Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients.

Background: Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. Methods: Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. Results: Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGFβ pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83–5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47–7.54; p = 0.0038). Conclusion: Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.

Aim/Background: Although patients with metastatic colorectal cancer (mCRC) bearing KRAS-exon2-wild-type could benefit from cetuximab treatment, ∼ 45% of these patients were refractory to such a therapy. This study aims to identify additional genetic markers that can enhance the prediction of the cetuximab treatment response.Methods: 53 mCRC patients with wild-type KRAS exon2 were treated with cetuximab/ irinotecan-based chemotherapy in first-line or third-line setting. Formalin-fixed paraffin-embedded samples obtained from primary tumor of all subjects were analyzed for the mutational status of 10 genes in the EGFR pathway using next-generation sequencing technology. Results: We detected KRAS (exon 3 and 4) mutations in 5 patients, NRAS mutations in 4 patients, and BRAF mutations in 6 patients. Except for 1 patient with an NRAS mutation who was a responder, all other patients harboring KRAS, NRAS, or BRAF mutations are non-responders, indicating the predictive role of these genetic mutations for poor cetuximab responsivness. The Kaplan-Mirer analysis revealed that patients with KRAS or BRAF mutations have a significantly shorter progress-free survival. Conclusions: Our results suggest that genetic testing for KRAS in combination with NRAS and BRAF provides a stronger predictive power and should be implemented to improve the response rate of cetuximab for mCRC patients. Disclosure: All authors have declared no conflicts of interest.

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