3435 - Impact of the NRF-2/KEAP-1 Signaling Pathway on Treatment Response in Rectal Cancer Patients Treated with Neoadjuvant Chemo-Radiotherapy

Purpose/Objective(s): Resistance to radiation therapy is an important problem in the management of cancer. Nuclear factor-erythroid 2 related factor 2 (NRF-2)/Kelch-like ECH-associated protein 1 (KEAP-1) signaling pathway plays a role in the expression of genes involved in antioxidant, anti-inflammatory, and detoxification processes. Activation of the pathway results in NRF-2 overexpression which is responsible for radiation resistance in tumor cells by inhibiting cytotoxic effect of radiation. Aim of the study is to evaluate the impact of chemoradiation (CRT) on NRF-2/KEAP-1 signaling pathway and predictive value of pre-treatment NRF-2/KEAP-1 signaling for treatment response in rectal cancer patients.

Materials/Methods: A total of 34 rectal cancer patients treated with neoadjuvant CRT were included. The female/male ratio was 5/29. The clinical T stage was T2 in 2 patients, T3 in 29, and T4 in 3. Thirty-two patients had cN (+) disease. Thirty patients received chemotherapy (C) following CRT, 4 patients were treated with CRT only, due to the toxicities of C. Radiotherapy doses were 50.4-56 Gy for the primary tumor and 50.4 Gy for the regional lymph nodes, in 28 fractions concurrent with daily Capecitabine. FOLFOX/CAPEOX regimens were applied for 4-6 cycles. Clinical (n=8) or pathological (n=5) complete responses were classified as complete response (CR), and the other response groups as non-complete response (nCR) (n=21). Blood samples obtained before CRT and a day after completion of CRT were centrifuged at 4°C with 4000 rpm for 10 minutes and serum samples were collected. Serum NRF-2 and KEAP-1 levels were measured using the ELISA method. Mann-Whitney U test, Wilcoxon Signed Rank Test, and ROC analysis were used for statistical analyses.

Results: Median age was 57 (41-81). Post-CRT NRF-2 (p= 0.006) and KEAP-1 (p< 0.001) levels were significantly increased compared to pre-CRT levels. Mean (± SD) pre-and post-CRT NRF-2 levels were 0.158 (± 0.076) and 0.262 (± 0.326) ng/mL, and pre-and post-CRT KEAP-1 levels were 0.270 (± 0.284) and 0.295 (± 0.255) ng/mL, respectively. Pre-CRT NRF-2 and KEAP-1 levels were compared between patients with CR and nCR. Pre-CRT NRF2 levels were significantly lower in patients with CR compared to nCR (p=0.042). Pre-CRT KEAP-1 levels were not significantly different between the response groups (p> 0.05) (Table). The cut-off value for serum NRF2 was 0.135 ng/mL (AUC=0.709, p=0.043, 95% CI (0.513-0.905), sensitivity: 77%, specificity: 57%).

Conclusion: Chemoradiation induces the activation of NRF-2/KEAP-1 signaling pathway. Pre-CRT levels of NRF-2 may be used to predict the response to neoadjuvant treatment, patients with higher pre-CRT NRF-2 levels are more resistant to treatment with lower CR rates.