The prognostic role of HIF-1 alpha and NF-kappa B expression in RAS wild-type metastatic colorectal cancer: A Turkish Oncology Group (TOG) study

Background Not all RAS wild-type metastatic colorectal cancer (mCRC) patients experience the same benefit from anti-epidermal growth factor receptor (EGFR) treatments. Studies have shown that nuclear factor-kappa B (NF-kappa B), hypoxia-inducible factor-1 alpha (HIF-1 alpha), interleukin 8 (IL-8) and transforming growth factor beta (TGF-beta) may be therapeutic targets for mCRC. The aim of this study was to clarify the prognostic value of NF-kappa B, HIF-1 alpha, IL-8, and TGF-beta expression in patients with left-sided mCRC receiving EGFR inhibitors. Methods Patients with RAS wild-type, left-sided mCRC treated with anti-EGFR on the first line between September 2013 and April 2022 were included. Immunohistochemical staining for NF-kappa B, HIF-1 alpha, IL-8 and TGF-beta was performed from tumor tissues of 88 patients. Patients were divided into NF-kappa B, HIF-1 alpha, IL-8 and TGF-beta expression positive and negative group, moreover, expression positive group were also divided into two group as expression intensity low and high group. The median follow-up was 25.2 months. Results Median progression-free survival (PFS) was 8.1 (6-10.2) months in the cetuximab group, 11.3 (8.5-14) months in the panitumumab group (p = 0.09). Median overall survival (OS) was 23.9 (4.3-43.4) months in the cetuximab group, 26.9 (15.9-31.9) months in the panitumumab group (p = 0.8). Cytoplasmic NF-kappa B expression was present in all patients. The mOS was 19.8 (11-28.6) months in NF-kappa B expression intensity low group and 36.5 (20.1-52.8) months in high group (p = 0.03). The mOS of the HIF-1 alpha expression negative group was significantly longer compared with expression positive group (p = 0.014). There was no significant difference in IL-8 and TGF-beta expression status on mOS and mPFS (for all, p > 0.05). Positive expression of HIF-1 alpha was poor prognostic for mOS in the univariate analysis (HR:2.7, 95% CI 1.18-6.52, p = 0.02) and in multivariate analysis (HR 3.69, 95% CI 1.41-9.6, p = 0.008). High cytoplasmic expression intensity of NF-kappa B was found to have a good prognostic value for mOS (HR 0.47, 95% CI 0.26-0.85, p = 0.01). Conclusion High cytoplasmic expression intensity of NF-kappa B and negative expression of HIF-1 alpha could be a good prognostic marker for mOS in RAS wild-type left-sided mCRC.