Predictive impact of RNF43 mutation (mut) in patients (pts) with pMMR/MSS BRAF V600E mutated metastatic colorectal cancer (mCRC) treated with target therapy (TT) or chemotherapy (CT).
Authors: Germani Marco Maria , Moretto Roberto , Ros Montañá Javier , Intini Rossana , Ghelardi Filippo , Vetere Guglielmo , Toledo Rodrigo De Almeida , Bergamo Francesca , Randon Giovanni , Elez Elena , Lonardi Sara , Oldani Simone , Giordano Mirella , Rossini Daniele , Ferrari Bravo Walter , Ricagno Gianmarco , Vignali Paola , Ugolini Clara , Fontanini Gabriella , Cremolini Chiara 
Published: June 2023

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Background: Encorafenib plus cetuximab is a standard option in the treatment of BRAF V600E mut mCRC pts pre-treated with at least one systemic therapy. RNF43 is a negative regulator of WNT pathway. A recent study showed that RNF43 mutation is associated with better outcome among pMMR/MSS BRAF V600E mut mCRC patients treated with TT but not in an independent cohort of pts not treated with TT (Elez et al. Nat Med 2022). However, no comparison is available between TT vs CT as second-line (2L) treatment for pMMR/MSS BRAF V600E mut mCRC according to RNF43 mutational status. Methods: The predictive impact of RNF43 mut was evaluated in a real-life dataset of 126 pMMR/MSS BRAF V600E mut mCRC pts treated with TT (consisting of BRAF inhibitor + anti-EGFR antibody ± MEK inhibitor) vs CT ± target agent as 2L treatment. A cohort of 36 pts receiving TT after 2L was also analyzed. Results: Thirty-one (25%) and 95 (75%) out of 126 pMMR/MSS BRAF V600E mut tumours were RNF43 mut and RNF43 wt, respectively. In the RNF43 mut group 14 (45%) received CT and 17 (55%) TT; in the RNF43 wt group, 56 (59%) and 39 (42%) received CT and TT, respectively. Among RNF43 mut pts, those treated with TT reported longer PFS (7.1 vs 3.0 months, HR: 0.35 95%CI: 0.16-0.76, p = 0.006) and higher ORR (42% vs 0%, p = 0.009) than those receiving CT. On the other hand, no significant difference was observed among RNF43 wt patients in terms of PFS (4.3 vs 3.7 months, HR: 0.69 95% CI: 0.45-1.05, p = 0.080) and ORR (28% vs 16%, p = 0.24). However, no significant interaction between treatment effect and RNF43 mutational status was reported in terms of PFS (pinteraction= 0.17) and ORR (pinteraction= 0.96). After excluding 36 pts in the CT group that received TT after 2L, no interaction effect was observed also in terms of OS (pinteraction= 0.53). However, among RNF43 mut pts, those treated with TT reported longer OS (16.5 vs 10.1 months; HR: 0.34 95% CI: 0.11-1.00, p = 0.049), while no significant difference was observed among RNF43 wt pts (10.6 vs 6.6 months; HR: 0.66 95% CI: 0.39-1.11; p = 0.12). In the group receiving TT after 2L, 9 (25%) out of 36 cases were RNF43 mut and achieved higher ORR (78% vs 26%, p = 0.014) and longer PFS (10.1 vs 4 months; HR: 0.35 95%CI: 0.14-0.88; p = 0.020) and OS (11.7 vs 7 months; HR: 0.35 95%CI: 0.15-0.82; p = 0.012) than RNF43 wt (N = 27). Conclusions: pMMR/MSS BRAF V600E mut mCRC patients achieve benefit from TT vs CT independently of RNF43 mutational status, but a higher magnitude of benefit from TT is observed among those with RNF43 mut tumors. These findings deserve confirmation in past and current randomized trials (i.e. BEACON and BREAKWATER).