Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the most common cancer types worldwide [1]
Our study is the first to identify the predictive utility of PTPRD/PTPRT genetic variants in metastatic CRC (mCRC) patients receiving bevacizumab-based chemotherapy
Our results showed that deleterious mutations in PTPRT, but not mutations in other genes frequently mutated in our cohort, such as TP53, KRAS, APC, and SYNE1, were associated with lack of bevacizumab response
Summary
Colorectal cancer (CRC) is one of the most common cancer types worldwide [1]. It accounts for 8.5% of all tumor-related mortality, and it is the fourth most common cause of cancer death [1].Colorectal cancer diagnosed at an early stage is associated with a good prognosis. Colorectal cancer (CRC) is one of the most common cancer types worldwide [1] It accounts for 8.5% of all tumor-related mortality, and it is the fourth most common cause of cancer death [1]. Metastatic CRC (mCRC) patients have a poor prognosis, and mCRC accounts for the high mortality rates associated with CRC. Novel targeted agents combined with chemotherapy or used alone have largely improved therapy outcomes for mCRC patients, and some agents are already established in the clinic. These target agents include the anti-epidermal growth factor receptor (EGFR). There are no established predictive markers for bevacizumab response
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