Abstract
Purpose We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). Methods The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. Results Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. Conclusions In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.
Highlights
Cetuximab plus chemotherapy regimens are typically used in the first-line treatment of RAS wild-type metastatic colorectal cancer [1,2,3]
We focused on 230 mutations in 219 universal genes in primary tumors and corresponding liver metastases in whole exome sequencing (WES) data according to cancer evolution model [16]
We reported the construction and validation of a predictive model for the response to cetuximab plus chemotherapy in patients with liver-limited metastatic colorectal cancer (mCRC) in a firstline treatment setting
Summary
Cetuximab plus chemotherapy regimens are typically used in the first-line treatment of RAS wild-type metastatic colorectal cancer (mCRC) [1,2,3]. Our previous trial [4] (NCT01564810) compared first-line chemotherapy plus cetuximab with chemotherapy alone in Chinese patients with initially unresectable liver-limited KRAS exon 2 wild-type mCRC and achieved the primary end point of the conversion rate to the radical resection of liver metastases (LM), whereas the objective response rate (ORR) was finitely improved by exclusion of patients with RAS mutations. To further refine patient selection, other markers, including BRAF mutation [5], PIK3CA mutations, loss of PTEN [6, 7], and amplification of MET and ERBB2 [8, 9], were investigated. Increasing evidences indicated predictive value of primary tumor location, but the underlying biological mechanism was still largely unknown [10]
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