title: Survival prediction for pancreatic cancer patients receiving gemcitabine treatment.
abstract: Although gemcitabine monotherapy is the standard treatment for advanced pancreatic cancer, patient outcome varies significantly, and a considerable number do not benefit adequately. We therefore searched for new biomarkers predictive of overall patient survival. Using LC-MS, we compared the base-line plasma proteome between 29 representative patients with advanced pancreatic cancer who died within 100 days and 31 patients who survived for more than 400 days after receiving at least two cycles of the same gemcitabine monotherapy. Identified biomarker candidates were then challenged in a larger cohort of 304 patients treated with the same protocol using reverse-phase protein microarray. Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities differed significantly between the two groups (p < 0.001, Welch's t test). Two MS peaks with the highest statistical significance (p = 2.6 x 10(-4) and p = 5.0 x 10(-4)) were revealed to be derived from alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, respectively. The levels of alpha(1)-antitrypsin (p = 8.9 x 10(-8)) and alpha(1)-antichymotrypsin (p = 0.001) were significantly correlated with the overall survival of the 304 patients. We selected alpha(1)-antitrypsin (p = 0.0001), leukocyte count (p = 0.066), alkaline phosphatase (p = 8.3 x 10(-8)), and performance status (p = 0.003) using multivariate Cox regression analysis and constructed a scoring system (nomogram) that was able to identify a group of high risk patients having a short median survival time of 150 days (95% confidence interval, 123-187 days; p = 2.0 x 10(-15), log rank test). The accuracy of this model for prognostication was internally validated and showed good calibration and discrimination with a bootstrap-corrected concordance index of 0.672. In conclusion, an increased level of alpha(1)-antitrypsin is a biomarker that predicts short overall survival of patients with advanced pancreatic cancer receiving gemcitabine monotherapy. Although an external validation study will be necessary, the current model may be useful for identifying patients unsuitable for the standardized therapy.
authors.affiliation: Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan. mail: jmatsuba@ncc.go.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsubara
authors.forename: Masaya
authors.initials: M
authors.lastname: Ono
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Honda
authors.forename: Ayako
authors.initials: A
authors.lastname: Negishi
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.forename: Emiko
authors.initials: E
authors.lastname: Sugiyama
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Junichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Ayako
authors.initials: A
authors.lastname: Shoji
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sakuma
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000302:isolation & purification / Q000378:metabolism; D002138:Calibration; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055088:Early Detection of Cancer / Q000379:methods / Q000592:standards; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine