title: ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA. Electronic address: jajani@mdanderson.org.
authors.forename: J A
authors.initials: JA
authors.lastname: Ajani
authors.affiliation: Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: S
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: T
authors.initials: T
authors.lastname: Taketa
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sudo
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wadhwa
authors.affiliation: Department of Cardiac and Thoracic Surgery, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Hofstetter
authors.affiliation: Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: R
authors.initials: R
authors.lastname: Komaki
authors.affiliation: Department of Pathology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Maru
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Bhutani
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: B
authors.initials: B
authors.lastname: Weston
authors.affiliation: Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: V
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: S
authors.initials: S
authors.lastname: Honjo
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Scott
authors.affiliation: Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Skinner
authors.affiliation: Department of Genetics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, USA.
authors.forename: D
authors.initials: D
authors.lastname: Berry
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000080924:Aldehyde Dehydrogenase 1 Family; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D050697:Retinal Dehydrogenase / Q000032:analysis* / Q000235:genetics
chemical_list: D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: ALDH-1; Chemotherapy resistance; Esophageal carcinoma; Predictive markers; Prognosis; Radiation resistance