Impact of WNT/B-catenin alterations and metastasis location among patients with metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI) combinations.

person Javier Ros Montañá Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain info_outline Javier Ros Montañá, Iosune Baraibar, Victor Navarro Garces, Nadia Saoudi Gonzalez, Sharela Vega, Sergio Bueno, Ariadna Garcia, Francesc Salva, Raquel Comas, Marta Rodríguez Castells, Omar Saavedra, Guzman Alonso, Elena Garralda, Josep Tabernero, Ana Vivancos, Elena Elez

Authors person Javier Ros Montañá Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain info_outline Javier Ros Montañá, Iosune Baraibar, Victor Navarro Garces, Nadia Saoudi Gonzalez, Sharela Vega, Sergio Bueno, Ariadna Garcia, Francesc Salva, Raquel Comas, Marta Rodríguez Castells, Omar Saavedra, Guzman Alonso, Elena Garralda, Josep Tabernero, Ana Vivancos, Elena Elez Organizations Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron University Hospital, Barcelona, Spain, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d’Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain, Corporacion Sanitaria Parc Tauli, Sabadell, Spain, Next Oncology, Barcelona, Spain, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain Abstract Disclosures Research Funding Other This research has been partially funded by CaixaResearch Advanced Oncology Research Program supported by Fundació La Caixa (LCF/PR/CE07/50610001) Background: Emerging evidence suggests that WNT mutations and liver/peritoneal metastases in mCRC may have an immunosuppressive role that could affect ICI activity. Aim: To evaluate the impact of WNT alterations and liver/peritoneal metastasis among patients with mCRC treated with ICi. Methods: Patients from Vall d’Hebron Hospital, with mCRC treated with ICI from 2017-2022 were included. WNT alterations (APC, AXIN1/2, CTNNB1, FBXW7, EPHB2, RNF43 and SOX9) were evaluated using NGS (tissue). Clinical outcomes were calculated using survival Kaplan-Meier curves. Patients' characteristics were collected retrospectively. Results: Overall, 104 patients were included (66 MSI patients and 38 MSS patients). Among MSI patients, median age was 63 years (22-95), with 53% female, and 64% of patients received immunotherapy in 1st or 2nd line. Regarding tumor characteristics, 72% were right-sided and 82% harbored WNT alterations. 75% of patients presented with liver/peritoneal metastases. Patients with WNT mutations and peritoneal/liver metastases exhibit lower ORR (46% vs 57% p 0.5 and 45% vs 75%, p 0.03 respectively). Peritoneal/liver metastases were associated with lower PFS (HR 3.6 CI95% 1.27-10.24 p 0.02 respectively). Overall, tumors with WNT pathway alterations tend to have shorter PFS and OS. Liver metastases were associated with lower OS (NR vs 34 months HR 2.49 CI95% 1.01-6.17 p 0.05). Table summarizes outcomes. Among MSS patients, median age was 57 years (41-75), with 25% female and 92% of patients receiving immunotherapy > = 3rd line. Regarding tumor characteristics, 78% were left-sided and 90% harboured WNT alterations. 79%, of patients presented with liver or peritoneal metastases. WNT mutations were not associated with ORR, patients without liver/peritoneal metastases tend to have higher ORR (12.5% vs 3.3% p 0.335). Patients with WNT alterations had worse PFS (9.23 vs 1.87 months, p 0.12), and liver metastases were associated with lower PFS (6.98 vs 1.79 months HR 2.87 CI95% 1.17-7.09 p:0.02). Regarding OS, tumors harboring WNT alterations have shorter OS (8.4 vs 12 months p 0.63). The presence of liver or peritoneal metastases was associated with lower OS (NR vs 7.85 months HR 3.69 CI95% 1.09-12.55 p: 0.04). Conclusions: In our cohort, WNT pathway mutations, and liver metastases were associated with worse ORR, PFS, and OS regardless of MSI status. These findings need further validation in a prospective cohort. MSS n:38 MSI n:66 Liver (Y/N) Peritoneal (Y/N) Liver or Peritoneal (Y/N) WNT mutation (Y/N) Liver (Y/N) Peritoneal (Y/N) Liver or Peritoneal (Y/N) WNT mutation (Y/N) ORR (%) 3.3 vs 12.5 12.5 vs 3.3 3 vs 12.5 3.7 vs 0 47 vs 57 44 vs 65 45 vs 75 46 vs 57 PFS (months) 1.79 vs 6.9 2 vs 1.86 1.79 vs 6.9 1.87 vs 9.23 7.26 vs 16 6.5 vs NR 7.75 vs NR 10.25 vs NR OS (months) 7.8 vs NR 9.13 vs 8.28 7.8 vs NR 8.44 vs 12 34 vs NR 45 vs NR 45 vs NR 39 vs NR