DMET Plus Research Articles

SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin.

Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.

A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics.

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (p = 0.01) and as prognostic of survival (p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an “inflammatory-score” and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease.

Risk factors for cisplatin-induced acute kidney injury: A pilot study on the usefulness of genetic variants for predicting nephrotoxicity in clinical practice.

Several studies have reported risk factors for predicting cisplatin-induced acute kidney injury (AKI), including old age, female sex, smoking, hypoalbuminemia, hypokalemia, hypomagnesemia, a high body surface area, advanced cancer and the total dose of cisplatin administered. Recently, some studies have focused on the associations between genetic alterations in the genes coding for renal drug transporters, such as organic cation transporter 2 (OCT2), and the nephrotoxicity of cisplatin. However, genetic variants have not been fully elucidated for clinical use. Patients who had received cisplatin (≥50 mg/m2)-containing chemotherapy as a first-line treatment were considered as eligible for the present study. The occurrence of AKI and its associations with baseline characteristics, conventional biomarkers and single-nucleotide variants (SNV) were assessed. AKI was defined as an increase in the serum creatinine level of >0.3 mg/dl or to 1.5-2 times the baseline level. Genotyping was conducted using the DMET platform (DMET Plus), which characterizes 1,936 genetic variants (1,931 SNV and 5 copy number variations) in 231 genes. Between April 2014 and June 2016, a total of 28 patients (22 men and 6 women) were enrolled. AKI occurred in 8 of the 28 enrolled patients (28.6%). Univariate analyses demonstrated that the urinary β2-microglobulin level and body surface area were significantly higher in the AKI group (P<0.05). As regards the associations between AKI and SNV, none of the examined SNV were found to be associated with cisplatin-induced AKI. The findings of the present study suggested that certain clinical factors were associated with the onset of AKI, but no associations were identified with genetic factors, including OCT2. Although this was a small pilot study, the findings indicated that genetic factors may not be of value for predicting AKI in clinical practice.

Contemporary pharmacogenetic assays in view of the PharmGKB database.

Six modern PGx assays were compared with the Pharmacogenomics Knowledge Base (PharmGKB) to determine the proportion of the currently known PGx genotypes that are assessed by these assays. Investigated assays were 'Ion AmpliSeq Pharmacogenomics', 'iPLEX PGx Pro', 'DMET Plus,' 'PharmcoScan,' 'Living DNA' and '23andMe.' PharmGKB contains 3474 clinical annotations of which 75, 70 and 45% can be determined by PharmacoScan, Living DNA and 23andMe, respectively. The other assays are designed to test a specific subset of PGx variants. Assaying all known PGx variants would only comprise a minor fraction of the current assays' capacity. Unfortunately, this is not achieved. Moreover, not necessarily the variants with the highest effects or the highest evidence are selected.

Variations in plasma concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer.

Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Duplicate or triplicate specimens were obtained from 179 patients at 3-month intervals. In 80 patients, genotyping for tamoxifen metabolizing enzymes was performed using the DMET Plus array and long-range PCR. Plasma concentrations of tamoxifen and its metabolites showed wide variations among patients. The following genetic polymorphisms were associated with the plasma concentrations when body mass index and tamoxifen concentrations were considered as co-variables: CYP1A2 -2467delT, CYP2B6 genotype, CYP2D6 activity score (AS), and FMO3 441C>T. CYP2D6 AS and three variants in the SULT1E1 gene showed correlation with ratios of tamoxifen metabolites. CYP2D6 AS was the only variable that showed associations with both metabolite concentration and ratio: endoxifen (P < 0.001), NDM (P < 0.001), endoxifen/NDM (P < 0.001), NDM/tamoxifen (P < 0.001), and 4-OH tamoxifen/tamoxifen (P = 0.005). Serial measurements of 448 plasma concentrations in 179 patients at 3-month intervals showed wide intra-individual variation. Our study showed that genetic polymorphisms can in part determine the baseline concentrations of tamoxifen and its metabolites. However, marked intra-individual variations during follow-up monitoring were observed, and this could not be explained by genotype. Therefore, serial measurements of tamoxifen and its metabolites would be helpful in monitoring in vivo tamoxifen metabolic status.

