Impact of LKB1 status on radiation outcome in patients with stage III non-small-cell lung cancer

Abstract

Preclinical studies suggest that loss of LKB1 expression renders cancer cells less responsive to radiation partly through NRF2-mediated upregulation of antioxidant enzymes protecting against radiation-induced DNA damage. Here we investigated the association of an alteration in this pathway with radio-resistance in lung cancer patients. Patients with locally advanced non-small cell lung cancer (LA-NSCLC) who were treated with chemoradiotherapy (CRT) and analyzed for LKB1 expression using semiquantitative immunohistochemistry. Clinical characteristics and expression of LKB1 were analyzed for association with radiotherapy outcomes. We analyzed 74 available tumor specimens from 178 patients. After a median follow-up of 40.7 months, 2-year cumulative incidence of locoregional recurrence (LRR) in patients who had LKB1^Low expression was significantly higher than those with LKB1^High expression (68.8% vs. 31.3%, P = 0.0001). LKB1^Low expression was found significantly associated with a higher incidence of distant metastases (DM) (P = 0.0008), shorter disease-free survival (DFS) (P = 0.006), and worse overall survival (OS) (P = 0.02) compared to LKB1^High expression. Moreover, patients with LKB1^Low expression showed a significantly higher 2-year cumulative incidence of LRR (77.6% vs. 21%; P = 0.02), higher DM recurrence (P = 0.002), and shorter OS (P < 0.0001) compared with the EGFR-mutant group. For all patients with LKB1^Low who had LRR, these recurrences occurred within the field of radiation, in contrast to those with LKB1^High expression having both in-field, marginal, and out-of-field failures. LKB1 expression may serve as a potential biomarker for poor outcomes after receiving radiation in LA-NSCLC patients. Further studies to confirm the association and application are warranted.

Keywords: Liver kinase B1; Locoregional recurrence; Non-small cell lung cancer; Nuclear factor erythroid 2-like 2; Radiotherapy.

Figure 1

LKB1 expression status correlates with radiation outcome. (A) Cumulative incidence locoregional recurrence (LRR). Patients with low LKB1 expression had a significantly higher cumulative incidence of LRR than high LKB1 expression (P = 0.0001). (B) Cumulative incidence of distant metastatic (DM) recurrence. LKB1^Low patients was also associated with higher DM recurrence than in LKB1^High patients (P = 0.0008). (C) Disease-free survival (DFS). DFS was significantly worse in LKB1^Low patients than in LKB1^High patients (P = 0.006) and (D) Overall survival (OS). OS was significantly worse in LKB1^Low patients than in LKB1^High patients (P = 0.02).

Figure 2

Cumulative incidence of LRR and DM recurrence according to LKB1 expression status and histologic subtype. (A) In non-squamous cell carcinoma subtype, LKB1^Low patients had a significantly higher cumulative incidence of LRR than in LKB1^High patients (P = 0.0001); however (B), there were not detected among squamous cell carcinoma subtype. (C) The cumulative incidence of DM recurrence in non-squamous cell carcinoma subtype, LKB1^Low patients had a significantly higher cumulative incidence of LRR than in LKB1^High patients (P < 0.0001); however (D), there were not detected among squamous cell carcinoma subtype.

Figure 3

Pattern of locoregional disease according to LKB1 expression status. All LKB1^Low patients had in-field failures with 10 type A and 2 type B failures. LKB1^High patients, distribution of failure type included 7 in-field (six type A and one for both type A and B), 4 marginal and 2 out-of-field (P = 0.03).