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

Abstract

Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with <i>BRAFV600E</i>-mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in <i>RNF43</i>, 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) <i>BRAFV600E</i>-mut mCRC treated with TT. Here, we explored the effect of <i>RNF43</i> mutations on the efficacy of second-line TT versus standard chemotherapy (CT). A retrospective cohort of patients with pMMR/MSS <i>BRAFV600E</i>-mut tumors, available <i>RNF43</i> mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed. One hundred thirty-two patients with pMMR/MSS <i>BRAFV600E</i>-mut mCRC were included. <i>RNF43</i> was found mut in 34 (26%) cases. Among <i>RNF43</i> mutants, TT was associated with longer PFS (7.7 <i>v</i> 3.0 months; <i>P</i> = .002) and higher overall response rate (ORR; 45% <i>v</i> 0%; <i>P</i> = .009) compared with CT. Conversely, among <i>RNF43</i> wild-type (wt) patients, only a trend for longer PFS (4.5 <i>v</i> 3.7 months; <i>P</i> = .064) favoring TT, with no differences in ORR (<i>P</i> = .14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 <i>v</i> 10.1 months; <i>P</i> = .022) and a numerically OS advantage (10.6 <i>v</i> 6.6 months; <i>P</i> = .068) were reported for TT both in the <i>RNF43</i>-mut and in the <i>RNF43</i> wt groups. However, no interaction effect was reported between <i>RNF43</i> mutational status and treatment in ORR (<i>P</i>_interaction = .96), PFS (<i>P</i>_interaction = .13), and OS (<i>P</i>_interaction = .44). Patients with pMMR/MSS <i>BRAFV600E</i>-mut mCRC achieve benefit from TT versus CT independently of <i>RNF43</i> mutational status, although a higher magnitude of benefit from TT is observed in <i>RNF43</i>-mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials.