Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Autor:	Negrao MV; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Araujo HA; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lamberti G; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Cooper AJ; Massachussetts General Hospital, Boston, Massachusetts., Akhave NS; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zhou T; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Delasos L; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio., Hicks JK; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida., Aldea M; Institut Gustave Roussy, Villejuif, France.; Paris-Saclay University, Paris, France., Minuti G; Istituto Nazionale Tumori IRCCS 'Regina Elena,' Rome, Italy., Hines J; University of Chicago Medical Center, Chicago, Illinois., Aredo JV; Stanford University, Stanford, California., Dennis MJ; Moores Cancer Center, University of California San Diego, San Diego, California., Chakrabarti T; Department of Medicine, Division of Hematology and Oncology, University of California San Francisco, San Francisco, California., Scott SC; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Bironzo P; Department of Oncology, University of Turin, Turin, Italy., Scheffler M; Department for Internal Medicine, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany., Christopoulos P; Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases at Heidelberg University Hospital, Heidelberg, Germany., Stenzinger A; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany., Riess JW; University of California Davis Comprehensive Cancer Center, Sacramento, California., Kim SY; Yale School of Medicine, New Haven, Connecticut., Goldberg SB; Yale School of Medicine, New Haven, Connecticut., Li M; Division of Medical Oncology, The Ohio State University-James Comprehensive Cancer Center, Columbus, Ohio., Wang Q; Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Qing Y; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ni Y; Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Do MT; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lee R; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ricciuti B; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Alessi JV; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Wang J; Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Resuli B; Istituto Nazionale Tumori IRCCS 'Regina Elena,' Rome, Italy., Landi L; Istituto Nazionale Tumori IRCCS 'Regina Elena,' Rome, Italy., Tseng SC; Department of Radiology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts., Nishino M; Department of Radiology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts., Digumarthy SR; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts., Rinsurongkawong W; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Rinsurongkawong V; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Vaporciyan AA; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Blumenschein GR; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zhang J; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Owen DH; Division of Medical Oncology, The Ohio State University-James Comprehensive Cancer Center, Columbus, Ohio., Blakely CM; Department of Medicine, Division of Hematology and Oncology, University of California San Francisco, San Francisco, California., Mountzios G; Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece., Shu CA; Department of Medicine, Columbia University, New York, New York., Bestvina CM; University of Chicago Medical Center, Chicago, Illinois., Garassino MC; University of Chicago Medical Center, Chicago, Illinois., Marrone KA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland., Gray JE; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida., Patel SP; Moores Cancer Center, University of California San Diego, San Diego, California., Cummings AL; University of California Los Angeles, Los Angeles, California., Wakelee HA; Stanford University, Stanford, California., Wolf J; Department for Internal Medicine, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany., Scagliotti GV; Department of Oncology, University of Turin, S. Luigi Hospital, Turin, Italy., Cappuzzo F; Istituto Nazionale Tumori IRCCS 'Regina Elena,' Rome, Italy., Barlesi F; Institut Gustave Roussy, Villejuif, France.; Paris-Saclay University, Paris, France., Patil PD; Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio., Drusbosky L; Guardant Health, Redwood City, California., Gibbons DL; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Meric-Bernstam F; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lee JJ; Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Heymach JV; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hong DS; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Heist RS; Massachussetts General Hospital, Boston, Massachusetts., Awad MM; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Skoulidis F; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2023 Jul 07; Vol. 13 (7), pp. 1556-1571.
DOI:	10.1158/2159-8290.CD-22-1420
Abstrakt:	Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. Significance: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu