KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.
Identifieur interne : 000300 ( Main/Exploration ); précédent : 000299; suivant : 000301KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.
Auteurs : D. Marinelli [Italie] ; M. Mazzotta [Italie] ; S. Scalera [Italie] ; I. Terrenato [Italie] ; F. Sperati [Italie] ; L. D'Ambrosio [Italie] ; M. Pallocca [Italie] ; G. Corleone [Italie] ; E. Krasniqi [Italie] ; L. Pizzuti [Italie] ; M. Barba [Italie] ; S. Carpano [Italie] ; P. Vici [Italie] ; M. Filetti [Italie] ; R. Giusti [Italie] ; A. Vecchione [Italie] ; M. Occhipinti [Italie] ; A. Gelibter [Italie] ; A. Botticelli [Italie] ; F. De Nicola [Italie] ; L. Ciuffreda [Italie] ; F. Goeman [Italie] ; E. Gallo [Italie] ; P. Visca [Italie] ; E. Pescarmona [Italie] ; M. Fanciulli [Italie] ; R. De Maria [Italie] ; P. Marchetti [Italie] ; G. Ciliberto [Italie] ; M. Maugeri-Saccà [Italie]Source :
- Annals of oncology : official journal of the European Society for Medical Oncology [ 1569-8041 ] ; 2020.
Abstract
BACKGROUND
Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
PATIENTS AND METHODS
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
RESULTS
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
CONCLUSIONS
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
DOI: 10.1016/j.annonc.2020.08.2105
PubMed: 32866624
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.</title><author><name sortKey="Marinelli, D" sort="Marinelli, D" uniqKey="Marinelli D" first="D" last="Marinelli">D. Marinelli</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Mazzotta, M" sort="Mazzotta, M" uniqKey="Mazzotta M" first="M" last="Mazzotta">M. Mazzotta</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Scalera, S" sort="Scalera, S" uniqKey="Scalera S" first="S" last="Scalera">S. Scalera</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Terrenato, I" sort="Terrenato, I" uniqKey="Terrenato I" first="I" last="Terrenato">I. Terrenato</name><affiliation wicri:level="3"><nlm:affiliation>Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Sperati, F" sort="Sperati, F" uniqKey="Sperati F" first="F" last="Sperati">F. Sperati</name><affiliation wicri:level="3"><nlm:affiliation>Biostatistics Unit, San Gallicano Dermatological Institute IRCCS, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Biostatistics Unit, San Gallicano Dermatological Institute IRCCS, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="D Ambrosio, L" sort="D Ambrosio, L" uniqKey="D Ambrosio L" first="L" last="D'Ambrosio">L. D'Ambrosio</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pallocca, M" sort="Pallocca, M" uniqKey="Pallocca M" first="M" last="Pallocca">M. Pallocca</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Corleone, G" sort="Corleone, G" uniqKey="Corleone G" first="G" last="Corleone">G. Corleone</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Krasniqi, E" sort="Krasniqi, E" uniqKey="Krasniqi E" first="E" last="Krasniqi">E. Krasniqi</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pizzuti, L" sort="Pizzuti, L" uniqKey="Pizzuti L" first="L" last="Pizzuti">L. Pizzuti</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Barba, M" sort="Barba, M" uniqKey="Barba M" first="M" last="Barba">M. Barba</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Carpano, S" sort="Carpano, S" uniqKey="Carpano S" first="S" last="Carpano">S. Carpano</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Vici, P" sort="Vici, P" uniqKey="Vici P" first="P" last="Vici">P. Vici</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Filetti, M" sort="Filetti, M" uniqKey="Filetti M" first="M" last="Filetti">M. Filetti</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Giusti, R" sort="Giusti, R" uniqKey="Giusti R" first="R" last="Giusti">R. Giusti</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit, Sant'Andrea Hospital, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Vecchione, A" sort="Vecchione, A" uniqKey="Vecchione A" first="A" last="Vecchione">A. Vecchione</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Pathology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Pathology Unit, Sant'Andrea Hospital, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Occhipinti, M" sort="Occhipinti, M" uniqKey="Occhipinti M" first="M" last="Occhipinti">M. Occhipinti</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Gelibter, A" sort="Gelibter, A" uniqKey="Gelibter A" first="A" last="Gelibter">A. Gelibter</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Botticelli, A" sort="Botticelli, A" uniqKey="Botticelli