Abstract
BackgroundPre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer. However, there are no established biomarkers that can predict the pathological response and clinical outcome to CRT.MethodsImmunohistochemical staining was performed in tissue arrays constructed from core tissue specimens taken before treatment and from operative specimens from 112 patients who received 5-FU based pre-operative CRT and surgery. Expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1 were assessed and correlated with tumor regression grades and disease free survival.ResultsOf the 112 patients (M/F 74/38, median age: 62), 20 (17.9%) patients achieved pathologic complete remission (pCR). In analyzing the associations between marker expressions and tumor regression grades, high p21 expression at the pretreatment biopsy was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). In the multivariate analysis, high p21 expression level at the pre-treatment biopsy was significantly associated with poor DFS (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). High CD166 expression level at the pretreatment biopsy was also associated with poor DFS (p = 0.003; HR 5.61; 95% CI 1.81, 17.35).ConclusionThese show high p21 and CD166 expression at the pretreatment biopsy were associated with tumor regression and poor prognosis in patients treated with 5-FU based CRT. Larger, prospective and functional studies are warranted to determine the role of p21 and CD166 as predictive biomarker of response to CRT.
Highlights
Pre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer
The present study showed that high p21 expression level in the pre-CRT specimen was associated with poor pathologic regression and worse disease free survival (DFS) after CRT
Our study showed that expression levels of potential cancer stem cell markers, especially CD 166, increased after preoperative CRT and high expression of CD166 was significantly associated with poor DFS
Summary
Pre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer. There are no established biomarkers that can predict the pathological response and clinical outcome to CRT. Since the report of CAO/ARO/AIO-94 trial showing an improved local recurrence rate and reduced toxicity with preoperative chemoradiotherapy (CRT), pre-operative CRT has become the standard treatment option for clinical stage T3/4 or node positive rectal cancer [1]. There have been numerous reports on clinical and pathological biomarkers that can predict response to preoperative CRT, suggesting p53, p21, Ki67, bax, bcl-2, thymidylate synthase, etc. As predictive markers of response to preoperative CRT [3,4,5,6,7] Those studies suffer from a relatively small number of patients, their retrospective nature and limited availability of archived samples. There are still no validated biomarkers that can predict the response to CRT yet
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