A combined oncogenic pathway signature of BRAF , KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction
Open accessAbstract
Objective: To develop gene expression profiles that characterise KRAS -, BRAF - or PIK3CA -activated- tumours, and to explore whether these profiles might be helpful in predicting the response to the epidermal growth factor receptor (EGFR) pathway inhibitors better than mutation status alone. Design: Fresh frozen tumour samples from 381 colorectal cancer (CRC) patients were collected and mutations in KRAS , BRAF and PIK3CA were assessed. Using microarray data, three individual oncogenic and a combined model were developed and validated in an independent set of 80 CRC patients, and in a dataset from metastatic CRC patients treated with cetuximab. Results: 175 tumours (45.9%) harboured oncogenic mutations in KRAS (30.2%), BRAF (11.0%) and PIK3CA (11.5%). Activating mutation signatures for KRAS (75 genes), for BRAF (58 genes,) and for PIK3CA (49 genes) were developed. The development of a combined oncogenic pathway signature-classified tumours as ‘activated oncogenic’, or as ‘wildtype-like’ with a sensitivity of 90.3% and a specificity of 61.7%. The identified signature revealed other mechanisms that can activate ERK/MAPK pathway in KRAS , BRAF and PIK3CA wildtype patients. The combined signature is associated with response to cetuximab treatment in patients with metastatic CRC (HR 2.51, p<0.0009). Conclusion: A combined oncogenic pathway signature allows the identification of patients with an active EGFR-signalling pathway that could benefit from downstream pathway inhibition.
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High mRNA levels of either amphiregulin or epiregulin may predict a better response to cetuximab.
“while high mRNA levels of either amphiregulin or epiregulin may predict a better response [21, 116-119]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [21]
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- Authors
- Tian, S., Simon, I., Moreno, V., Roepman, P., Tabernero, J., Snel, M., van't Veer, L., Salazar, R., Bernards, R., & Capella, G.
- Affiliations
- Agendia (Netherlands) (NL)
- Research and Development, Agendia BV, Amsterdam, The Netherlands
- Universitat Autònoma de Barcelona (ES)
- Universitat de Barcelona (ES)
- IDIBELL, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2012-07-14
- Volume
- 62
- Issue
- 4
- Pages
- 540-549
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC3596735
- OpenAlex
- W2111905790
- Cited by
- 128
- References
- 34
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 18 · 2020: 8 · 2019: 18 · 2018: 9 · 2017: 7 · 2016: 14 · 2015: 12 · 2014: 16 · 2013: 12 · 2012: 2
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- European Commission
- Universiteit Leiden
- Leids Universitair Medisch Centrum
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- colorectal cancer, KRAS mutation, BRAF mutation, PIK3CA mutation, gene expression profiling, metastatic colorectal cancer, tumor classification
- MeSH terms
- Cetuximab, Antibodies, Monoclonal, Antineoplastic Agents, DNA Mutational Analysis, Humans, Mutation, Neoplasm Staging, Proto-Oncogene Proteins, ROC Curve, Sensitivity and Specificity, Biomarkers, Tumor, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), ras Proteins, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Gene Expression Profiling, Microarray Analysis, Proto-Oncogene Proteins B-raf, Class I Phosphatidylinositol 3-Kinases, Antibodies, Monoclonal, Humanized
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