A" first="A" last="Botticelli">A. Botticelli</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="De Nicola, F" sort="De Nicola, F" uniqKey="De Nicola F" first="F" last="De Nicola">F. De Nicola</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Ciuffreda, L" sort="Ciuffreda, L" uniqKey="Ciuffreda L" first="L" last="Ciuffreda">L. Ciuffreda</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Goeman, F" sort="Goeman, F" uniqKey="Goeman F" first="F" last="Goeman">F. Goeman</name><affiliation wicri:level="3"><nlm:affiliation>Oncogenomic and Epigenetic Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Oncogenomic and Epigenetic Unit, IRCCS "Regina Elena" National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Gallo, E" sort="Gallo, E" uniqKey="Gallo E" first="E" last="Gallo">E. Gallo</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Visca, P" sort="Visca, P" uniqKey="Visca P" first="P" last="Visca">P. Visca</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pescarmona, E" sort="Pescarmona, E" uniqKey="Pescarmona E" first="E" last="Pescarmona">E. Pescarmona</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Fanciulli, M" sort="Fanciulli, M" uniqKey="Fanciulli M" first="M" last="Fanciulli">M. Fanciulli</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="De Maria, R" sort="De Maria, R" uniqKey="De Maria R" first="R" last="De Maria">R. De Maria</name><affiliation wicri:level="3"><nlm:affiliation>Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Marchetti, P" sort="Marchetti, P" uniqKey="Marchetti P" first="P" last="Marchetti">P. Marchetti</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy; Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy; Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Ciliberto, G" sort="Ciliberto, G" uniqKey="Ciliberto G" first="G" last="Ciliberto">G. Ciliberto</name><affiliation wicri:level="3"><nlm:affiliation>Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Maugeri Sacca, M" sort="Maugeri Sacca, M" uniqKey="Maugeri Sacca M" first="M" last="Maugeri-Saccà">M. Maugeri-Saccà</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Electronic address: marcello.maugerisacca@ifo.gov.it.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32866624</idno><idno type="pmid">32866624</idno><idno type="doi">10.1016/j.annonc.2020.08.2105</idno><idno type="wicri:Area/Main/Corpus">000122</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000122</idno><idno type="wicri:Area/Main/Curation">000122</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000122</idno><idno type="wicri:Area/Main/Exploration">000122</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.</title><author><name sortKey="Marinelli, D" sort="Marinelli, D" uniqKey="Marinelli D" first="D" last="Marinelli">D. Marinelli</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Mazzotta, M" sort="Mazzotta, M" uniqKey="Mazzotta M" first="M" last="Mazzotta">M. Mazzotta</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Scalera, S" sort="Scalera, S" uniqKey="Scalera S" first="S" last="Scalera">S. Scalera</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Terrenato, I" sort="Terrenato, I" uniqKey="Terrenato I" first="I" last="Terrenato">I. Terrenato</name><affiliation wicri:level="3"><nlm:affiliation>Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Sperati, F" sort="Sperati, F" uniqKey="Sperati F" first="F" last="Sperati">F. Sperati</name><affiliation wicri:level="3"><nlm:affiliation>Biostatistics Unit, San Gallicano Dermatological Institute IRCCS, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Biostatistics Unit, San Gallicano Dermatological Institute IRCCS, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="D Ambrosio, L" sort="D Ambrosio, L" uniqKey="D Ambrosio L" first="L" last="D'Ambrosio">L. D'Ambrosio</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pallocca, M" sort="Pallocca, M" uniqKey="Pallocca M" first="M" last="Pallocca">M. Pallocca</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Corleone, G" sort="Corleone, G" uniqKey="Corleone G" first="G" last="Corleone">G. Corleone</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Krasniqi, E" sort="Krasniqi, E" uniqKey="Krasniqi E" first="E" last="Krasniqi">E. Krasniqi</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pizzuti, L" sort="Pizzuti, L" uniqKey="Pizzuti L" first="L" last="Pizzuti">L. Pizzuti</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Barba, M" sort="Barba, M" uniqKey="Barba M" first="M" last="Barba">M. Barba</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Carpano, S" sort="Carpano, S" uniqKey="Carpano