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American Association for Cancer Research 2009 Annual Meeting PGx Abstracts


"Pharmacogenetic biomarker development in gastric cancer; UGT1A genotyping for prediction of irinotecan toxicity in Korean gastric cancer patients"

The objective of the study, by Lee et al., was to evaluate the frequencies of UGT1A polymorphism in Korean gastric cancer patients, and to determine whether UGT1A polymorphism is associated with toxicity and efficacy of irinotecan in gastric cancer patients.

Researchers investigated polymorphisms of UGT1A subtypes in 396 Korean gastric cancer patients and extracted genomic data from peripheral blood mononuclear cells. The researchers also genotyped polymorphisms of UGT1A1*6, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 by direct sequencing, and used genotyped-based toxicity to look at in 125 irinotecan-treated patients.

In the study, UGT1A1*6 genotype, which was not found in Caucasians, showed high incidence in Koreans, especially in gastric cancer patients. The incidence of UG1A1*28 polymorphism was low in Korean gastric cancer patients, compared to Caucasians. Meanwhile, incidence of UGT1A1*60 polymorphism was higher in Korean gastric cancer patients than normal Korean group, whereas the incidence of UGT1A9*22 polymorphism was similar in Korean group but higher than in Caucasian group.

"Each genotype showed no correlation with clinicopathologic parameters such as histology, stage or total bilirubin," the authors noted in the abstract. The incidence of grade III/IV neutropenia and diarrhea after irinotecan-containing regimen was more common in patients with UGT1A1*6 polymorphism. But other UGT1A polymorphisms showed no association with irinotecan toxicity.

"We confirmed that the incidence of UGT1A polymorphisms of Korean gastric cancer patients showed unique patterns compared to Caucasians, and some other Asians, in part," the authors concluded. "Also, we observed that UGT1A1*6 was associated with irinotecan toxicity.

"These findings provide the evidence that pharmacogenetic-based approach could lead to the effective personalized anticancer treatment for Korean patients with gastric cancer," the study authors said.

"Characterizing the pharmacogenetic pathway of cisplatin and carboplatin in the NCI 60 cancer cell lines"

Using the 60 cell lines from the National Cancer Institutes' Anticancer Drug Screen, Deeken et al., from Georgetown University Medical Center, in Washington DC, tested whether the pharmacological pathway that a drug traverses can be useful in determining the relevance of pharmacogenetics to platinum-based anticancer therapy.

Researchers measured the expression levels for 36 genes in the NCI-60 lines thought to play a role in the platinum drug pathway using the Affymetrix U133 array. Using simple linear regression, expression levels were correlated with the IC-50 drug concentrations of cisplatin and carboplatin in each cell line using simple linear regression.

"Seven and nine genes correlated with the IC50 of carboplatin and cisplatin, respectively," the study authors reported. "Using a multivariable analysis, four genes were found to fit the model for each drug."

Genes in the carboplatin model were GSTM1, REV3L, SLC7A8, and MPO. Genes included in the cisplatin model were GSTM1, GSTT1, ERCC6, and SLC19A1. Genetic variations and haplotypes in these and other genes were found to be significantly associated with drug cytotoxicity.

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"As the pharmacologic pathways of anticancer drugs become better defined, investigation into the relative importance of each protein in a pathway, as well as of genetic variations in those proteins, should improve our understanding of chemotherapy drug disposition," the study authors concluded. "Findings using pre-clinical models such as the NCI 60 can then be tested in the clinic with the goal of using pharmacogenetics to better individualize therapy for cancer patients."

"The FCGR3A Phe158Val polymorphism is an independent predictive factor for the efficacy of cetuximab in advanced colorectal cancer (ACC): a study of the Dutch Colorectal Cancer Group (DCCG)"

Previous research has identified germ-line polymorphisms in the EGFR, EGF, CCND1, FCGR2A and FCGR3A genes as potential markers for response to cetuximab. However, in this study, Pander et al. set out to determine if any of these polymorphisms are truly predictive of treatment response, independent of KRAS mutation status and acneiform skin rash.

Researchers isolated DNA from peripheral blood of advance ACC patients who were treated in the CAIRO2 trial of the DCCG with first line oxaliplatin, capecitabine and bevacizumab (arm A) or with the same regimen plus cetuximab (arm B). The following polymorphisms were analyzed using Taqman: EGF 61A>G, CCND1 870G>A, FCGR2A His131Arg and FCGR3A Phe158Val. The EGFR intron 1 CA-repeat polymorphism was analyzed using fragment analysis.

The primary endpoint was polymorphism association with progression-free survival, and the secondary endpoint was association with overall survival and acneiform skin rash. In the study, 564 patients were evaluated, with 282 enrolled in each arm.

"The FCGR3A Phe158Val polymorphism is independently associated with PFS and acneiform skin toxicity in ACC patients who are treated with cetuximab added to chemotherapy and bevacizumab," the study authors concluded.

"Cytochrome P450 1B1 (CYP1B1) gene polymorphisms as predictors of anticancer drug activity: Studies with in vitro models"

In this study, Robert et al. from the Institut Bergonie, in Bordeaux, France, looked at four non-synonymous SNPs of CYP1B1 associated with risk of breast, lung, prostate and head-and-neck cancers and with tumor response to anticancer drugs.

Extracting DNA from the panel of 60 human tumor cell lines of the National Cancer Institute, researchers identified CYP1B1 rs10012 (48G), rs1056827 (A119S), rs1056836 (V432L), and rs1800440 (N453S) with frequencies of 20 percent (48G), 9 percent (A119S), 49 percent (V432L), and 21 percent (N453S).

