Carlotta Antoniotti1, W Michael Korn2, Federica Marmorino1, Daniele Rossini1, Sara Lonardi3, Gianluca Masi1, Giovanni Randon4, Veronica Conca1, Alessandra Boccaccino1, Gianluca Tomasello5, Alessandro Passardi6, Jeff Swensen2, Clara Ugolini7, Matthew Oberley2, Emiliano Tamburini8, Mariaelena Casagrande9, Valeriy Domenyuk2, Gabriella Fontanini7, Mirella Giordano7, Jim Abraham2, David Spetzler2, Alfredo Falcone1, Heinz-Josef Lenz10, Chiara Cremolini11. 1. Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. 2. Caris Life Sciences, Phoenix, AZ, USA. 3. Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 4. Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 5. Department of Medical Oncology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy. 6. Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy. 7. Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy. 8. Oncology Unit, Ospedale degli Infermi, Rimini, Italy. 9. Department of Oncology, University and General Hospital, Udine, Italy. 10. University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 11. Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. Electronic address: chiaracremolini@gmail.com.
Abstract
BACKGROUND: We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. MATERIAL AND METHODS: Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7-16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. RESULTS: Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28-1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. CONCLUSIONS: Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity.
BACKGROUND: We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. MATERIAL AND METHODS: Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7-16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. RESULTS: Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28-1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. CONCLUSIONS: Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity.
Authors: Richard K Yang; Hui Chen; Sinchita Roy-Chowdhuri; Asif Rashid; Hector Alvarez; Mark Routbort; Keyur P Patel; Raja Luthra; L Jeffrey Medeiros; Gokce A Toruner Journal: Cancers (Basel) Date: 2022-09-20 Impact factor: 6.575