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Contains fulltext : 292912.pdf (Publisher’s version ) (Open Access) BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd.

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression-free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p < 0.001). Our study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety.

Background: Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the available evidence and to assess the potential value of genotyping of UGT1A1*28 and UGT1A1*6 in patients before starting treatment with irinotecan to reduce the risk of severe toxicity.Methods: The literature was selected and assessed based on five pre-specified criteria: 1) the level of evidence for associations between UGT1A1 polymorphisms and irinotecan-induced severe toxicity, 2) clinical validity and utility of pre-therapeutic genotyping of UGT1A1, 3) safety and tolerability of irinotecan in carriers of UGT1A1 polymorphisms, 4) availability of specific dose recommendations for irinotecan in carriers of UGT1A1 polymorphisms, 5) evidence of cost benefits of pre-therapeutic genotyping of UGT1A1.Results: On all five criteria, study results were favourable for pre-therapeutic genotyping of UGT1A1. A high level of evidence (level I) was found for a higher incidence of irinotecan-induced severe toxicity in homozygous carriers of UGT1A1*28 or UGT1A1*6. The clinical validity and utility of this genetic test proved to be acceptable. Dose-finding studies showed a lower maximum tolerated dose in homozygous variant allele carriers, and most of the drug labels and guidelines recommend a dose reduction of 25-30% in these patients. In addition, pre-therapeutic genotyping of UGT1A1 is likely to save costs.Conclusion: Pre-therapeutic genotyping of UGT1A1 in patients initiating treatment with irinotecan improves patient safety, is likely to be cost-saving, and should, therefore, become standard of care. (C) 2020 The Author(s). Published by Elsevier Ltd.

3574 Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G > A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).

The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G and c.1601G>A. The predictive value of MIR27A variants for early-onset grade ≥3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95% CI: 0.87-1.82, p = 0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24-19.7, p = 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47-18.0, p = 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27-4.37, p = 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.06-1.17, p = 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83-15.7, p = 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity.

The fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5′-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1,605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. Our study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with fluoropyrimidines. What's new? Fluoropyrimidines are among the most commonly used anticancer drugs. Fluoropyrimidines act by inhibiting thymidylate synthase, encoded by the gene TYMS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964, has been shown to reduce TS activity in vitro, but its effect in patients is unknown. We determined the clinical relevance of this variant as a predictor of severe fluoropyrimidine-induced toxicity in a cohort of 1605 patients treated with fluoropyrimidine-based chemotherapy, and demonstrate for the first time that rs183205964 is associated with risk of early severe toxicity.

BACKGROUND: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study. METHODS: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5'-UTR VNTR and TYMS 3'-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q16 ng ml(-1)) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P

Background The objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care. Patients and Methods A total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early – i.e. cycle one or two – severe (grade ≥ 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis. Results Among 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade ≥3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio [OR] 0.85 per 10 ml/min/1.73 m 2 , p = 0.0007), body surface area (BSA) (OR 0.33 per m 2 , p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade ≥3 toxicity was 0.704 (95% confidence interval 0.666–0.743, optimism-corrected AUC 0.690). Conclusion Renal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care.

Learning Objectives After completing this course, the reader will be able to: Identify genetic variants of glutathione S-transferase and uridine diphosphoglucuronosyl transferase that have been shown to affect clinical outcomes in patients with cancer and describe the general effects of these variants with respect to standard treatment.Describe potential treatment considerations in patients with cancer who have genetic polymorphisms that affect Phase II metabolism of anticancer drugs. CME This article is available for continuing medical education credit at CME.TheOncologist.com Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed.

Learning Objectives After completing this course, the reader will be able to: Identify genetic polymorphisms within pharmacodynamic candidate genes that are potential predictive markers for treatment outcome with anticancer drugs.Describe treatment selection considerations in patients with cancer who have genetic polymorphisms that could influence pharmacodynamic aspects of anticancer therapy. CME This article is available for continuing medical education credit at CME.TheOncologist.com Response to treatment with anticancer drugs is subject to wide interindividual variability. This variability is expressed not only as differences in severity and type of toxicity, but also as differences in effectiveness. Variability in the constitution of genes involved in the pharmacokinetic and pharmacodynamic pathways of anticancer drugs has been shown to possibly translate into differences in treatment outcome. The overall knowledge in the field of pharmacogenetics has tremendously increased over the last couple of years, and has thereby provided opportunities for patient-tailored anticancer therapy. In previous parts of this series, we described pharmacogenetic variability in anticancer phase I and phase II drug metabolism and drug transport. This fourth part of a four-part series of reviews is focused on pharmacodynamic variability and encompasses genetic variation in drug target genes such as those encoding thymidylate synthase, methylene tetrahydrofolate reductase, and ribonucleotide reductase. Furthermore, genetic variability in other pharmacodynamic candidate genes involved in response to anticancer drugs is discussed, including genes involved in DNA repair such as those encoding excision repair crosscomplementing group 1 and group 2, x-ray crosscomplementing group 1 and group 3, and breast cancer genes 1 and 2. Finally, somatic mutations in KRAS and the gene encoding epidermal growth factor receptor (EGFR) and implications for EGFR-targeted drugs are discussed. Potential implications and opportunities for patient and drug selection for genotype-driven anticancer therapy are outlined.