S" first="S" last="Carpano">S. Carpano</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Vici, P" sort="Vici, P" uniqKey="Vici P" first="P" last="Vici">P. Vici</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Filetti, M" sort="Filetti, M" uniqKey="Filetti M" first="M" last="Filetti">M. Filetti</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Giusti, R" sort="Giusti, R" uniqKey="Giusti R" first="R" last="Giusti">R. Giusti</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit, Sant'Andrea Hospital, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Vecchione, A" sort="Vecchione, A" uniqKey="Vecchione A" first="A" last="Vecchione">A. Vecchione</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Pathology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Pathology Unit, Sant'Andrea Hospital, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Occhipinti, M" sort="Occhipinti, M" uniqKey="Occhipinti M" first="M" last="Occhipinti">M. Occhipinti</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Gelibter, A" sort="Gelibter, A" uniqKey="Gelibter A" first="A" last="Gelibter">A. Gelibter</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Botticelli, A" sort="Botticelli, A" uniqKey="Botticelli A" first="A" last="Botticelli">A. Botticelli</name><affiliation wicri:level="3"><nlm:affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="De Nicola, F" sort="De Nicola, F" uniqKey="De Nicola F" first="F" last="De Nicola">F. De Nicola</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Ciuffreda, L" sort="Ciuffreda, L" uniqKey="Ciuffreda L" first="L" last="Ciuffreda">L. Ciuffreda</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Goeman, F" sort="Goeman, F" uniqKey="Goeman F" first="F" last="Goeman">F. Goeman</name><affiliation wicri:level="3"><nlm:affiliation>Oncogenomic and Epigenetic Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Oncogenomic and Epigenetic Unit, IRCCS "Regina Elena" National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Gallo, E" sort="Gallo, E" uniqKey="Gallo E" first="E" last="Gallo">E. Gallo</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Visca, P" sort="Visca, P" uniqKey="Visca P" first="P" last="Visca">P. Visca</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Pescarmona, E" sort="Pescarmona, E" uniqKey="Pescarmona E" first="E" last="Pescarmona">E. Pescarmona</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Fanciulli, M" sort="Fanciulli, M" uniqKey="Fanciulli M" first="M" last="Fanciulli">M. Fanciulli</name><affiliation wicri:level="3"><nlm:affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="De Maria, R" sort="De Maria, R" uniqKey="De Maria R" first="R" last="De Maria">R. De Maria</name><affiliation wicri:level="3"><nlm:affiliation>Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Marchetti, P" sort="Marchetti, P" uniqKey="Marchetti P" first="P" last="Marchetti">P. Marchetti</name><affiliation wicri:level="3"><nlm:affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy; Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy; Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Ciliberto, G" sort="Ciliberto, G" uniqKey="Ciliberto G" first="G" last="Ciliberto">G. Ciliberto</name><affiliation wicri:level="3"><nlm:affiliation>Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Maugeri Sacca, M" sort="Maugeri Sacca, M" uniqKey="Maugeri Sacca M" first="M" last="Maugeri-Saccà">M. Maugeri-Saccà</name><affiliation wicri:level="3"><nlm:affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Electronic address: marcello.maugerisacca@ifo.gov.it.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author></analytic><series><title level="j">Annals of oncology : official journal of the European Society for Medical Oncology</title><idno type="eISSN">1569-8041</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.</p></div><div type="abstract" xml:lang="en"><p><b>PATIENTS AND METHODS</b></p><p>KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.</p></div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32866624</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>02</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1569-8041</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Aug</Month><Day>28</Day></PubDate></JournalIssue><Title>Annals of oncology : official journal of the European Society for Medical Oncology</Title><ISOAbbreviation>Ann Oncol</ISOAbbreviation></Journal><ArticleTitle>KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">S0923-7534(20)42170-2</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.annonc.2020.08.2105</ELocationID><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.