Aromatase inhibitors in elderly patients with advanced breast cancer: An exploratory pharmacogenetic study.

11058 Background: Aromatase inhibitors (AIs) are the first choice for older patients (pts) with estrogen-receptor (ER) positive advanced breast cancer (BC). Yet, response is variable and difficult to predict. Some pts exhibit very good long-lasting response whereas others rapidly progress even after initial response. Factors such as tumor subtype (i.e., luminal A vs B) or BMI have been reported to correlate with response but so far no predictive marker is available. The aim of this study was to identify gene variants associated with AIs response in elderly pts with advanced BC. Methods: Genomic DNA from peripheral blood of 55 pts with locally advanced or metastatic breast cancer was analyzed with DMET Plus GeneChip array (Affymetrix, Santa Clara, CA), appropriateness of data was evaluated with DMET Console and statistically relevant variants were assessed with DMET-Analyzer. Median age was 79 years (IQR, 73-86), all patients had ER-positive HER-2 negative BC. Clinico-pathologic factors were evaluated for ...

O2-032 - Comprehensive Analysis of Genetic Polymorphisms and Irinotecan-Induced Adverse Events in Japanese Gastrointestinal Cancer Patients: A Dmet Microarray Profiling Study

ABSTRACT Background Irinotecan is a key drug in the treatment of colorectal and gastric cancer, which may occasionally cause severe adverse events (AEs), especially neutropenia and diarrhea. Although UDP-glucuronosyltransferase (UGT)1A1 polymorphisms are used as biomarkers for predicting AEs, the effect of UGT1a1 in clinical use is limited, suggesting that there is a possibility of the existence of other, unknown biomarkers. Methods Fourteen gastrointestinal cancer (five gastric, nine colorectal) patients who had undergone irinotecan-based chemotherapy were enrolled. DNA extracted from peripheral blood cells was genotyped by the DMET Plus microarray system, and 1931 gene polymorphisms were investigated. The relationship between AEs and polymorphisms was analyzed statistically. Results Eleven polymorphisms showed the P-value of A(P32P) showed a significant relationship (P Conclusions CYP2F1_96G > A polymorphism showed significant association with diarrhea. The association of UGT1A1*6 polymorphism and neutropenia was confirmed, as in previous reports.

Imputation reliability on DNA biallelic markers for drug metabolism studies

BackgroundImputation is a statistical process used to predict genotypes of loci not directly assayed in a sample of individuals. Our goal is to measure the performance of imputation in predicting the genotype of the best known gene polymorphisms involved in drug metabolism using a common SNP array genotyping platform generally exploited in genome wide association studies.MethodsThirty-nine (39) individuals were genotyped with both Affymetrix Genome Wide Human SNP 6.0 (AFFY) and Affymetrix DMET Plus (DMET) platforms. AFFY and DMET contain nearly 900000 and 1931 markers respectively. We used a 1000 Genomes Pilot + HapMap 3 reference panel. Imputation was performed using the computer program Impute, version 2. SNPs contained in DMET, but not imputed, were analysed studying markers around their chromosome regions. The efficacy of the imputation was measured evaluating the number of successfully imputed SNPs (SSNPs).ResultsThe imputation predicted the genotypes of 654 SNPs not present in the AFFY array, but contained in the DMET array. Approximately 1000 SNPs were not annotated in the reference panel and therefore they could not be directly imputed. After testing three different imputed genotype calling threshold (IGCT), we observed that imputation performs at its best for IGCT value equal to 50%, with rate of SSNPs (MAF > 0.05) equal to 85%.ConclusionsMost of the genes involved in drug metabolism can be imputed with high efficacy using standard genome-wide genotyping platforms and imputing procedures.

