Y. Shimada1, Y. Tajima1, M. Nagahashi1, H. Ichikawa1, M. Nakano1, H. Kameyama1, J. Sakata1, T. Kobayashi1, Y. Takii2, S. Okuda3, K. Takabe4,5, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, , Japan 2Niigata Cancer Center Hospital,Department Of Surgery,Niigata, , Japan 3Niigata University Graduate School Of Medical And Dental Sciences,Division Of Bioinformatics,Niigata, , Japan 4Roswell Park Cancer Institute,Breast Surgery,Buffalo, NY, USA 5University At Buffalo Jacobs School Of Medicine And Biomedical Sciences,Department Of Surgery,Buffalo, NY, USA
Introduction: Recent advances of comprehensive genomic sequencing (CGS) enables to detect not only BRAF V600E mutation but also BRAF non-V600E mutations in a single assay. While it has been proved that BRAF V600E mutation in colorectal cancer shows poor prognosis and poor response to anti-EGFR therapy, clinical significance of BRAF non-V600E mutation has not been fully investigated. The present work aimed to describe clinicopathological characteristics and clinical outcome of BRAF non-V600E mutant type compared with BRAF wild-type and BRAF V600E mutant-type.
Methods: One-hundred-eleven Stage IV CRC patients were analyzed. We investigated genetic alterations using 415-gene panel, which includes BRAF V600E and non-V600E mutations. The differences of clinicopathological characteristics and genetic alterations were analyzed among BRAF wild-type, BRAF V600E mutant-type, and BRAF non-V600E mutant-type using Fisher’s exact test. Overall survival (OS) and Progression-free survival (PFS) in response to targeted therapies were analyzed among the 3 groups using log-rank test.
Results: CGS revealed that 98 patients (88%), 7 patients (6%), and 6 patients (6%) were BRAF wild-type, BRAF V600E mutant-type, and BRAF non-V600E mutant-type, respectively. The variants of BRAF non-V600E in each 6 patients were as follows: G469A, G469A and V502I, D594G, I326V, N581Y, D594G. BRAF V600E mutant-type were more frequently right-sided, histopathological grade 3, mucinous type, and with multiple peritoneal metastases distant from primary lesion. BRAF non-V600E mutant-type were more frequently left-sided, non-mucinous type, and with bilateral multiple lung metastases. While BRAF V600E mutant-type showed significantly worse OS than BRAF wild-type and non-V600E mutant-type (P < 0.001 and P = 0.038, respectively), BRAF non-V600E mutant-type showed no significant difference compared with BRAF wild-type. Two of 6 patients with BRAF non-V600E mutation underwent R0 resection and showed no evidence of disease at final follow-up. In 47 patients with anti-EGFR therapy, while BRAF V600E mutant-type showed significantly worse PFS than BRAF wild-type (P = 0.013), BRAF non-V600E mutant-type showed no significant difference compared with BRAF wild-type. In 73 patients with anti-VEGF therapy, there was no significant difference on PFS among the 3 groups.
Conclusion: BRAF non-V600E mutant-type demonstrates different clinicopathological characteristics and clinical outcome from BRAF V600E mutant-type. Further preclinical and clinical investigations are needed to clarify the role of BRAF non-V600E mutation in colorectal cancer.