"All allelic variants of CYP1B1 appeared significantly associated with reduced cytotoxicity of numerous anticancer agents, especially alkylating agents, camptothecins and antimetabolites," the study authors reported.

For example, cell lines homozygous for the V432L allele were less sensitive to camptothecins than cells harboring other genotypes, according the authors. The study yielded no significant association either between CYP1B1 expression and drug cytotoxicity, with the exception of diaminocyclohexane platinum compounds for which cytotoxicity was negatively correlated with CYP1B1 expression.

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"These observations open the way to clinical studies exploring whether CYP1B1 polymorphisms can be used for predicting overall tumor sensitivity to anticancer drugs," the study authors concluded.

"Genetic variations in genes encoding microRNA processing genes are associated with overall survival in non_small cell lung cancer patients"

In the study, Pu et al. from the MD Anderson Cancer Center tested whether global dysregulation of the miRNA processing pathway could result in tumorgenesis or variation in clinical outcomes.

Researchers genotyped 70 SNPs from eight miRNA processing genes in 598 advance staged non-small cell lung cancer patients treated with first-line platinum-based chemotherapy with or without radiation and analyzed for association with overall survival.

Of the 70 SNPs, 10 were found to be associated with survival, and three SNPs from RNASEN, the gene encoding for Drosha, were found to be significant, the researchers reported. Patients with at least one variant allele for rs7735863 were associated with a significantly increased risk of death compared to patients with wild-type genotype.

In the study, researchers identified three risk groups with "dramatically different" median survival times of 22.17 months, 12.67 months, and 8.91 months for patients with low, medium and high risk, respectively.

"These results suggest that genetic variations in the miRNA processing pathway genes may modulate overall survival in NSCLC patients receiving cisplatin-based chemotherapy," the researchers concluded. "With validation, this information could be used to aid the development of a personalized therapeutic prediction model for the selection of the optimal chemotherapeutic regimen."

"Gemcitabine pharmacogenomics: Biomarker identification using a genome-wide association approach"

The abstract presented by Li et al. from Mayo Clinic, used a cell-based model to perform genome-wide association studies and test a hypothesis that variation across the genome might affect gemcitabine response.

Previous pharmacogenomics studies of gemcitabine, a cytidine analogue drug used to treat pancreatic and breast cancers, have focused mainly on variation in genes involved in the gemcitabine metabolism and bioactivation pathway.

In the present study, researchers looked at SNPs and basal mRNA expression data were obtained using Illumina HumanHap 550K SNP BeadChips and Affymetrix U133 Plus 2.0 GeneChips for 203 ethnically-defined "Human Variation Panel" lymphoblastoid cell lines.

Researchers identified 14 unique SNPs that were significantly associated with gemcitabine cytotoxicity and 23 genes with expression levels that were also correlated with gemcitabine cytotoxicity.

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"These results suggest that genetic variation in gene expression as a result of trans- regulation can contribute to drug cytotoxicity," the researchers concluded. "The application of this type of genome-wide approach using a cell-based model system, when combined with complementary functional validation, can make it possible to identify pharmacogenomic biomarkers for both gemcitabine effect and drug mechanism action.

"New predictive markers for sensitivity of non-small-cell lung cancer to microtubule targeting drugs"

In this study, by Hoffmann et al. from Bayer Schering Pharma and several German research institutions, tested Sagopilone, a selectively optimized fully synthetic epothilone, in 22 well characterized patient-derived non-small-cell lung cancer models.

In the study, genome-wide gene expression analyses of these models reported an increase in the number of genes associated with the hypoxia response pathway in xenografts that did not respond to Sagopilone.

"A high level of anti-tumor activity was observed in xenografts with an activated HIF1/hypoxia pathway when Sagopilone was administered with drugs targeting VEGF signaling, compared with either agent alone," the study authors reported. "Mutation or gene expression analysis of TP53, EGFR, and K-ras revealed a significant correlation between TP53 mutational status or mRNA expression level and Sagopilone response (p

According to researchers, "the study has demonstrated, that results obtained with these clinically relevant patient-derived tumor models provide further insight into the mechanism of action of new drugs and may help to identify patients which more likely will benefit from the treatment."

"Interactions between MDM2 copy number, SNP309 and P53 mutation status, and their impact on drug response in cancer cells"

In the study presented by He et al. from the University of Chicago, researchers evaluated the interrelationships between SNP309, MDM2 gene expression, MDM2 amplification and P53 mutations, as well as their correlations with responsiveness to common chemotherapeutic drugs tested in the NCI-60 cancer cell panel.

Researchers genotyped SNP309 in the NCI-60 cancer cell lines, measured gene expression and gene copy number using RT-PCR in MDM2 gene expression and gene copy number, and assessed the correlation between these genetic alterations in MDM2, their relationship with P53 mutations, and the cytotoxicity of 111 drugs with known mechanisms of action.

According to the abstract, in the overall NCI60 cell panel, MDM2 gene expression was not associated with SNP309, but with increased gene copy number. However, SNP309 strongly determined the MDM2 gene expression in cancer cells with wild type P53, the researchers reported.

Cancer cells with wild-type P53 also had significantly higher MDM2 copies. In the overall panel, MDM2 copy number was significantly correlated with increased sensitivity to commonly used alkylating agents and topoisomerase I and II inhibitors.

"This effect was independent of the P53 mutation status," the researchers reported. "Although SNP309 had a minimum effect on the cytotoxicity of major anti-cancer agents in the whole panel, it was significantly associated with increased sensitivity to alkylating agents and topoisomerase I inhibitors in the cells with wild type P53.

"Our data suggested that there is a strong interaction between MDM2 copy number, SNP309, and P53 mutation status, and this may consequently affect the cellular response to anti-cancer agents," the researchers concluded.