ALDH‐1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients. Issue 1 (28th October 2013)

• Record Type: Journal Article
• Authors: Ajani, J.A.; Wang, X.; Song, S.; Suzuki, A.; Taketa, T.; Sudo, K.; Wadhwa, R.; Hofstetter, W.L.; Komaki, R.; Maru, D.M.; Lee, J.H.; Bhutani, M.S.; Weston, B.; Baladandayuthapani, V.; Yao, Y.; Honjo, S.; Scott, A.W.; Skinner, H.D.; Johnson, R.L.; Berry, D.
• Is Part Of: Molecular oncology. Volume 8:Issue 1(2014:Jan.)
• Page Start: 142
• Page End: 149
• Publication Date: 2013-10-28
• Subjects: Esophageal carcinoma -- Chemotherapy resistance -- Radiation resistance -- ALDH‐1 -- Predictive markers -- Prognosis; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2013.10.007
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Purpose: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase‐1 (ALDH‐1) could be associated with response. Methods: The labeling indices (LIs) of ALDH‐1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3‐fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non‐clinical experiments in EC cells were performed to generate complimentary data. Results: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH‐1 LI was 0.2 (range, 0.01–0.85). There was a significant association between pathCR and low ALDH‐1 LI (p ≤ 0.001; odds‐ratio [OR] = 0.432). The 3‐fold cross validation led to a concordance index (C‐index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH‐1 LI (p ≤ 0.001; OR = 3.782). The 3‐fold cross validation led to the C‐index of 0.960 for the fitted model. In several cell lines, higher ALDH‐1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH‐1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH‐1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH‐1− cells. Conclusions: Our clinical and non‐clinical data demonstrate that ALDH‐1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients. Highlights: ALDH‐1, a stem cell biomarker, was examined in 167 untreated adenocarcinoma of the esophagus. ALDH‐1 expression levels correlated with resistance or response to chemoradiation Non‐clinical experiments correlated with clinical observations. First demonstration of ALDH‐1 as a predictive biomarker.