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Copy Number Changes Can Be a Predictor for Hemoglobin Reduction After S-1 Monotherapy in Gastric Cancer

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Copy Number Changes Can Be a Predictor for Hemoglobin Reduction After S-1 Monotherapy in Gastric Cancer 787-796 26/1/2009 02:41 ÌÌ ™ÂÏ›‰·787 INTERNATIONAL JOURNAL OF ONCOLOGY 34: 787-796, 2009 787 Copy number changes can be a predictor for hemoglobin reduction after S-1 monotherapy in gastric cancer HEI CHEUL JEUNG1,3, SUN YOUNG RHA1,2,3, CHAN HEE PARK1,2, CHONG-KUN IM1,2,3, SANG JOON SHIN1,3, JOONG BAE AHN1,3, SUNG HOON NOH1,2,4, JAE KYUNG ROH1,2,3 and HYUN CHEOL CHUNG1,2,3 1Cancer Metastasis Research Center, Yonsei Cancer Center, 2Brain Korea 21 Project for Medical Science, Departments of 3Internal Medicine and 4Surgery, Yonsei University College of Medicine, Seoul, Korea Received September 17, 2008; Accepted December 9, 2008 DOI: 10.3892/ijo_00000204 Abstract. Anemia is a unique side effect in Korean gastric 3 genes can be developed into a biomarker in predicting S-1 cancer patients after S-1 monotherapy. We studied gastric treatment-related anemia. cancer patients from a phase II trial of S-1 monotherapy with a 2-week treatment and 1-week rest schedule. Patients from a Introduction phase II trial of S-1 monotherapy with a 4-week treatment and 2-week rest were used as a reference group. The patients were Fluoropyrimidine is still the main drug used for the treatment categorized into two groups based on the degree of hemoglobin of gastric cancer. The target enzyme of 5-fluoropyrimidine reduction per cycle of S-1: the mild reduction group (MRG (5-FU), thymidylate synthase (TS), can be inhibited ΔHb/cycle ≤1.0) or severe reduction group (SRG ΔHb/cycle continuously by protracted infusion of 5-FU (1). A continuous >1.0). ΔHb/cycle was calculated from maximum reduction of exposure to 5-FU can be also achieved by frequent hemoglobin per one cycle of the treatment. Microarray-CGH administration of oral 5-FU or a 5-FU prodrug. S-1 is a new was performed using a 17K cDNA microarray containing drug consisting of the 5-FU prodrug [ftorafur (FT)], the 15,723 unique genes. We selected genes with copy number dihydropyrimidine dehydrogenase (DPD) inhibitor [5-chloro- variation defined as amplification (log2R/G >0.68) or deletion 2,4-dihydroxypyrimidine (CDHP)] and the phosphoribosyl (log2R/G <-0.68), and a genetic aberration frequency transferase inhibitor (oxonic acid) (2). Conversion of FT to difference of ≥30% between the MRG and the SRG. There 5-FU is catalyzed by cytochrome P450 2A6 and occurs were no differences in clinical factors, S-1 treatment-related predominantly in the liver and tumor (3). Thymidine factors (dose, dose intensity), toxicity, S-1 metabolism-related phosphorylase has been postulated to play a role in this gene copy numbers (CYP2A6, DPD), or progression-free conversion. Eighty percent of 5-FU is eliminated by survival between the MRG and the SRG. Three genes were degradation catalyzed by DPD (4), which is competitively selected from microarray-CGH and logistic regression model: inhibited by CDHP (5). Thus, co-administration of CDHP logit LN(Z) = (1.321) + (1.038 x PTX1) + (0.211 x MYO5A) with FT results in a 5-10 times higher 5-FU concentration + (0.516 x ZNF664). In the SRG, all 3 genes showed a trend in the tumor compared to that in tumors treated by FT or 5- of higher copy numbers than the MRG. There were no FU alone. Oxonic acid inhibits the conversion of 5-FU to common anemia-related genes identified from different 5-fluorouridine-5'-monophosphate, a precursor of 5-fluoro- chemotherapy schedule of S-1 monotherapy. The logistics 2'-deoxyuridine-5'-monophosphate (FdUMP), which inhibits obtained from 3 genes predicted the hemoglobin reduction the target enzyme of TS without affecting the pharmacokinetics with an accuracy of 78%. The AUC was 0.744 for the final of 5-FU. regression model. The combined copy number changes of the In phase I trials, the most common dose limiting toxicity (DLT) in Caucasians was diarrhea regardless of the treatment schedule, duration, or dosage of S-1 monotherapy. However, _________________________________________ with a modified schedule of a 2-week treatment and a 1-week rest schedule (2-1 week schedule), there were no grade IV toxicities, even with diarrhea as the DLT (6). In a small Correspondence to: Dr Hyun Cheol Chung, Yonsei Cancer Center, Japanese retrospective study, the overall toxicity was lower for Yonsei University College of Medicine, 134, Shinchon-Dong, Seodaemun-Ku, Seoul 120-752, Korea a 2-1 week schedule compared to that of a 4-week treatment E-mail: [email protected] and a 2-week rest schedule (4-2 week schedule) (7). The major toxicity in Asian patients was granulocytopenia. Interestingly, Key words: S-1, gastric cancer, anemia, microarray-CGH, prediction in Korean patients, anemia was the major grade III-IV toxicity with the 4-2 week schedule, which was not that frequently found in Japanese or European