</AbstractText><AbstractText Label="PATIENTS AND METHODS" NlmCategory="METHODS">KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.</AbstractText><CopyrightInformation>Copyright © 2020 European Society for Medical Oncology. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Marinelli</LastName><ForeName>D</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mazzotta</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Scalera</LastName><ForeName>S</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Terrenato</LastName><ForeName>I</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sperati</LastName><ForeName>F</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Biostatistics Unit, San Gallicano Dermatological Institute IRCCS, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>D'Ambrosio</LastName><ForeName>L</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pallocca</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Corleone</LastName><ForeName>G</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Krasniqi</LastName><ForeName>E</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pizzuti</LastName><ForeName>L</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Barba</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Carpano</LastName><ForeName>S</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vici</LastName><ForeName>P</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Filetti</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Giusti</LastName><ForeName>R</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vecchione</LastName><ForeName>A</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Clinical and Molecular Medicine, Pathology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Occhipinti</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gelibter</LastName><ForeName>A</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Botticelli</LastName><ForeName>A</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Nicola</LastName><ForeName>F</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ciuffreda</LastName><ForeName>L</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Goeman</LastName><ForeName>F</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Oncogenomic and Epigenetic Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gallo</LastName><ForeName>E</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Visca</LastName><ForeName>P</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pescarmona</LastName><ForeName>E</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fanciulli</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Maria</LastName><ForeName>R</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marchetti</LastName><ForeName>P</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy; Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ciliberto</LastName><ForeName>G</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Maugeri-Saccà</LastName><ForeName>M</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Electronic address: marcello.maugerisacca@ifo.gov.it.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>08</Month><Day>28</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Ann Oncol</MedlineTA><NlmUniqueID>9007735</NlmUniqueID><ISSNLinking>0923-7534</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">KEAP1 co-mutations</Keyword><Keyword MajorTopicYN="N">immunogenomic</Keyword><Keyword MajorTopicYN="N">immunotherapy</Keyword><Keyword MajorTopicYN="N">lung adenocarcinoma</Keyword><Keyword MajorTopicYN="N">tumor mutational burden</Keyword></KeywordList><CoiStatement>Disclosure LP received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees from Roche, Pfizer, Novartis, Gentili. PVici received travel grants from Eisai, Roche, Pfizer, Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili. RG received advisory boards/honoraria/speakers' fee from Astra Zeneca and Roche. RDM is a scientific advisory board member at Exosomics SpA (Siena IT), HiberCell Inc. (New York, NY), Kiromic Inc. (Houston, TX) and Exiris Inc. (Rome, IT). All other authors declare no conflicts of interest. Data sharing Data concerning the Rome cohort are provided in supplementary Data File S1, available at https://doi.org/10.1016/j.annonc.2020.08.2105. The MSKCC and DFCI studies are available at www.cbioportal.org. The OAK and POPLAR trials are available as supplementary information in Gandara DR et al.(23) Immunogenomic features related to the TCGA LUAD study were downloaded from the CRI iAtlas Portal (available at www.cri-iatlas.org).