Comprehensive analysis of genetic polymorphisms and irinotecan-induced adverse events in Japanese gastrointestinal cancer patients: A DMET microarray profiling study.

e21108 Background: Irinotecan is a key drug in the treatment of colorectal and gastric cancer, that may occasionally cause severe adverse events (AEs), especially neutropenia and diarrhea. Although UDP-glucuronosyltransferase (UGT)1A1 polymorphisms are used as biomarkers for predicting AEs, the effect of UGT1A1 polymorphism in clinical use is limited, suggesting that there is a possibility of the existence of other, unknown biomarkers. Methods: Fourteen gastrointestinal cancer (5 gastric, 9 colorectal) patients who had undergone irinotecan-based chemotherapy were enrolled. DNA extracted from peripheral blood cells was genotyped by the DMET Plus microarray system, and 1,931 gene polymorphisms were investigated. The relationship between AEs and polymorphisms was analyzed statistically. Results: Eleven polymorphisms showed the P value &lt; 0.05 with grade 3,4 neutropenia, but no statistically significant polymorphisms were found after the correction of multiple comparisons. With respect to the association with diarrhea, 12 polymorphisms showed P &lt;0.05, and even after the correction of multiple comparisons, CYP2F1_96G&gt;A(P32P) showed a significant relationship (P&lt;0.00001). With respect to the relationship between UGT1A1*6, *28 polymorphisms and AEs, *6 polymorphism showed significant (P=0.044) association with grade 4 neutropenia. Conclusions: CYP2F1_96G&gt;A showed significant association with diarrhea. The association of UGT1A1*6 polymorphism and neutropenia was confirmed, as in previous reports.

Interrogation of polymorphisms in drug metabolism or transport genes and peripheral neuropathy during paclitaxel treatment.

10515 Background: Peripheral neuropathy is the most common severe toxicity in patients treated with paclitaxel. Putative genetic mutations in genes relevant to drug metabolism, distribution, and elimination may explain the differences in risk of neurotoxicity among patients. Using a genotyping platform that interrogates nearly 2,000 known variants in drug exposure genes, we hypothesized that polymorphisms could be identified which modulate a patient’s risk of neuropathy during paclitaxel treatment. Methods: Subjects included in this study were treated for breast cancer with paclitaxel-containing regimens. Clinical data, including patient characteristics and toxicity, was collected prospectively in an observational registry. Blood was collected at diagnosis and genotyped using the Affymetrix DMET Plus chip at Gentris. The primary endpoint was grade 2+ neuropathy as defined by NCI CTC criteria. Statistical analysis was carried out using Fisher’s exact test for each SNP, without assumption of a specific genetic model. For this hypothesis-generating study, a p-value of &lt;0.001 was selected for significance. Results: 412 breast cancer patients treated with paclitaxel were included in the analysis. The median age was 50, 107 (26%) were African-American, and 48 (12%) had preexisting diabetes. The prevalence of grade 2+ neuropathy was 18.5% in the cohort. After exclusion of SNPs based on call rate, Hardy-Weinberg equilibrium, and allele frequency, 564 SNPs were interrogated for an association with grade 2+ neuropathy. Two SNPs, rs3788007 (ABCG1_43706676G&gt;A[Intron]) and rs6163 (CYP17A1_195G&gt;T[S65S]), were associated with grade 2+ neurotoxicity p=0.0003 (OR=3.54, 95% CI: 1.77-7.72) and p=0.0008 (OR=0.35, 95%CI: 0.18-0.66), respectively. Conclusions: We identified two SNPs, both in genes not previously investigated in paclitaxel pharmacogenetic studies, which were associated with modified risk of paclitaxel-induced neuropathy. Both genes are implicated in endogenous steroid biology, which is thought to be relevant to neuropathy development, and one SNP (rs6163) is in high LD (r2=0.93) with a SNP recently reported to be associated with bortezomib-induced neuropathy.

