Clinical Practice Points
Non-V600 B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) mutated metastatic colorectal cancer (mCRC) has a better prognosis than V600 BRAF mCRC Non-V600 mutations can be further subdivided into class II or III variants; class III variants might respond to anti-epidermal growth factor receptor (EGFR) therapy.
We describe an mCRC patient with a G466V (class III) BRAF variant found in the primary tumor before anti-EGFR therapy, but not in a liver metastasis after anti-EGFR exposure. A reduction in the BRAF variant between pre- and post-treatment plasma samples was discordant with a concomitant increase in circulating tumor DNA (ctDNA) levels of comutations and radiologic progression in metastatic lesions.
There was copy number neutral loss of heterozygosity (CN-LOH) at the BRAF coding region in the liver biopsy. The CN-LOH might have resulted in loss of the class III BRAF variant that chronologically corresponded with a decrease of this variant in ctDNA.
In a retrospective cohort from 2 institutions, we show that the relative variant allele frequency (rVAF) of non-V600 BRAF mutations (0.74) is lower than for rVAF of V600 (class I) BRAF mutations (1.00; P < .0001). Among non-V600 mutations, class III (P < .0001) but not class II mutations (P = .10) had statistically lower allele frequencies than V600 mutations.
Discordant responses between ctDNA levels of comutations can occur because of tumor heterogeneity and evolutionary pressures.
The CN-LOH described might be a novel mechanism of resistance to anti-EGFR therapy because wild type BRAF is less RAS signaling-dependent than class III variants. Non-V600 BRAF occurs at a lower rVAF than V600 BRAF mutations and may undergo clonal selection.