Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative
Background Although conflicting results emerged from different studies, the tumor mutational burden (TMB) appears as one of most reliable biomarkers of sensitivity to immune checkpoint inhibitors. Several laboratories are reporting TMB values when performing comprehensive genomic profiling (CGP) wit...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/2/e007800.full |
| _version_ | 1827338088221769728 |
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| author | Nicola Normanno Paolo Chiodini Riziero Esposito Abate Raffaella Pasquale Alessandra Sacco Vittorio Simeon Monica Rosaria Maiello Daniela Frezzetti |
| author_facet | Nicola Normanno Paolo Chiodini Riziero Esposito Abate Raffaella Pasquale Alessandra Sacco Vittorio Simeon Monica Rosaria Maiello Daniela Frezzetti |
| author_sort | Nicola Normanno |
| collection | DOAJ |
| description | Background Although conflicting results emerged from different studies, the tumor mutational burden (TMB) appears as one of most reliable biomarkers of sensitivity to immune checkpoint inhibitors. Several laboratories are reporting TMB values when performing comprehensive genomic profiling (CGP) without providing a clinical interpretation, due to the lack of validated cut-off values. The International Quality Network for Pathology launched an initiative to harmonize TMB testing with CGP assay and favor the clinical implementation of this biomarker.Methods TMB evaluation was performed with three commercially available CGP panels, TruSight Oncology 500 (TSO500), Oncomine Comprehensive Plus Assay (OCA) and QIAseq Multimodal Panel (QIA), versus the reference assay FoundationOne CDx (F1CDx). Archived clinical samples derived from 60 patients with non-small cell lung cancer were used for TMB assessment. Adjusted cut-off values for each panel were calculated.Results Testing was successful for 91.7%, 100%, 96.7% and 100% of cases using F1CDx, TSO500, OCA and QIA, respectively. The matrix comparison analysis, between the F1CDx and CGP assays, showed a linear correlation for all three panels, with a higher correlation between F1CDx and TSO500 (rho=0.88) than in the other two comparisons (rho=0.77 for QIA; 0.72 for OCA). The TSO500 showed the best area under the curve (AUC, value 0.96), with a statistically significant difference when compared with the AUC of OCA (0.83, p value=0.01) and QIA (0.88, p value=0.028). The Youden Index calculation allowed us to extrapolate TMB cut-offs of the different panels corresponding to the 10 mutations/megabase (muts/Mb) cut-off of F1CDx: 10.19, 10.4 and 12.37 muts/Mb for TSO500, OCA and QIA, respectively. Using these values, we calculated the relative accuracy measures for the three panels. TSO500 showed 86% specificity and 96% sensitivity, while OCA and QIA had lower yet similar values of specificity and sensitivity (73% and 88%, respectively).Conclusion This study estimated TMB cut-off values for commercially available CGP panels. The results showed a good performance of all panels on clinical samples and the calculated cut-offs support better accuracy measures for TSO500. The validated cut-off values can drive clinical interpretation of TMB testing in clinical research and clinical practice. |
| first_indexed | 2024-03-07T19:08:48Z |
| format | Article |
| id | doaj.art-d22bb570ecbd49d5be9ee43d7c0ddb86 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-07T19:08:48Z |
| publishDate | 2024-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-d22bb570ecbd49d5be9ee43d7c0ddb862024-03-01T06:00:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-02-0112210.1136/jitc-2023-007800Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiativeNicola Normanno0Paolo Chiodini1Riziero Esposito Abate2Raffaella Pasquale3Alessandra Sacco4Vittorio Simeon5Monica Rosaria Maiello6Daniela Frezzetti7Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, ItalyMedical Statistics Unit, Department of Mental Health and Public Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, ItalyCell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, ItalyMedical Genetics Laboratory, AORN S.G. Moscati, Avellino, ItalyCell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, ItalyMedical Statistics Unit, Department of Mental Health and Public Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, ItalyCell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, ItalyCell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G.Pascale, Napoli, ItalyBackground Although conflicting results emerged from different studies, the tumor mutational burden (TMB) appears as one of most reliable biomarkers of sensitivity to immune checkpoint inhibitors. Several laboratories are reporting TMB values when performing comprehensive genomic profiling (CGP) without providing a clinical interpretation, due to the lack of validated cut-off values. The International Quality Network for Pathology launched an initiative to harmonize TMB testing with CGP assay and favor the clinical implementation of this biomarker.Methods TMB evaluation was performed with three commercially available CGP panels, TruSight Oncology 500 (TSO500), Oncomine Comprehensive Plus Assay (OCA) and QIAseq Multimodal Panel (QIA), versus the reference assay FoundationOne CDx (F1CDx). Archived clinical samples derived from 60 patients with non-small cell lung cancer were used for TMB assessment. Adjusted cut-off values for each panel were calculated.Results Testing was successful for 91.7%, 100%, 96.7% and 100% of cases using F1CDx, TSO500, OCA and QIA, respectively. The matrix comparison analysis, between the F1CDx and CGP assays, showed a linear correlation for all three panels, with a higher correlation between F1CDx and TSO500 (rho=0.88) than in the other two comparisons (rho=0.77 for QIA; 0.72 for OCA). The TSO500 showed the best area under the curve (AUC, value 0.96), with a statistically significant difference when compared with the AUC of OCA (0.83, p value=0.01) and QIA (0.88, p value=0.028). The Youden Index calculation allowed us to extrapolate TMB cut-offs of the different panels corresponding to the 10 mutations/megabase (muts/Mb) cut-off of F1CDx: 10.19, 10.4 and 12.37 muts/Mb for TSO500, OCA and QIA, respectively. Using these values, we calculated the relative accuracy measures for the three panels. TSO500 showed 86% specificity and 96% sensitivity, while OCA and QIA had lower yet similar values of specificity and sensitivity (73% and 88%, respectively).Conclusion This study estimated TMB cut-off values for commercially available CGP panels. The results showed a good performance of all panels on clinical samples and the calculated cut-offs support better accuracy measures for TSO500. The validated cut-off values can drive clinical interpretation of TMB testing in clinical research and clinical practice.https://jitc.bmj.com/content/12/2/e007800.full |
| spellingShingle | Nicola Normanno Paolo Chiodini Riziero Esposito Abate Raffaella Pasquale Alessandra Sacco Vittorio Simeon Monica Rosaria Maiello Daniela Frezzetti Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative Journal for ImmunoTherapy of Cancer |
| title | Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative |
| title_full | Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative |
| title_fullStr | Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative |
| title_full_unstemmed | Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative |
| title_short | Harmonization of tumor mutation burden testing with comprehensive genomic profiling assays: an IQN Path initiative |
| title_sort | harmonization of tumor mutation burden testing with comprehensive genomic profiling assays an iqn path initiative |
| url | https://jitc.bmj.com/content/12/2/e007800.full |
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