University of Oulu

Osterlund E, Ristimäki A, Kytölä S, Kuopio T, Heervä E, Muhonen T, Halonen P, Kallio R, Soveri L-M, Sundström J, Keinänen M, Ålgars A, Ristamäki R, Sorbye H, Pfeiffer P, Nunes L, Salminen T, Lamminmäki A, Mäkinen MJ, Sjöblom T, Isoniemi H, Glimelius B and Osterlund P (2022) KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer. Front. Oncol. 12:826073. doi: 10.3389/fonc.2022.826073

KRAS-G12C mutation in one real-life and three population-based Nordic cohorts of metastatic colorectal cancer

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Author: Osterlund, Emerik1; Ristimäki, Ari2,3; Kytölä, Soili4,5;
Organizations: 1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
2Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
3Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
4Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
5Department of Genetics, University of Helsinki, Helsinki, Finland
6Department of Pathology, Central Finland Hospital Nova, Jyväskylä, Finland
7Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
8Department of Oncology, Turku University Hospital, Turku, Finland
9Department of Oncology, University of Turku, Turku, Finland
10Department of Oncology, South Carelia Central Hospital, Lappeenranta, Finland
11Department of Oncology, University of Helsinki, Helsinki, Finland
12Department of Oncology, Helsinki University Hospital, Helsinki, Finland
13Department of Oncology, Oulu University Hospital, Oulu, Finland
14Department of Oncology, University of Oulu, Oulu, Finland
15Home Care, Geriatric Clinic and Palliative Care, Joint Municipal Authority for Health Care and Social Services in Keski-Uusimaa, Hyvinkää, Finland
16Department of Pathology, Turku University Hospital, Turku, Finland
17Institute of Biomedicine, University of Turku, Turku, Finland
18Department of Genetics, Fimlab Laboratories, Tampere, Finland
19Department of Oncology, Haukeland University Hospital, Bergen, Norway
20Department of Clinical Science, University of Bergen, Bergen, Norway
21Department of Oncology, Odense University Hospital, Odense, Denmark
22Department of Clinical Research, University of Southern Denmark, Odense, Denmark
23Department of Oncology, Tampere University Hospital, Tampere, Finland
24Department of Oncology, University of Tampere, Tampere, Finland
25Department of Oncology, Kuopio University Hospital, Kuopio, Finland
26Department of Medicine, University of Eastern Finland, Kuopio, Finland
27Department of Pathology, Oulu University Hospital, Oulu, Finland
28Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu, and Medical Research Center Oulu, Oulu, Finland
29Department of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
30Department of Surgery, University of Helsinki, Helsinki, Finland
31Department of Gastrointestinal Oncology, Karolinska Universitetssjukhuset, Stockholm, Sweden
32Department of Oncology/Pathology, Karolinska Institutet, Stockholm, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.7 MB)
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Language: English
Published: Frontiers Media, 2022
Publish Date: 2022-05-10


Background: KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.

Methods: Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan–Meier, and differences were compared using Cox regression, adjusted for baseline factors.

Results: The KRAS-G12C frequency was 2%–4% of all tested in the seven cohorts (mean 3%) and 4%–8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74–1.42, reference KRAS-G12C) nor within treatment groups defined as “systemic chemotherapy, alone or with biologics”, “metastasectomy and/or ablations”, or “best supportive care”, RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.

Conclusions: In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.

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Series: Frontiers in oncology
ISSN: 2234-943X
ISSN-E: 2234-943X
ISSN-L: 2234-943X
Volume: 12
Article number: 826073
DOI: 10.3389/fonc.2022.826073
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: Finska Läkaresällskapet (2016, 2018, 2019, 2020, 2021, 2022), The Finnish Cancer Foundation (2019-2020, 2021, 2022-2023), The Competitive State Research Financing of the Expert Responsibility Area of Tampere, Turku, Helsinki, Oulu and Kuopio University Hospitals (2016, 2017, 2018, 2019, 2020, 2021, 2022), Tampere and Helsinki University Hospital Research Funds (Tukisäätiö 2019, 2020; OOO 2020), The Sigrid Jusélius Foundation (2017, 2021), and The Swedish Cancer Society (2016, 2019) have provided grants. The infrastructure of the RAXO-study, with blood sampling, database, and study nurses, was supported by pharmaceutical companies: Amgen (unrestricted grants, 2012-2020), Lilly (2012-2017), Merck KGaA (2012-2020), Roche Oy (2012-2020), Sanofi (2012-2017), and Servier (unrestricted grant, 2016-2020). Amgen also partly supported the NGS analysis performed in patients included in the Uppsala region cohort. The funding sources had no role in the design and conduct of the study, collection, analysis and interpretation of the data, or decision to submit the manuscript for publication.
Copyright information: © 2022 Osterlund, Ristimäki, Kytölä, Kuopio, Heervä, Muhonen, Halonen, Kallio, Soveri, Sundström, Keinänen, Ålgars, Ristamäki, Sorbye, Pfeiffer, Nunes, Salminen, Lamminmäki, Mäkinen, Sjöblom, Isoniemi, Glimelius and Osterlund. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.