Original Research Tumour mutational burden, microsatellite instability, and actionable alterations in metastatic colorectal cancer: Next-generation sequencing results of TRIBE2 study

被引：18

作者：

Antoniotti, Carlotta ^{[1
,2
]}

Korn, W. Michael ^{[3
]}

Marmorino, Federica ^{[1
,2
]}

Rossini, Daniele ^{[1
,2
]}

Lonardi, Sara ^{[4
,13
]}

Masi, Gianluca ^{[1
,2
]}

Randon, Giovanni ^{[5
,6
]}

Conca, Veronica ^{[1
,2
]}

Boccaccino, Alessandra ^{[1
,2
]}

Tomasello, Gianluca ^{[7
]}

Passardi, Alessandro ^{[8
]}

Swensen, Jeff ^{[3
]}

Ugolini, Clara ^{[9
]}

Oberley, Matthew ^{[3
]}

Tamburini, Emiliano ^{[10
]}

Casagrande, Mariaelena ^{[11
]}

Domenyuk, Valeriy ^{[3
]}

Fontanini, Gabriella ^{[9
]}

Giordano, Mirella ^{[9
]}

Abraham, Jim ^{[3
]}

Spetzler, David ^{[3
]}

Falcone, Alfredo ^{[1
,2
]}

Lenz, Heinz-Josef ^{[12
]}

Cremolini, Chiara ^{[1
,2
]}

机构：

[1] Univ Hosp Pisa, Dept Oncol, Pisa, Italy

[2] Univ Pisa, Dept Translat Res & New Technol Med, Pisa, Italy

[3] Caris Life Sci, Phoenix, AZ USA

[4] Veneto Inst Oncol IOV IRCCS, Dept Oncol, Early Phase Clin Trial Unit, Padua, Italy

[5] Univ Milan, Oncol & Hematooncol Dept, Milan, Italy

[6] Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Milan, Italy

[7] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Med Oncol, Milan, Italy

[8] IRCCS Ist Romagnolo Studio Tumori IRST Dino Amado, Dept Med Oncol, Meldola, Italy

[9] Univ Pisa, Med Mol Pathol & Crit Area, Dept Surg, Pisa, Italy

[10] Osped Infermi, Oncol Unit, Rimini, Italy

[11] Univ & Gen Hosp, Dept Oncol, Udine, Italy

[12] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90007 USA

[13] Veneto Inst Oncol IOV IRCCS, Dept Oncol, Med Oncol Unit 1, Padua, Italy

来源：

EUROPEAN JOURNAL OF CANCER | 2021年 / 155卷

关键词：

cancer; Tumour mutational burden; Microsatellite instability; POLE mutation; MMR genes mutations; Actionable alterations; NGS; Metastatic colorectal; MISMATCH REPAIR DEFICIENCY; POSITIVE SOLID TUMORS; POLYMERASE-EPSILON; POOLED ANALYSIS; RAS MUTATIONS; PD-1; BLOCKADE; OPEN-LABEL; NIVOLUMAB; MULTICENTER; IPILIMUMAB;

D O I：

10.1016/j.ejca.2021.06.037

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 Z 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. 2021 Elsevier Ltd. All rights reserved.

引用

页码：73 / 84

页数：12

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