Assessing the utility of whole genome amplified DNA as a template for DMET Plus array

Large amounts of high quality DNA are typically required for high-throughput genotyping arrays but sometimes study participant DNA is in limited supply. Multiple displacement amplification (MDA)-based whole genome amplification is an in vitro technique that permits the genetic analysis of limited amounts of high molecular weight genomic DNA (gDNA). The performance of MDA-whole genome amplified DNA (wgaDNA) as a template for DMET Plus (Affymetrix) was assessed. wgaDNA was generated from gDNA from three HapMap CEU cell lines and 11 breast cancer patients. One HapMap sample and three patient samples were randomly selected for replication to assess reproducibility. Accuracy was assessed by comparing the wgaDNA genotypes with gDNA genotypes. The kappa (κ) statistic was used to measure genotype concordance between paired gDNA-wgaDNA and wgaDNA-wgaDNA samples. Copy number variants (CNV) were not included in concordance analysis in this study. A good genotype call rate of 98.8%±1.06% (mean±standard deviation, 1931 markers) was observed for all 18 wgaDNA samples with three samples having call rates lower than 98%. High genotype concordance rates were observed between four HapMap wgaDNA-gDNA pairs (98.5%, κ=0.9817, p<0.0001, 1931 markers) and 14 patient wgaDNA-gDNA pairs (100%, κ=1.00, p<0.0001, 19 markers among CYP2D6 and CYP2C19). Excellent genotype concordance was also observed between four independently amplified duplicate samples (98.0%, κ=0.9745; p<0.0001, 1931 markers). MDA-produced wgaDNA provides accurate and reproducible genotypes with the DMET Plus array and is therefore a suitable template for this targeted pharmacogenetic genotyping array.

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose

In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.

Impact of polymorphisms on docetaxel-induced neutropenia in Japanese patients with gynecologic cancer.

e13015 Background: Docetaxel is a key drug for the treatment of patients with gynecologic cancer. However, docetaxel-induced neutropenia, which may occur as a result of individual genetic variation, is a significant side effect of this therapy. In this study, we examined the correlation between previously reported single nucleotide polymorphisms (SNPs), rs12762549 in ABCC2 and rs11045585 in SLCO1B3, rs2740574 in CYP3A4, rs776746 in CYP3A5 and severe docetaxel-induced neutropenia in a population comprising gynecologic cancer patients who were treated with a docetaxel-contained combination therapy. Methods: Fifty-one gynecologic cancer patients treated with docetaxel were genotyped. Of these, 46 patients were treated with a combination of docetaxel and carboplatin and 5 with a combination of docetaxel and gemcitabine. We performed the TaqMan SNP genotyping assay to evaluate SNPs in ABCC2 and SLCO1B3. The DMET Plus genotyping platform (DMET) was used to evaluate other SNPs. Results: The reported scoring system using ABCC2 and SLCO1B3 did not show any significant correlation with severe neutropenia due to docetaxel. When we focused on the 42 patients treated with DC combination therapy, the homozygotes either rs12762549 in ABCC2 or rs776746 in CYP3A5 are significantly predominant in the 19 patients having grade 4 neutropenia. Conclusions: Our results suggest that the risk of severe neutropenia among Japanese gynecologic cancer patients treated with DC might be predicted by genotyping SNPs of ABCC2 and CYP3A5.

Identification of A Pharmacogenomic Profile Associated with High Sensitivity and Low Toxicity to a Combination of Gemtuzumab Ozogamicin Plus Fludarabine, Cytarabine, Idarubicin Regimen In CD33-Positive Acute Myeloid Leukemia (AML) Patients

