Abstract
BackgroundCetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients’ response in order to maximize the benefit.MethodsIn this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed.ResultsPatients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients.ConclusionsOur results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.
Highlights
Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer patients with only ~ 20% response rate
Current treatment of unresectable metastatic Colorectal cancer (CRC) in advanced stage mainly relies on fluoropyrimidine-based chemotherapies alone or in combination with Bevacizumab according to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) in Colon Cancer [6, 7]
Prognostic biomarkers for cetuximab treatment is limited to the activating mutations of KRAS and NRAS, which have been approved for poor response to cetuximab [11,12,13]
Summary
An anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients’ response in order to maximize the benefit. Prognostic biomarkers for cetuximab treatment is limited to the activating mutations of KRAS and NRAS, which have been approved for poor response to cetuximab [11,12,13]. All the aforementioned biomarkers could not adequately explain the poor response rate, and limits patients to get maximal benefit from cetuximabbased therapy
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