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
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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.
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