allergy, RC581-607

الوصف: Immunotherapy has dramatically changed the treatment landscape for several tumor types. However, the impact of previous radiotherapy (RT) on response to immunotherapy is still unknown. We report the case of a 58-year-old female diagnosed with a squamous anal cell carcinoma previously treated with RT and having a dissociated response to anti-PD1 agent. An extensive analysis of the immune contexture performed on the tissue collected from both previously RT-treated and RT-untreated lesions confirmed differences on immune microenvironment, highlighting the potential impact of radiotherapy on the immune response.

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.745146/fullTest; https://doaj.org/toc/1664-3224Test; https://doaj.org/article/a9848339c5df4201aff9b1a92b7f8bfdTest

الإتاحة: https://doi.org/10.3389/fimmu.2021.745146Test
https://doaj.org/article/a9848339c5df4201aff9b1a92b7f8bfdTest

المؤلفون: Patricia, Martin-Romano, Leo, Colmet-Daage, Daphne, Morel, Capucine, Baldini, Loic, Verlingue, Rastilav, Bahleda, Anas, Gazzah, Stephan, Champiat, Andree, Varga, Jean Marie, Michot, Maud, Ngo-Camus, Claudio, Nicotra, Aurelien, Marabelle, Jean Charles, Soria, Etienne, Rouleau, Ludovic, Lacroix, Antoine, Hollebecque, Christophe, Massard, Sophie, Postel-Vinay

المصدر: European Journal of Cancer. 173:133-145

مصطلحات موضوعية: Cancer Research, Oncology, Neoplasms, Mutation, Exome Sequencing, Biomarkers, Tumor, Humans, Precision Medicine, Epigenesis, Genetic

الوصف: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected.Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p amp;lt; 0.001). Outcome was not correlated with the presence of EGA.Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8024c5c9089cc5c5e59f2323e9efe197Test
https://doi.org/10.1016/j.ejca.2022.06.014Test