RNF43 Mutations Warrant Further Validation for Potential to Prioritise Anti-EGFR/BRAF Combinations in Selected Patients with BRAFV600E-Mutated mCRC

Findings from a cohort of patients with metastatic BRAFV600E-mutated metastatic colorectal cancer (mCRC) treated with anti-BRAF/EGFR combination therapy suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumour activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimise the clinical management of these patients. In particular, the data show that patients with microsatellite stable (MSS) BRAFV600E-mutated mCRC harbouring loss-of-function mutations in RNF43 respond favourably to anti-BRAF/EGFR combination therapy, whereas those with functional RNF43 derived limited benefit. The results are published by Elena Elez and Rodrigo A. Toledo of the Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus in Barcelona, Spain and colleagues on 12 September 2022 in the Nature Medicine.

BRAFV600E mutation is found in approximately 10% of patients with mCRC, and its clinical presentation is often associated with a predominance of right-sided proximal tumours, high prevalence (nearly 30%) of microsatellite instability (MSI), refractoriness to standard-of-care therapies and an unfavourable prognosis..Compared to BRAF wild-type, BRAFV600E-mutated tumours also associate with specific molecular features, including a low frequency of APC mutations and a high rate of mutations in the tumour suppressor gene RNF43, a RING E3 ubiquitin ligase involved in suppression of the WNT–β-catenin pathway through promoting the degradation of FZD/WNT receptors.

The investigators sought to explore genetic biomarkers with a predictive value that can contribute to refining the stratification of patients with BRAFV600E-mutated mCRC treated with anti-BRAF/EGFR combination therapy. They applied whole-exome sequencing and/or targeted gene sequencing on baseline tumour and/or plasma cell-free DNA samples from a large cohort of patients with BRAFV600E-mutated mCRC treated with anti-BRAF/EGFR therapy, as well as from a control cohort of patients with BRAFV600E-mutated mCRC who received standard chemotherapies and antiangiogenic agents and not exposed to anti-BRAF, and integrated these data with clinical correlates of response and survival.

In a discovery cohort of patients with BRAFV600E-mutated mCRC treated with anti-BRAF/EGFR therapy, the study team found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with MSS tumours.

Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit with 72.7% versus 30.8% (p = 0.03), as well as longer progression-free survival (PFS, hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.12–0.75; p = 0.01) and overall survival (OS, HR 0.26; 95% CI 0.10–0.71; p = 0.008) in patients with MSS RNF43-mutated versus MSS RNF43 wild-type tumours.

MSI tumours invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. The study team found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS BRAFV600E-mutated mCRC not exposed to anti-BRAF therapies.

The authors commented that their findings identified molecular subtypes based on MSS/MSI status and RNF43 mutations and uncovered the predictive value of RNF43 mutations as a biomarker of clinical outcome, including increased overall response rate, PFS and OS, to anti-BRAF/EGFR combination therapies. Future research should explore incorporating RNF43 mutations in routine testing along with BRAF and MSS/MSI status and evaluate their integration with other transcriptomic, microbiome or microenvironmental indicators for optimising the clinical management of this heterogeneous and complex disease.

The authors acknowledged support from multiple commercial and non-profit institutions.