title: High serum levels of vascular endothelial growth factor-A and transforming growth factor-β1 before neoadjuvant chemoradiotherapy predict poor outcomes in patients with esophageal squamous cell carcinoma receiving combined modality therapy.
abstract: OBJECTIVE
  This study was aimed at using proximity ligation assay (PLA) followed by enzyme-linked immunosorbent assay (ELISA) to identify serum biomarkers that predict treatment response and survival for patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy.
  
  
  METHODS
  Seventy-nine patients with ESCC receiving CCRT of taxane-based/5-fluorouracil-based chemotherapy and 40 Gy followed by surgery were enrolled. Serum samples were collected before and <1 month after CCRT. Fifteen biomarkers were analyzed using PLA. Biomarkers significantly correlating with pathological response/survival were verified by ELISA. Associations of the serum level of biomarkers and clinical factors with pathological response, disease-free survival (DFS), and overall survival (OS) were evaluated by analysis of variance and log-rank tests.
  
  
  RESULTS
  Thirty patients had complete response (38 %), 37 had microscopic residual disease (47 %), and 12 had macroscopic residual disease (15 %). With a median follow-up of 52.8 months, the median DFS was 43 months. Among the 15 biomarkers screened by PLA, vascular endothelial growth factor (VEGF)-A and transforming growth factor (TGF)-β1 were significantly associated with pathological response and/or DFS. These biomarkers were further analyzed by ELISA to confirm initial biomarker findings by PLA. After ELISA of these two markers, only VEGF-A levels were significantly correlated with pathological response. On multivariate analysis, patients with combined high pre-CCRT VEGF-A and TGF-β1 levels (greater than or equal to the median), independent of pathological response, had significantly worse DFS (11 months vs. median not reached; p = 0.007) and OS (16 vs. 46 months; p = 0.07).
  
  
  CONCLUSIONS
  Pre-CCRT serum VEGF-A and TGF-β1 levels may be used to predict pathological response and survivals for ESCC patients receiving combined-modality therapy.
authors.affiliation: Department of Radiation Oncology, Stanford University, Stanford, CA, USA.
authors.forename: Jason Chia-Hsien
authors.initials: JC
authors.lastname: Cheng
authors.forename: Madeline S
authors.initials: MS
authors.lastname: Graber
authors.forename: Feng-Ming
authors.initials: FM
authors.lastname: Hsu
authors.forename: Chiao-Ling
authors.initials: CL
authors.lastname: Tsai
authors.forename: Leon
authors.initials: L
authors.lastname: Castaneda
authors.forename: Jang-Ming
authors.initials: JM
authors.lastname: Lee
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chang
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D002294:Carcinoma, Squamous Cell / Q000097:blood* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D004938:Esophageal Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D011879:Radiotherapy Dosage; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000097:blood*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
chemical_list: D014408:Biomarkers, Tumor; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil