Autophagy-related proteins Beclin-1 and LC3 predict cetuximab efficacy in advanced colorectal cancer

Abstract

Aim: To investigate the utility of Beclin-1 and LC3, two autophagy-related proteins, in predicting the cetuximab efficacy in advanced colorectal cancer (ACRC).

Methods: The data of 85 patients with ACRC treated at the Sun Yat-sen University Cancer Center from March 1, 2005 to December 31, 2008 were studied, including 45 cases treated with cetuximab-containing chemotherapy and 40 cases treated with non-cetuximab-containing chemotherapy. Beclin-1 and LC3 expression was evaluated by immunohistochemistry, and KRAS status was evaluated by polymerase chain reaction.

Results: Beclin-1 and LC3 expression in ACRC was significantly correlated (r = 0.44, P < 0.01); however, LC3 was more highly expressed in cancerous tissues than in normal tissues (Z = -2.63, P < 0.01). In the cetuximab-containing chemotherapy group, patients with low LC3 expression had higher objective response rates (ORRs) than those with high LC3 expression (52.9% vs 17.9%, P = 0.01), and patients with low Beclin-1 expression had a longer median progression-free survival (PFS) than their counterparts with higher Beclin-1 expression (9.0 mo vs 3.0 mo, P = 0.01). However, neither of these predictive relationships was detected in the group treated with non-cetuximab-containing chemotherapy. Patients with wild-type KRAS had higher ORRs (42.3% vs 9.1%, P = 0.049) and disease control rates (DCRs) (73.1% vs 36.4%, P = 0.035), and longer median PFS (5.5 mo vs 2.5 mo, P = 0.02) than those with mutant KRAS in the cetuximab-containing chemotherapy group. Neither Beclin-1 (P = 0.52) nor LC3 (P = 0.32) expression was significantly correlated with KRAS status.

Conclusion: Patients with low Beclin-1 expression had a longer PFS than those with high Beclin-1 expression, and patients with low LC3 expression had a higher ORR in ACRC patients treated with cetuximab-containing chemotherapy.

Keywords: Beclin-1; Cetuximab; Colorectal neoplasms; Drug therapy; LC3.

Figure 1

Immunohistochemical photomicrographs of Beclin-1 and LC-3 in colorectal cancer tissues and colorectal normal tissues (200 ×). A, B: Beclin-1 displayed strongest cytoplasm staining in colorectal cancer (CRC) tissues and weak positive staining in normal tissues: C, D: LC3 displayed intense granular staining of the cytoplasm in CRC tissues but absent in normal tissues.

Figure 2

Progression-free survival of advanced colorectal cancer patients with low and high Beclin-1 expression in cetuximab-containing chemotherapy group. The median PFS of the patients with low and high Beclin-1 expression (a low expression defined as immuhistochemistry score < 6.0 and a high expression defined as immuhistochemistry score ≥ 6.0.) was 9.0 mo and 3.0 mo respectively (P = 0.01). PFS: Progression-free survival.

Figure 3

Progression-free survival of advanced colorectal cancer patients with KRAS wild type and patients with KRAS mutation treated by cetuximab-containing chemotherapy. Thirty-seven of 45 patients were successfully tested KRAS gene in cetuximab-containing chemotherapy group, the median PFS of patients with KRAS wild type was significantly higher than that of patients with KRAS mutation ( 5.0 mo and 2.5 mo, respectively, P = 0.02). PFS: Progression-free survival.