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

2^nd-line target therapy outperforms chemotherapy in patients with BRAFV600E-mut mCRC regardless of RNF43 status. 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 (P _interaction =.96), PFS (P _interaction =.13), and OS (P _interaction =.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. [ABSTRACT FROM AUTHOR]