Originally published as JCO Early Release 10.1200/JCO.2008.19.9745 on March 16 2009

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Identification of a Predictive Biomarker for Hematologic Toxicities of Gemcitabine

From the Chemotherapy Division, National Cancer Center Research Institute; Hepatobiliary and Pancreatic Oncology Division and Clinical Laboratory Division, National Cancer Center Hospital; Project Team for Pharmacogenetics, National Institute of Health Sciences; BioBusiness Group, Mitsui Knowledge Industry, Tokyo; Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital East, Kashiwa; and Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Corresponding author: Tesshi Yamada, MD, PhD, Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail: tyamada{at}ncc.go.jp.

Purpose Gemcitabine monotherapy is the current standard for patients with advanced pancreatic cancer, but the occurrence of severe neutropenia and thrombocytopenia can sometimes be life threatening. This study aimed to discover a new diagnostic method for predicting the hematologic toxicities of gemcitabine.

Patients and Methods Using quantitative mass spectrometry (MS), we compared the baseline plasma proteomes of 25 patients who had developed severe hematologic adverse events (grade 3 to 4 neutropenia and/or grade 2 to 4 thrombocytopenia) within the first two cycles of gemcitabine with those of 22 patients who had not (grade 0).

Results We identified 757 peptide peaks whose intensities were significantly different (P < .001, Welch t test) among a total of 60,888. The MS peak with the highest statistical significance (P = .0000282) was revealed to be derived from haptoglobin by tandem MS. A scoring system (nomogram) based on the values of haptoglobin, haptoglobin phenotype, neutrophil count, platelet count, and body-surface area was constructed to estimate the risk of hematologic adverse events (grade 3 to 4 neutropenia and/or grade 2 to 4 thrombocytopenia) with an area under curve value of 0.782 in a cohort of 166 patients with pancreatic cancer. Predictive ability of the system was confirmed in two independent validation cohorts consisting of 87 and 52 patients with area under the curve values of 0.655 and 0.747, respectively.

Conclusion Although the precise mechanism responsible for the correlation of haptoglobin with the future onset of hematologic toxicities remains to be clarified, our prediction model seems to have high practical utility for tailoring the treatment of patients receiving gemcitabine.

Supported by the Program for Promotion of Fundamental Studies in Health Sciences conducted by the National Institute of Biomedical Innovation of Japan, the Third-Term Comprehensive Control Research for Cancer conducted by the Ministry of Health and Labor of Japan, and generous grants from the Naito Foundation, the Princess Takamatsu Cancer Research Fund, and the Foundation for the Promotion of Cancer Research. These sponsors had no role in the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the article for publication, or the writing of the article.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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