Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres
Abstract Background The current therapeutic algorithm for Advanced Stage Melanoma comprises of alternating lines of Targeted and Immuno-therapy, mostly via Immune-Checkpoint blockade. While Comprehensive Genomic Profiling of solid tumours has been approved as a companion diagnostic, still no approve...
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BMC
2024-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04776-2 |
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| author | Matteo Pallocca Ivan Molineris Enrico Berrino Benedetta Marcozzi Martina Betti Lauretta Levati Stefania D’Atri Chiara Menin Gabriele Madonna Paola Ghiorzo Jenny Bulgarelli Virgina Ferraresi Tiziana Venesio Monica Rodolfo Licia Rivoltini Luisa Lanfrancone Paolo Antonio Ascierto Luca Mazzarella Pier Giuseppe Pelicci Ruggero De Maria Gennaro Ciliberto Enzo Medico Giandomenico Russo |
| author_facet | Matteo Pallocca Ivan Molineris Enrico Berrino Benedetta Marcozzi Martina Betti Lauretta Levati Stefania D’Atri Chiara Menin Gabriele Madonna Paola Ghiorzo Jenny Bulgarelli Virgina Ferraresi Tiziana Venesio Monica Rodolfo Licia Rivoltini Luisa Lanfrancone Paolo Antonio Ascierto Luca Mazzarella Pier Giuseppe Pelicci Ruggero De Maria Gennaro Ciliberto Enzo Medico Giandomenico Russo |
| author_sort | Matteo Pallocca |
| collection | DOAJ |
| description | Abstract Background The current therapeutic algorithm for Advanced Stage Melanoma comprises of alternating lines of Targeted and Immuno-therapy, mostly via Immune-Checkpoint blockade. While Comprehensive Genomic Profiling of solid tumours has been approved as a companion diagnostic, still no approved predictive biomarkers are available for Melanoma aside from BRAF mutations and the controversial Tumor Mutational Burden. This study presents the results of a Multi-Centre Observational Clinical Trial of Comprehensive Genomic Profiling on Target and Immuno-therapy treated advanced Melanoma. Methods 82 samples, collected from 7 Italian Cancer Centres of FFPE-archived Metastatic Melanoma and matched blood were sequenced via a custom-made 184-gene amplicon-based NGS panel. Sequencing and bioinformatics analysis was performed at a central hub. Primary analysis was carried out via the Ion Reporter framework. Secondary analysis and Machine Learning modelling comprising of uni and multivariate, COX/Lasso combination, and Random Forest, was implemented via custom R/Python scripting. Results The genomics landscape of the ACC-mela cohort is comparable at the somatic level for Single Nucleotide Variants and INDELs aside a few gene targets. All the clinically relevant targets such as BRAF and NRAS have a comparable distribution thus suggesting the value of larger scale sequencing in melanoma. No comparability is reached at the CNV level due to biotechnological biases and cohort numerosity. Tumour Mutational Burden is slightly higher in median for Complete Responders but fails to achieve statistical significance in Kaplan–Meier survival analysis via several thresholding strategies. Mutations on PDGFRB, NOTCH3 and RET were shown to have a positive effect on Immune-checkpoint treatment Overall and Disease-Free Survival, while variants in NOTCH4 were found to be detrimental for both endpoints. Conclusions The results presented in this study show the value and the challenge of a genomics-driven network trial. The data can be also a valuable resource as a validation cohort for Immunotherapy and Target therapy genomic biomarker research. |
| first_indexed | 2024-03-08T16:14:36Z |
| format | Article |
| id | doaj.art-aa5718450c4648a7bae3716959838906 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2025-02-18T14:17:13Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-aa5718450c4648a7bae37169598389062024-10-28T09:08:01ZengBMCJournal of Translational Medicine1479-58762024-01-012211710.1186/s12967-023-04776-2Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer CentresMatteo Pallocca0Ivan Molineris1Enrico Berrino2Benedetta Marcozzi3Martina Betti4Lauretta Levati5Stefania D’Atri6Chiara Menin7Gabriele Madonna8Paola Ghiorzo9Jenny Bulgarelli10Virgina Ferraresi11Tiziana Venesio12Monica Rodolfo13Licia Rivoltini14Luisa Lanfrancone15Paolo Antonio Ascierto16Luca Mazzarella17Pier Giuseppe Pelicci18Ruggero De Maria19Gennaro Ciliberto20Enzo Medico21Giandomenico Russo22Institute of Experimental Endocrinology and Oncology, National Research CouncilDepartment of Life Science and System Biology, University of TurinCandiolo Cancer Institute, FPO-IRCCSBiostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer InstituteBiostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer InstituteLaboratory of Molecular Oncology, IDI-IRCCSLaboratory of Molecular Oncology, IDI-IRCCSImmunology and Oncological Molecular