Background:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (CRC). KRAS mutation analysis is usually performed on primary tumour tissue because metastatic tissue is often not available. However, controversial data are available on the concordance of test results between primary tumours and corresponding metastases. We assessed the concordance of KRAS mutation status in a study of 305 primary colorectal tumours and their corresponding liver metastases.Methods:Patients with histologically confirmed CRC who underwent surgical resection of the primary tumour and biopsy or surgical resection of the corresponding liver metastasis were included. KRAS mutation analysis was performed for codons 12 and 13.Results:KRAS mutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), we found a discordance between primary tumour and metastasis: 5 primary tumours had a KRAS mutation with a wild-type metastasis, 1 primary tumour was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a different KRAS mutation.Conclusion:We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6–98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0% 95% CI 0.7–4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis.

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BACKGROUND: Mutations in the KRAS oncogene occur in 30-60% of the patients with colorectal cancer (CRC). Constitutively activation of the KRAS protein leads to growth, proliferation, and survival of CRC cells. KRAS mutation is an early event during colorectal carcinogenesis, therefore all tumor cells including metastatic cells are expected to have the same mutation status. We investigated the KRAS mutation status in primaries and metastatic tissue of patients with liver and lung metastasis. METHODS: Patients with histological confirmed CRC who underwent surgical resection of the primary tumor and biopsy or surgical resection of the corresponding liver (n = 304) or lung metastasis (n = 90) were included. KRAS mutation analysis was performed for codons 12 and 13 using sequencing analysis. We used Next Generation Sequencing (NGS) to further evaluate a patient with a discordance in KRAS mutation status between the primary and metastasis. RESULTS: KRAS mutations were detected in 35.3% of the 304 primary tumors with liver metastases. In 11 cases (3.6%), we found a discordance between primary tumor and metastasis: 5 primary tumors had a KRAS mutation with a wild-type metastasis, 1 primary tumor was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumor and the metastasis had a different KRAS mutation. NGS of the patient with a wild type primary tumor and a KRAS mutation in the liver metastases revealed a KRAS mutation in 7.5% of the primary tumor cells. KRAS mutations were detected in 46.7% of the 90 primary tumors with lung metastases. The KRAS mutation frequency in lung metastases was 55.6%. A discordance in KRAS mutation status between primary tumors and metastasis was observed in 8 cases (8.9%). In all these patients the primary tumors had a KRAS wild-type while the lung metastasis showed a KRAS mutation. CONCLUSION: We observed a higher KRAS mutation frequency in primary CRC with lung metastases compared to primary CRC with liver metastases (p=0.038). Increased discordance in the lung metastases might indicate that these originate in very small subclones of the primary. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 432. doi:1538-7445.AM2012-432