patients (8). With the 2-1 week schedule, anemia was still the major toxicity in Korean 787-796 26/1/2009 02:41 ÌÌ ™ÂÏ›‰·788 788 JEUNG et al: S-1-INDUCED ANEMIA PREDICTION BY MICROARRAY-CGH patients (9). This kind of ethnic difference in S-1 toxicity on the degree of hemoglobin (Hb) reduction (ΔHb; the lowest may come from genomic differences associated with S-1 hemoglobin - initial hemoglobin) per cycle (mg/dl) of S-1: mild metabolism. reduction group (MRG, ΔHb/cycle ≤1.0) or severe reduction The PK profiles for Japanese patients were quite similar group (SRG, ΔHb/cycle >1.0). to those of Korean patients. The AUC of 5-FU in Korean patients increased only marginally at a higher dosage (80 mg/ cDNA-based microarray-CGH. We used a 17K cDNA m2 vs. 70 mg/m2), suggesting that the conversion of FT to microarray-CGH containing 15,723 unique genes. The entire 5-FU is almost saturated at the 70 mg/m2 dosage. This gender-matched study was performed according to an conversion level was similar to that seen in the Japanese approved protocol of the Cancer Metastasis Research Center population (10). Because the PK study could not explain the (CMRC), Yonsei University College of Medicine, Korea discrepancy in the incidences of anemia observed between (11,12). Briefly, 8 μg of genomic DNA was isolated from Korean and Japanese or Caucasian patients, we reported a patients' peripheral mononuclear cells and labeled with Cy3- pharmacogenomic study using genomic DNA (8). A or Cy5-dUTP, using a Bioprime labeling kit (Invitrogen, pharmacogenomic study can be done using either genomic Carlsbad, CA, USA). The labeled probes were then mixed DNA from peripheral blood mononuclear cells or tumor with human Cot-1 DNA (Gibco-BRL, Gaithersburg, MD, DNA from the cancer. Since genomic DNA is considered to USA), yeast t-RNA (Gibco-BRL), and poly-A RNA (Sigma, represent the genetic information from the normal tissue, and St. Louis, MO, USA). After concentration and denaturation, not from the tumor tissue (11), we used genomic DNA from the probe mixture was applied to a microarray and hybridized peripheral blood mononuclear cells. in a chamber at 65˚C for 16 h. After hydridization, the slides With the patients who had been treated by the 2-1 week were scanned using a GenePix 4000B scanner (Axon schedule of S-1 monotherapy, we compared the clinical factors Instruments, Foster City, CA, USA) and the TIFF images were and the copy number changes of S-1 metabolism-related analyzed. The intensity signal of each spot was transformed as genes, such as cytochrome p450 2A6 (CYP 2A6) and DPD, a log2 red to green (R/G) ratio. Whole microarray spots were between patients with severe and mild anemia. We also mapped for their chromosomal location, using the software performed an additional pharmacogenomic study with SOURCE (http://genome-www5.stanford.edu/cgi-bin/ microarray-CGH and compared the results to the study source/sourceSearch) and DAVID (http://apps1.niaid.nih. from patients treated by the 4-2 week schedule of S-1 mono- gov/david/). A within-slide global normalization was applied, therapy. which subtracted the median intensity ratio of the log2(R/G) from the log2-transformed data. Materials and methods Anemia-related gene selection. To identify anemia-related Patients. We studied the data of 27 patients from the phase II genes that can differentiate the MRG from the SRG, we trial (9) who had been treated by the 2-1 week schedule (group selected genes showing; i) copy number changes defined as A). From these patients we obtained genomic DNA from amplification (log2R/G >0.68) or deletion (log2R/G <-0.68), lymphocytes. We also used data of 36 patients from a phase and ii) genetic aberration frequency difference of ≥30% II trial (8) who had been treated by the 4-2 week schedule as between the MRG and the SRG with a statistical significance a reference group (group B). Patients were required to have of p-value <0.05 (13). The selected genes were clustered and histologically confirmed gastric adenocarcinoma with visualized using CLUSTER and TREEVIEW (12). inoperable or metastatic disease, age ≥18 years, performance status ≤3 according to the criteria of Eastern Cooperative Logistic regression model. By univariate analysis, clinical Oncology Group (ECOG), a life expectancy of ≥3 months, factors and genes that correlate with hemoglobin reduction no prior chemotherapy for advanced disease (adjuvant were selected. Then, using the binary outcomes of the MRG chemotherapy should have been completed at least 6 months and SRG as a dependent variable, the best logistic regression before enrollment), bidimensionally measurable lesions and model was identified by performing stepwise selection adequate organ functions [WBC ≥4,000/μl, platelets among factors selected from univariate analysis as follows; ≥100,000/μl, serum creatinine ≤1.5 x upper limit of normal logit LN(Z) = (constant) + (A x PTX1) + (B x MYO5A) + (ULN), total bilirubin ≤1.25 x ULN and serum amino- (C x ZNF664).
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