D Marinelli1, M Mazzotta2, S Scalera3, I Terrenato4, F Sperati5, L D'Ambrosio3, M Pallocca3, G Corleone3, E Krasniqi2, L Pizzuti2, M Barba2, S Carpano2, P Vici2, M Filetti1, R Giusti6, A Vecchione7, M Occhipinti8, A Gelibter8, A Botticelli8, F De Nicola3, L Ciuffreda3, F Goeman9, E Gallo10, P Visca10, E Pescarmona10, M Fanciulli3, R De Maria11, P Marchetti12, G Ciliberto13, M Maugeri-Saccà14. 1. Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy. 2. Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 3. SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 4. Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 5. Biostatistics Unit, San Gallicano Dermatological Institute IRCCS, Rome, Italy. 6. Medical Oncology Unit, Sant'Andrea Hospital, Rome, Italy. 7. Department of Clinical and Molecular Medicine, Pathology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy. 8. Medical Oncology Unit B, Policlinico Umberto I, Sapienza University, Rome, Italy. 9. Oncogenomic and Epigenetic Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy. 10. Department of Pathology, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 11. Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of General Pathology, Università Cattolica del Sacro Cuore, Rome, Italy. 12. 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. 13. Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 14. Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Electronic address: marcello.maugerisacca@ifo.gov.it.
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.
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.
Authors: Richard S P Huang; James Haberberger; Lukas Harries; Eric Severson; Daniel L Duncan; N Lynn Ferguson; Amanda Hemmerich; Claire Edgerly; Karthikeyan Murugesan; Jinpeng Xiao; Deborah McEwan; Oliver Holmes; Matthew Hiemenz; Jeffrey Venstrom; Julia A Elvin; James Creeden; Douglas I Lin; Jeffrey S Ross; Shakti H Ramkissoon Journal: Oncologist Date: 2021-03-25
Authors: Diego L Kaen; Nicolas Minatta; Alessandro Russo; Umberto Malapelle; Diego de Miguel-Pérez; Christian Rolfo Journal: Adv Exp Med Biol Date: 2021 Impact factor: 2.622