Identification of a predictive biomarker for hematologic toxicities of gemcitabine.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Matsubara
Junichi
J
Chemotherapy Division, National Cancer Center Research Institute, Tokyo, Japan.
Ono
Masaya
M
Negishi
Ayako
A
Ueno
Hideki
H
Okusaka
Takuji
T
Furuse
Junji
J
Furuta
Koh
K
Sugiyama
Emiko
E
Saito
Yoshiro
Y
Kaniwa
Nahoko
N
Sawada
Junichi
J
Honda
Kazufumi
K
Sakuma
Tomohiro
T
Chiba
Tsutomu
T
Saijo
Nagahiro
N
Hirohashi
Setsuo
S
Yamada
Tesshi
T
D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D015415:Biomarkers; D001798:Blood Proteins / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006242:Haptoglobins / Q000032:analysis*; D006801:Humans; D016015:Logistic Models; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D010641:Phenotype; D013921:Thrombocytopenia / Q000139:chemically induced*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D001798:Blood Proteins; D006242:Haptoglobins; D003841:Deoxycytidine; D000093542:Gemcitabine