Survival Prediction for Pancreatic Cancer Patients Receiving Gemcitabine Treatment

Junichi Matsubara, Masaya Ono, Kazufumi Honda, Ayako Negishi,  Hideki Ueno, Takuji Okusaka, Junji Furuse, Koh Furuta, Emiko Sugiyama,  Yoshiro Saito, Nahoko Kaniwa, Junichi Sawada, Ayako Shoji, Tomohiro Sakuma, Tsutomu Chiba, Nagahiro Saijo, Setsuo Hirohashi, and Tesshi Yamada


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 liquid chromatography and mass spectrometry (LC-MS), we compared the baseline 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 to 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=2.6×10-4 and P=5.0×10-4) were revealed to be derived from α1-antitrypsin and α1-antichymotrypsin, respectively. The levels of α1-antitrypsin (P=8.9×10-8) and α1-antichymotrypsin (P=0.001) were significantly correlated with the overall survival of the 304 patients. We selected α1-antitrypsin (P=0.0001), leukocyte count (P=0.066), alkaline phosphatase (P=8.3×10-8), 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% CI, 123 to 187 days; P=2.0×10-15, 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 α1-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.


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