ABSTRACT
The collagen gel droplet-embedded drug sensitivity test (CD-DST) was revealed to be useful for predicting the effect of S-1 adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC). However, collection of an adequate number of PDAC cells is difficult due to the surrounding fibroblasts. Thus, the aim of this study was to discover novel biomarkers to predict chemosensitivity based on the CD-DST results. Proteomics analysis was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Candidate proteins were validated in patients with 5-FU CD-DST results via immunohistochemistry (IHC). The relationships between the candidate proteins and the effect of the adjuvant S-1 were investigated via IHC. Among the 2696 proteins extracted by LC-MS/MS, C1TC and SAHH could accurately predict the CD-DST results. Recurrence-free survival (RFS) was significantly improved in the IHC-positive group compared with the IHC-negative group in both factors. The negative group did not show a significant difference from the group that did not receive S-1. The double-positive group was associated with significantly prolonged RFS compared to the no adjuvant chemotherapy group. C1TC and SAHH have been shown to be useful biomarkers for predicting 5-FU sensitivity as a substitute for the CD-DST in adjuvant chemotherapy for PDAC.
Subject(s)
Adenocarcinoma/drug therapy , Adenosylhomocysteinase/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Drug Resistance, Neoplasm/genetics , Tensins/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Pharmacological/metabolism , Biomarkers, Tumor/genetics , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Chromatography, Liquid , Collagen/chemistry , Collagen/drug effects , Disease-Free Survival , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Male , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Proteomics , Tandem Mass SpectrometryABSTRACT
PURPOSE: We evaluated the clinical effectiveness of collagen gel droplet-embedded culture drug sensitivity tests (CD-DSTs) in predicting the efficacy of adjuvant chemo-therapeutic treatments for pancreatic cancer (PC). METHODS: The clinicopathological characteristics and prognoses of 22 PC patients who underwent CD-DST after pancreatectomy at Tohoku University between 2012 and 2016 were analyzed retrospectively. Eligibility criteria were resectable or borderline resectable PC, successful evaluation for 5-fluorouracil sensitivity by CD-DST, treatment with S-1 adjuvant chemotherapy, and no preoperative chemotherapy. RESULTS: The rate of successful evaluation by CD-DST was 52.3% in PC. The optimal T/C ratio, defined as the ratio of the number of cancer cells in the treatment group (T) to that in the control group (C), for 5-fluorouracil was 85% using receiver operating characteristic curve analysis. The sensitive group (T/C ratio < 85%; n = 11) had a better recurrence-free survival rate than the resistant group (T/C ratio ≥ 85%; n = 11; P = 0.029). A Cox proportional hazards regression model demonstrated that sensitivity to 5-fluorouracil was an independent predictor of recurrence on multivariate analysis (hazard ratio 3.28; 95.0% CI 1.20-9.84; P = 0.020). CONCLUSIONS: CD-DSTs helped to predict PC recurrence after S-1 adjuvant chemotherapy.