Learning Objectives After completing this course, the reader will be able to: List currently identified candidate genes involved in phase I metabolism that are potential pharmacogenetic markers in anticancer therapy.Describe the general effect on standard treatment of allelic variants of the candidate genes and the implications for individualized treatment. This article is available for continuing medical education credit at CME.TheOncologist.com Equivalent drug doses in anticancer chemotherapy may lead to wide interpatient variability in drug response reflected by differences in treatment response or in severity of adverse drug reactions. Differences in the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of a drug contribute to variation in treatment outcome among patients. An important factor responsible for this variability is genetic polymorphism in genes that are involved in PK/PD processes, including drug transporters, phase I and II metabolizing enzymes, and drug targets, and other genes that interfere with drug response. In order to achieve personalized pharmacotherapy, drug dosing and treatment selection based on genotype might help to increase treatment efficacy while reducing unnecessary toxicity. We present a series of four reviews about pharmacogenetic variability in anticancer drug treatment. This is the second review in the series and is focused on genetic variability in genes encoding drug transporters (ABCB1 and ABCG2) and phase I drug-metabolizing enzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DPYD, CDA and BLMH) and their associations with anticancer drug treatment outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are presented.

Purpose: The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses. Methods: Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1-14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome. Results: A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 plus capecitabine 850 mg/m2 b.i.d. The median number of treatment cycles was 6 (range 2-8). Grade ≤ 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4-7.6) and 11.0 months (95 % CI 7.9-14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival. Conclusion: Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome.

Purpose Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost–intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses. Methods and Materials Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinal lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m 2 (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m 2 b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD). Results A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m 2 b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed. Conclusions SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m 2 b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.

Learning Objectives After completing this course, the reader will be able to: Differentiate the candidate gene and genome-wide approaches to pharmacogenetic research and the impact of each on clinical study results.Describe the clinical implications of pharmacogenetic variability and its potential role in individualized treatment of patients with cancer. This article is available for continuing medical education credit at CME.TheOncologist.com Equivalent drug doses may lead to wide interpatient variability with regard to drug response, reflected by differences in drug activity and normal tissue toxicity. A major factor responsible for this variability is variation among patients in their genetic constitution. Genetic polymorphism may affect the activity of proteins encoded, which in turn may lead to changes in the pharmacokinetic and pharmacodynamic behavior of a drug, observed as differences in drug transport, drug metabolism, and pharmacodynamic drug effects. Recent insights into the functional effect of polymorphism in genes that are involved in the pharmacokinetics and pharmacodynamics of anticancer drugs have provided opportunities for patient-tailored therapy in oncology. Individualized pharmacotherapy based on genotype will help to increase treatment efficacy while reducing unnecessary toxicity, especially of drugs characterized by a narrow therapeutic window, such as anticancer drugs. We provide a series of four reviews aimed at implementing pharmacogenetic-based drug and dose prescription in the daily clinical setting for the practicing oncologist. This first part in the series describes the functional impact of genetic polymorphism and provides a general background to and insight into possible clinical consequences of pharmacogenetic variability. It also discusses different methodologies for clinical pharmacogenetic studies and provides a concise overview about the different laboratory technologies for genetic mutation analysis that are currently widely applied. Subsequently, pharmacogenetic association studies in anticancer drug transport, phase I and II drug metabolism, and pharmacodynamic drug effects are discussed in the rest of the series. Opportunities for patient-tailored pharmacotherapy are highlighted.

Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine. Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival. Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) = 0.57 (0.35–0.95)]. Conclusions: DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. ©2011 AACR.

TO THEEDITOR:We very much appreciate the prospective manner of the study conducted by Schwab et al, 1 in which fluorouracil (FU) treatment-related toxicity was correlated with genetic and nongenetic factors in patients treated with FU monotherapy-based regimens. The study elegantly illustrated the complex and diverse clinical pictureallelicvariantsmayinduce,andservesasamodelforprospective pharmacogenetic validation studies. However, we propose that theauthorstakeanotherpotentiallycrucialparameterintheiranalysis into account that might lead to a different interpretation of the study results. Toxicity to FU depends on the type of treatment regimen, also illustrated by Schwab et al, with the bolus Mayo regimen resulting in the highest overall grade 3/4 toxicity rate. Based on the study results presented,webelievethatdevelopmentofseveretoxicityinDPYD*2A heterozygotes is determined by the treatment regimen and not by mode of administration nor by sex. Schwabetalobservedthatonlysixoutof13DPYD*2Aheterozy

3606 Background: Fluoropyrimidines, although generally well tolerated, can induce life-threatening toxicity. The major known cause of intolerance is deficiency of the detoxifying enzyme dihydropyri...

3099 Background: Capecitabine is the oral prodrug of 5-FU, which is inactivated for 85% by dihydropyrimidine dehydrogenase (DPD, DPYD). The aim of this study was to determine the effect of DPYD SNP...

2557 Background: Results form (pre)clinical studies suggest that mTOR inhibitors are promising drugs for the treatment of various types of cancer. Everolimus seems the most attractive mTOR inhibito...