KRAS Mutations in Primary Colorectal Cancer Tumors and Related Metastases: A Potential Role in Prediction of Lung Metastasis

Abstract

Background KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status.Methodology/Principal Findings KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006).Conclusions/SignificanceOur results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to metastasize to the lung.

Association between KRAS mutation and lung metastasis in advanced colorectal cancer.

“…Second, KRAS status was obtained from routinely available archival material and does not incorporate potential discordance in KRAS status between a primary tumour and its metastases. However, KRAS mutations are thought to be highly concordant during the progression of the disease (Artale et al, 2008;EtienneGrimaldi et al, 2008;Santini et al, 2008;Cejas et al, 2009). Third, the traditional sequencing (Sanger) method (with B20% allele frequency as lowest threshold for detection) or a mass spectroscopy method (B15% allele frequency) for detection of KRAS mutations was used, both of which have lower sensitivity for mutation analysis than current next-generation sequencing approaches (B5% allele frequency; Jimeno et al, 2009;Plesec and Hunt, 2009).…”

Concordance of Predictive Markers for EGFR Inhibitors in Primary Tumors and Metastases in Colorectal Cancer: A Review

“…This might be relevant in patients who have already received chemotherapy, because tumor cells may be sparse in these cases. However, four of the 12 studies using sequencing mentioned that the samples tested in their study had to contain Ն70% tumor cells [28,45,47,54]. All four of them reported discordance in some cases.…”

KRAS, NRAS, PIK3CA Exon 20, and BRAF Genotypes in Synchronous and Metachronous Primary Colorectal Cancers

“…2 Since then, KRAS genotyping has become routine practice in many departments of surgical pathology; often, any available tumor-bearing sample is used for genotyping. This includes samples from the primary tumor, 18,19 particularly when a biopsy is not performed on liver metastases detected by computed tomographic scan. However, evidence is increasing that the KRAS mutational status is heterogeneous and no recommendations are made regarding which tumor should be tested (eg, primary tumor or liver metastasis).…”

“…Thus, testing of any primary tumor sample, as is often routinely performed in surgical pathology departments, may produce misleading results in many patients. 18,19 Likewise, attention must be given to studies in which discrepancies were observed between primary tumors and liver metastases. Although a de novo mutation is one putative explanation, a metachronous secondary CRC is another explanation.…”