Diagnostics, Oncological Institute, IOV IRCCS UOCMelanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. PascaleGenetics of Rare Cancers, IRCCS Ospedale Policlinico San MartinoImmunotherapy, Cell Therapy and Biobank Unit, IRCCS Istituto Romagnolo Per lo Studio dei Tumori (IRST) “Dino Amadori”Sarcoma and Rare Tumours Departmental Unit- IRCCS Regina Elena National Cancer Institute-RomeCandiolo Cancer Institute, FPO-IRCCSUnit of Translational Immunology, Department of Experimental Oncology, IRCCS Foundation National Cancer InstituteUnit of Translational Immunology, Department of Experimental Oncology, IRCCS Foundation National Cancer InstituteDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO)Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. PascaleDepartment of Experimental Oncology, European Institute of Oncology IRCCS (IEO)Department of Experimental Oncology, European Institute of Oncology IRCCS (IEO)Institute of General Pathology, Catholic University “Sacro Cuore”Scientific Direction, IRCCS Regina Elena National Cancer InstituteCandiolo Cancer Institute, FPO-IRCCSIstituto Dermopatico dell’Immacolata, IDI-IRCCSAbstract Background The current therapeutic algorithm for Advanced Stage Melanoma comprises of alternating lines of Targeted and Immuno-therapy, mostly via Immune-Checkpoint blockade. While Comprehensive Genomic Profiling of solid tumours has been approved as a companion diagnostic, still no approved predictive biomarkers are available for Melanoma aside from BRAF mutations and the controversial Tumor Mutational Burden. This study presents the results of a Multi-Centre Observational Clinical Trial of Comprehensive Genomic Profiling on Target and Immuno-therapy treated advanced Melanoma. Methods 82 samples, collected from 7 Italian Cancer Centres of FFPE-archived Metastatic Melanoma and matched blood were sequenced via a custom-made 184-gene amplicon-based NGS panel. Sequencing and bioinformatics analysis was performed at a central hub. Primary analysis was carried out via the Ion Reporter framework. Secondary analysis and Machine Learning modelling comprising of uni and multivariate, COX/Lasso combination, and Random Forest, was implemented via custom R/Python scripting. Results The genomics landscape of the ACC-mela cohort is comparable at the somatic level for Single Nucleotide Variants and INDELs aside a few gene targets. All the clinically relevant targets such as BRAF and NRAS have a comparable distribution thus suggesting the value of larger scale sequencing in melanoma. No comparability is reached at the CNV level due to biotechnological biases and cohort numerosity. Tumour Mutational Burden is slightly higher in median for Complete Responders but fails to achieve statistical significance in Kaplan–Meier survival analysis via several thresholding strategies. Mutations on PDGFRB, NOTCH3 and RET were shown to have a positive effect on Immune-checkpoint treatment Overall and Disease-Free Survival, while variants in NOTCH4 were found to be detrimental for both endpoints. Conclusions The results presented in this study show the value and the challenge of a genomics-driven network trial. The data can be also a valuable resource as a validation cohort for Immunotherapy and Target therapy genomic biomarker research.https://doi.org/10.1186/s12967-023-04776-2Comprehensive genomic profilingNetwork trialAlleanza Contro il CancroMelanomaSKCMImmuno-checkpoint inhibitors |
| spellingShingle | Matteo Pallocca Ivan Molineris Enrico Berrino Benedetta Marcozzi Martina Betti Lauretta Levati Stefania D’Atri Chiara Menin Gabriele Madonna Paola Ghiorzo Jenny Bulgarelli Virgina Ferraresi Tiziana Venesio Monica Rodolfo Licia Rivoltini Luisa Lanfrancone Paolo Antonio Ascierto Luca Mazzarella Pier Giuseppe Pelicci Ruggero De Maria Gennaro Ciliberto Enzo Medico Giandomenico Russo Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres Journal of Translational Medicine Comprehensive genomic profiling Network trial Alleanza Contro il Cancro Melanoma SKCM Immuno-checkpoint inhibitors |
| title | Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres |
| title_full | Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres |
| title_fullStr | Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres |
| title_full_unstemmed | Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres |
| title_short | Comprehensive genomic profiling on metastatic Melanoma: results from a network screening from 7 Italian Cancer Centres |
| title_sort | comprehensive genomic profiling on metastatic melanoma results from a network screening from 7 italian cancer centres |
| topic | Comprehensive genomic profiling Network trial Alleanza Contro il Cancro Melanoma SKCM Immuno-checkpoint inhibitors |
| url | https://doi.org/10.1186/s12967-023-04776-2 |
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