BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset?

Abstract

Background

B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary.

Objectives

To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS.

Results

Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively.

Conclusion

LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

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Correspondence to Vanessa Wong.

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Conflict of interest

Vanessa Wong’s research institution, Walter and Eliza Hall Institute of Medical Research, is the recipient of research grant funding from Pierre-Fabre, Amgen, Novartis, Roche, and Merck, for unrelated projects. Peter Gibbs has received research grants from Pierre-Fabre, honoraria from Roche, and consulting fees and lecture payments from MSD, Merck and Amgen. Jayesh Desai has received research grants from Roche/Genentech, Lilly, AstraZeneca, BeiGene, Novartis, Bristol Myers Squibb, and GlaxoSmithKline and consulting fees from Amgen, Pierre-Fabre, and BeiGene. Adnan Khattak, Brigette Ma, Jeanne Tie, Jeremy Shapiro, Louise Nott, Margaret Lee, Matthew Burge, Rachel Wong, Simone Steel, and Wei Hong have no conflicts of interest that might be relevant to the contents of this manuscript.

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Wong, V., Lee, M., Wong, R. et al. BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset?. Targ Oncol 16, 227–236 (2021). https://doi.org/10.1007/s11523-021-00793-7

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