TORONTO, 18 Oct, 2022 – Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Mutations in the BRAF oncogene of the MAPK pathway are present in 8-10% of cases. Metastatic CRC (mCRC) patients with BRAFV600E mutation carry a unique disease phenotype and aggressive clinical characteristics, including high tumor grade, peritoneal involvement, and therapy resistance. At present, BRAF and EGFR co-inhibition is recommended in the second-line setting. This targeted approach help patients achieve some survival benefits, but most patients inevitably develop disease progression. The mechanisms behind treatment failure to BRAF/EGFR-targeted combination therapy remain poorly understood, presenting barriers to identifying responders and improving clinical benefit.

A recent prospective study published in the Drug Resistance Updates, led by Sun Yat-sen University Cancer Center and Geneseeq Technology Inc. demonstrated that the analysis of ctDNA points to drug resistance mechanisms to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalized treatment strategies.

This study included 41 BRAFV600E mCRC patients enrolled in Sun Yat-sen University Cancer Center from July 2018 to June 2020. Tumor tissues and treatment-naïve plasma samples were collected before treatment. Serial blood samples were collected at the end of every four cycles of VIC treatment until disease progression to dissect the resistance mechanisms and to estimate the prognostic potentials. Tissue and plasma samples were profiled using whole-exome sequencing and the 425-gene Geneseeqprime panel sequencing, respectively.

The study shows that baseline ctDNA BRAFV600E level was related to a poor prognosis. On the other hand, if ctDNA BRAF is undetected at the first scan, patients showed prominent PFS improvement and dynamic ctDNA BRAFV600E level changes during/after treatment demonstrated a significant correlation with VIC-related response. Conclusively, NGS-based ctDNA profiling helps detect potential molecular alterations correlated with VIC response and resistance. RNF43 mutations were predominant in pre-treatment plasma samples of patients with long-term clinical benefits, with a response rate as high as 80% and significantly longer PFS after VIC treatment. In those tumors harbouring RNF43 mutations, researchers also observed two tumors achieved clinical responses to immunotherapy. Also, the study shows that acquired gene alterations in DNA damage repair pathways occur in 33% of patients post-VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumor mutation burden both at baseline and progression plasma compared to those without. The researchers identified several additional novel resistance mechanisms to VIC therapy such as TGFBR2 and SMAD4 loss-of-function mutations, and copy-number gains in PTK2, MYC, and GATA6.

These findings highlight the potential of ctDNA surveillance in disease monitor and personalized treatment management in mCRC.