Predicting the pathologic response of locally advanced rectal cancer to neoadjuvant concurrent chemoradiation using enzyme-linked immunosorbent assays (ELISAs) for biomarkers

Abstract

Purpose: To investigate the role of biomarkers including serum tissue inhibitor of metalloproteinases-1 (TIMP-1), urokinase plasminogen activator receptor, vascular endothelial growth factor, and epidermal growth factor receptor in predicting pathologic response to neoadjuvant chemoradiation (NACRT) for rectal cancer.

Methods: Between 2007 and 2009, 50 clinical TNM stage II or III patients were analyzed in this prospective study. Pre- and post-NACRT serum levels of biomarkers were assessed using ELISAs. The primary and secondary endpoints were pathologic complete response (pCR) and Mandard regression grade (MRG).

Results: The pCR was reported in 5 patients (10.0%). According to the MRG, fifteen patients (30.0%) were divided into group A (Grade I-II), the others in group B (Grade III-V). On univariate analysis, post-NACRT TIMP-1 showed notable significance with pCR (P = 0.092) and significant correlation with MRG group A (P = 0.003). Post-NACRT TIMP-1 ≤ 204.5 ng/mL as cut-off value by ROC curve was associated with more pCR and MRG group A patients (P = 0.016 and 0.002). Interval between NACRT and surgery was related to pCR with approached trend levels of significance (P = 0.05) and to MRG group A significantly on univariate analysis of clinical factors (P = 0.031). On multivariate analysis, post-NACRT TIMP-1 was not significantly related to pCR (P = 0.187), while it was significantly associated with MRG (P = 0.009). Among clinical responders, post-NACRT TIMP-1 level ≤ 204.5 ng/mL was significantly associated with pCR (P = 0.021) and MRG group A (P = 0.003).

Conclusions: Post-NACRT serum TIMP-1 could be used as a predictive marker of pathologic response to NACRT in rectal cancer, even in patients with clinical response.

Fig. 1

Overall survival (OS) and disease-free survival rates (DFS) according to pathologic complete response (pCR) or Mandard regression grade group (MRG). a OS according to pCR. The 5-year OS of pCR group was higher than non-pCR with no statistical significance (100 vs. 72.1 %, P = 0.204). b DFS according to pCR. The 5-year DFS of pCR group was higher than non-pCR with borderline statistical significant trend (100 vs. 54.7 %, P = 0.084). c OS according to MRG. The 5-year OS of MRG group A was significantly higher than group B (100 vs. 64.6 %, P = 0.014). d DFS according to MRG. The 5-year DFS of MRG group A was significantly higher than group B (86.2 vs. 47.7 %, P = 0.016)

Fig. 2

Survival analysis according to cut-off value of post-NACRT TIMP-1 level. a Kaplan–Meier curve of overall survival analysis depicted that there was no significant difference between two groups with post-NACRT TIMP-1 level ≤204.5 ng/mL and >204.5 ng/mL (P = 0.721). b Kaplan–Meier curve of disease-free survival rates (DFS) showed that there was also no statistically significant difference between two groups although groups having post-NACRT TIMP-1 level ≤204.5 ng/mL showed a better DFS than groups having post-NACRT TIMP-1 level >204.5 ng/mL (P = 0.159)