Available online 29 September 2022, 100883

ctDNA BRAF can reflect the tumour burden with aggressive clinical characteristics and impact clinical outcomes

Loss-of-function RNF43 mutant tumours respond well to VIC therapy

TGFBR2 and SMAD4 inactivating mutations, and amplification in PTK2, MYC, and GATA6 may be related to resistance

DDR pathway mutations probably contribute to resistance and poor survival outcomes after VIC treatment

This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC).

Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings.

BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitizes tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33% of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma.

Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalized treatment strategies.

BRAFV600E mutation

Colorectal cancer

Liquid biopsy

Drug resistance

© 2022 The Author(s). Published by Elsevier Ltd.