Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial

Arndt Stahler; Sebastian Stintzing; Jobst C von Einem; Christoph B Westphalen; Kathrin Heinrich; Nicole Krämer; Marlies Michl; Dominik P Modest; Ludwig Fischer von Weikersthal; Thomas Decker; Alexander Kiani; Tobias Heintges; Christoph Kahl; Frank Kullmann; Werner Scheithauer; Markus Moehler; Florian Kaiser; Thomas Kirchner; Andreas Jung; Volker Heinemann

doi:10.1016/j.ejca.2020.07.003

Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial

Eur J Cancer. 2020 Sep:137:250-259. doi: 10.1016/j.ejca.2020.07.003. Epub 2020 Aug 15.

Authors

Arndt Stahler¹, Sebastian Stintzing², Jobst C von Einem³, Christoph B Westphalen⁴, Kathrin Heinrich⁴, Nicole Krämer⁵, Marlies Michl⁴, Dominik P Modest⁶, Ludwig Fischer von Weikersthal⁷, Thomas Decker⁸, Alexander Kiani⁹, Tobias Heintges¹⁰, Christoph Kahl¹¹, Frank Kullmann¹², Werner Scheithauer¹³, Markus Moehler¹⁴, Florian Kaiser¹⁵, Thomas Kirchner¹⁶, Andreas Jung¹⁶, Volker Heinemann¹⁷

Affiliations

¹ Department of Medicine III, University Hospital, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. Electronic address: [email protected].
² Medical Department, Division of Hematology, Oncology and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
³ Medical Department, Division of Hematology, Oncology and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
⁴ Department of Medicine III, University Hospital, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
⁵ STABURO Statistical Consulting GmbH, Aschauer Strasse 26b, 81549, Munich, Germany.
⁶ Medical Department, Division of Hematology, Oncology and Tumor Immunology (CVK), Charité Universitaetsmedizin Berlin, MIttelallee 11, 10117, Berlin, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁷ Klinikum St. Marien, Oncology, Mariahilfbergweg 7, 92224, Amberg, Germany.
⁸ Onkologische Praxis, Elisabethenstrasse 19, 88212, Ravensburg, Germany.
⁹ Department of Medicine IV, Klinikum Bayreuth GmbH, Preuschwitzer Strasse 101, 95445, Bayreuth, Germany.
¹⁰ Department of Medicine II, Lukaskrankenhaus, Preussenstrasse 84, 41464, Neuss, Germany.
¹¹ Department of Hematology, Oncology and Palliative Care, Klinikum Magdeburg gGmbH, Birkenallee 34, 39130, Magdeburg, Germany.
¹² Department of Internal Medicine I, Klinikum Weiden, Soellnerstrasse 16, 92637, Weiden, Germany.
¹³ Department of Internal Medicine I & CCC, Medical University Vienna, Heiligenstaedter Strasse 46-48, 1090, Vienna, Austria.
¹⁴ University Medical Center Mainz, I. Dept. of Internal Medicine, Langenbeckstrasse 1, 55131, Mainz, Germany.
¹⁵ VK&K Studien GbR, Achdorfer Weg 5a, 84036, Landshut, Germany.
¹⁶ Institute of Pathology, University of Munich, Thalkirchner Strasse 36a, 80337, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
¹⁷ Department of Medicine III, University Hospital, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

PMID: 32810748
DOI: 10.1016/j.ejca.2020.07.003

Abstract

Background: Molecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology.

Material and methods: FoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB (TMB-H) and high-grade microsatellite instability (MSI-H) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Results: Three hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34-1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10-0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours.

Conclusions: RAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS.

Keywords: Metastatic colorectal cancer; Next-generation; Primary tumour location; Sequencing; Sidedness; Tumour mutational burden.

Publication types

Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Female
High-Throughput Nucleotide Sequencing / methods*
Humans
Male
Microsatellite Instability
Middle Aged
Neoplasm Metastasis
Polymorphism, Single Nucleotide / genetics*
Retrospective Studies
Tumor Burden / genetics*