AbstractAbstract 967Human genome sequence variation, in the form of single nucleotide polymorphisms (SNPs) as well as more complex structural variation (such as insertions, duplications and deletions) in drug-metabolizing enzyme and transporter genes (DMETs), affects each individual's response to anticancer agents and thus the likelihood of experiencing an adverse drug reaction. Therefore, understanding relationships between genetic variation and differential drug responses is a challenge to improve both the safety and efficacy of drugs. Accordingly, in order to investigate a potential association between SNPs and clinical response and toxicity, we comprehensively assessed the allele frequencies of 1931 genetic variations of 225 absorption, distribution, metabolism and excretion genes in 59 AML patients younger than 65 years, using the new Affymetrix drug-metabolizing enzyme and transport (DMET Plus) genotyping platform (Affymetrix, Inc. Santa Clara, CA, USA). All patients were enrolled in a phase III multicenter clinical trial combining low dose of Gemtuzumab-ozogamicin (GO) with FLAI regimen (Fludarabine, Cytarabine, Idarubicin) as Induction chemotherapy i (eudract: 2007–005248-26; ClinicalTrials.gov NCT00909168). The induction regimen (GO-FLAI) included fludarabine (25 mg/sqm) and Ara-C (2 g/sqm) on days 1–5, idarubicin (10 mg/sqm) on days 1, 3, and 5 and GO (3 mg/sqm) on day 6. Hematopoietic stem cell transplant was planned for all high risk AML patients in first complete remission (CR) after consolidation with intermediate doses of Ara-C and idarubicin (ID-AC and IDA). Cytogenetic, multidrug-resistance phenotype, FLT3 and NPM mutation status, WT1 quantitative expression analyses, were performed at diagnosis in all patients. Furthermore, high-resolution SNP array analysis by GeneChip® Human Mapping 250K NspI and Genome-Wide Human SNP 6.0 (Affymetrix) was also performed. DNA processing and genotype identifications were performed according to the Affymetrix DMET platform's instructions. All statistical analyses were performed using the R package 2.11.1. Allele frequencies estimation and principal component analyses (PCAs) were performed using the adegenet library, whereas an ad hoc R function was developed to compute two-side Fisher's exact test p-values for each SNP in order to test their association with clinical response and toxicity.Results of potential interest were limited to those in which the p-value was <0.01. The median SNP call rate was 99.48% (range, from 98.05 – 100%). Two samples were run in duplicate and results with “passed call rate” were compared across all the 1931 polymorphic sites, showing a repeatability of 99.99%. In an initial screening procedure, we tested the association among SNPs and response to the induction cycle (FLAI + Gemtuzumab-Ozogamicin). We compared the genotyping profiling of 50 patients in complete (81%) and partial (5%) remission versus that of patients (14%) with no response finding out that 2 SNPs in the alcohol dehydrogenase enzyme (ADH1A) were highly associated with response to therapy. Since genetic polymorphisms may influence the toxicity of chemotherapy drugs, we stratified SNPs according to liver toxicity and 2 genes (SLC22A5 and ABCC4) were found to be associated with a grade I/II liver toxicity. Moreover, SNPs in SLC7A8 and SULT2B1 genes were found to be strongly associated (p <0.001) with fever to gemtuzumab-ozogamicin and finally SNPs in UGT2B15, CYP2B6 and PPARD (peroxisome proliferator-activated receptor delta) were found to be associated with a higher level of expression of P-glycoprotein (defined as a mean fluorescence index > 6). In conclusion, we performed an exploratory pharmacogenomic study that related SNPs in multidrug enzymes and transporters genes with the efficacy and toxicity of a combination of Gemtuzumab-ozogamicin (GO) with FLAI regimen used in a clinical trial of AML patients younger than 65 years. We identified for the first time a pharmacogenomic panel made up of 1 gene (ADH1A) associated with clinical outcome and 4 genes associated with toxicity. Findings obtained from this exploratory study are being tested in a larger clinical sample sets to confirm the predictive value of the SNP panel. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integreted program (PIO), Programma di Ricerca Regione – Università 2007 – 2009. Disclosures:Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy.

Genetic polymorphisms of metabolizing enzymes and transporters correlate with pharmacokinetics (PK) and pharmacodynamics (PD) of amrubicin.

2577 Background: Amrubicin (AMR) is an active agent for lung cancer; however, substantial variability of its hematological toxicity has been observed. Genetic polymorphisms that correlate with PK/PD variabilities of AMR have not been elucidated. The aim of this study was to assess whether genetic polymorphisms correlate with PK/PD of AMR. Methods: AMR (40mg/m2) was administered on days 1-3 every 3-4 weeks with full PK samplings. DNA samples were extracted from peripheral blood mononuclear cells before treatment and 1,936 SNPs in 225 genes coding for a wide category of drug metabolizing enzymes and transporters were analyzed (DMET Plus Premier Pack). Results: Twenty-one patients with lung cancer were enrolled. Major toxicity was hematological and grade 4 neutropenia was observed in 13 out of 21 (61.9%) patients. Grade 4 neutropenia was significantly correlated with AMR (p=0.022) and its active metabolite amrubicinol (AMR-OH) clearance (CL) (p=0.004). Body-weight and serum total bilirubin were significantly...