Predictive Impact of RNF43 Mutations in Patients With Proficient Mismatch Repair/Microsatellite Stable BRAFV600E-Mutated Metastatic Colorectal Cancer Treated With Target Therapy or Chemotherapy.

Abstract

PURPOSE:

Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with BRAFV600E-mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in RNF43, encoding a negative regulator of the WNT pathway, were associated with longer progression-free survival (PFS) and overall survival (OS) in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) BRAFV600E-mut mCRC treated with TT. Here, we explored the effect of RNF43 mutations on the efficacy of second-line TT versus standard chemotherapy (CT).

METHODS:

A retrospective cohort of patients with pMMR/MSS BRAFV600E-mut tumors, available RNF43 mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed.

RESULTS:

One hundred thirty-two patients with pMMR/MSS BRAFV600E-mut mCRC were included. RNF43 was found mut in 34 (26%) cases. Among RNF43 mutants, TT was associated with longer PFS (7.7 v 3.0 months; P = .002) and higher overall response rate (ORR; 45% v 0%; P = .009) compared with CT. Conversely, among RNF43 wild-type (wt) patients, only a trend for longer PFS (4.5 v 3.7 months; P = .064) favoring TT, with no differences in ORR (P = .14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 v 10.1 months; P = .022) and a numerically OS advantage (10.6 v 6.6 months; P = .068) were reported for TT both in the RNF43-mut and in the RNF43 wt groups. However, no interaction effect was reported between RNF43 mutational status and treatment in ORR (Pinteraction = .96), PFS (Pinteraction = .13), and OS (Pinteraction = .44).

CONCLUSION:

Patients with pMMR/MSS BRAFV600E-mut mCRC achieve benefit from TT versus CT independently of RNF43 mutational status, although a higher magnitude of benefit from TT is observed in RNF43-mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials.

• Authors: Roberto Moretto, Marco Maria Germani, Javier Ros, Francesca Daniel, Filippo Ghelardi, Guglielmo Vetere, Mirella Giordano, Rodrigo De Almeida Toledo, Francesca Bergamo, Giovanni Randon, Elena Elez, Sara Lonardi, Filippo Pietrantonio, Paola Vignali, Daniele Rossini, Judit Matito, Clara Ugolini, Gabriella Fontanini, Gianluca Masi, Chiara Cremolini
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 7 Pg. e2300255 (Sep 2023) ISSN: 2473-4284 [Electronic] United States
• PMID: 37797285 (Publication Type: Journal Article)

Chemical References

• RNF43 protein, human
• Ubiquitin-Protein Ligases

Topics

• Humans
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Retrospective Studies
• DNA Mismatch Repair (genetics)
• Treatment Outcome
• Colonic Neoplasms (genetics)
• Rectal Neoplasms
• Mutation (genetics)
• Microsatellite Repeats
• Ubiquitin-Protein Ligases (genetics, therapeutic use)