</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>05</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2020</Year><Month>08</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>08</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>9</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>9</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>9</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32866624</ArticleId><ArticleId IdType="pii">S0923-7534(20)42170-2</ArticleId><ArticleId IdType="doi">10.1016/j.annonc.2020.08.2105</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Italie</li></country><region><li>Latium</li></region><settlement><li>Rome</li></settlement></list><tree><country name="Italie"><region name="Latium"><name sortKey="Marinelli, D" sort="Marinelli, D" uniqKey="Marinelli D" first="D" last="Marinelli">D. Marinelli</name></region><name sortKey="Barba, M" sort="Barba, M" uniqKey="Barba M" first="M" last="Barba">M. Barba</name><name sortKey="Botticelli, A" sort="Botticelli, A" uniqKey="Botticelli A" first="A" last="Botticelli">A. Botticelli</name><name sortKey="Carpano, S" sort="Carpano, S" uniqKey="Carpano S" first="S" last="Carpano">S. Carpano</name><name sortKey="Ciliberto, G" sort="Ciliberto, G" uniqKey="Ciliberto G" first="G" last="Ciliberto">G. Ciliberto</name><name sortKey="Ciuffreda, L" sort="Ciuffreda, L" uniqKey="Ciuffreda L" first="L" last="Ciuffreda">L. Ciuffreda</name><name sortKey="Corleone, G" sort="Corleone, G" uniqKey="Corleone G" first="G" last="Corleone">G. Corleone</name><name sortKey="D Ambrosio, L" sort="D Ambrosio, L" uniqKey="D Ambrosio L" first="L" last="D'Ambrosio">L. D'Ambrosio</name><name sortKey="De Maria, R" sort="De Maria, R" uniqKey="De Maria R" first="R" last="De Maria">R. De Maria</name><name sortKey="De Nicola, F" sort="De Nicola, F" uniqKey="De Nicola F" first="F" last="De Nicola">F. De Nicola</name><name sortKey="Fanciulli, M" sort="Fanciulli, M" uniqKey="Fanciulli M" first="M" last="Fanciulli">M. Fanciulli</name><name sortKey="Filetti, M" sort="Filetti, M" uniqKey="Filetti M" first="M" last="Filetti">M. Filetti</name><name sortKey="Gallo, E" sort="Gallo, E" uniqKey="Gallo E" first="E" last="Gallo">E. Gallo</name><name sortKey="Gelibter, A" sort="Gelibter, A" uniqKey="Gelibter A" first="A" last="Gelibter">A. Gelibter</name><name sortKey="Giusti, R" sort="Giusti, R" uniqKey="Giusti R" first="R" last="Giusti">R. Giusti</name><name sortKey="Goeman, F" sort="Goeman, F" uniqKey="Goeman F" first="F" last="Goeman">F. Goeman</name><name sortKey="Krasniqi, E" sort="Krasniqi, E" uniqKey="Krasniqi E" first="E" last="Krasniqi">E. Krasniqi</name><name sortKey="Marchetti, P" sort="Marchetti, P" uniqKey="Marchetti P" first="P" last="Marchetti">P. Marchetti</name><name sortKey="Maugeri Sacca, M" sort="Maugeri Sacca, M" uniqKey="Maugeri Sacca M" first="M" last="Maugeri-Saccà">M. Maugeri-Saccà</name><name sortKey="Mazzotta, M" sort="Mazzotta, M" uniqKey="Mazzotta M" first="M" last="Mazzotta">M. Mazzotta</name><name sortKey="Occhipinti, M" sort="Occhipinti, M" uniqKey="Occhipinti M" first="M" last="Occhipinti">M. Occhipinti</name><name sortKey="Pallocca, M" sort="Pallocca, M" uniqKey="Pallocca M" first="M" last="Pallocca">M. Pallocca</name><name sortKey="Pescarmona, E" sort="Pescarmona, E" uniqKey="Pescarmona E" first="E" last="Pescarmona">E. Pescarmona</name><name sortKey="Pizzuti, L" sort="Pizzuti, L" uniqKey="Pizzuti L" first="L" last="Pizzuti">L. Pizzuti</name><name sortKey="Scalera, S" sort="Scalera, S" uniqKey="Scalera S" first="S" last="Scalera">S. Scalera</name><name sortKey="Sperati, F" sort="Sperati, F" uniqKey="Sperati F" first="F" last="Sperati">F. Sperati</name><name sortKey="Terrenato, I" sort="Terrenato, I" uniqKey="Terrenato I" first="I" last="Terrenato">I. Terrenato</name><name sortKey="Vecchione, A" sort="Vecchione, A" uniqKey="Vecchione A" first="A" last="Vecchione">A. Vecchione</name><name sortKey="Vici, P" sort="Vici, P" uniqKey="Vici P" first="P" last="Vici">P. Vici</name><name sortKey="Visca, P" sort="Visca, P" uniqKey="Visca P" first="P" last="Visca">P. Visca</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Bois/explor/PoplarV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000300 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000300 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Bois
|area= PoplarV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:32866624
|texte= KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:32866624" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a PoplarV1
| This area was generated with Dilib version V0.6.37. |  |