SNPs Associated with Activity and Toxicity of Cabazitaxel in Patients with Advanced Urothelial Cell Carcinoma

Durán, Ignacio; Hagen, Carlos; Arranz, José Ángel; Apellaniz-Ruiz, María; Pérez-Valderrama, Begoña; Sala, Núria; Laínez, Núria; Muro, Xavier García-Del; Noguerón, Esther; Climent, Miguel Ángel; Maroto, Pablo; Font, Albert; García-Donás, Jesús; Gallardo, Enrique; López-Criado, Pilar; Alba, Aránzazu Gonzalez del; Sáez, María Isabel Corbí; Vázquez‐Estévez, Sergio; Luque, Raquel; Rodríguez‐Antona, Cristina

doi:10.2217/pgs.15.186

Cited by 8 publications

(8 citation statements)

References 31 publications

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“…Among these are three distinct positions in TUBB1 (Q43P/H, R307C, R359W) that occur with comparably high frequencies in the South-Asian population. While Q43P (AF SAS = 14%) has recently been associated with decreased progression-free survival in urothelial cell carcinoma when treated with cabazitaxel [ 74 ], less is known about the effects of the other two variants. Mapping the affected residues onto the 3D structure of docetaxel bound to tubulin (PDB ID 1tub [ 36 ]) shows that R359 interacts with the drug (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genetic variation in human drug-related genes

et al. 2017

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BackgroundVariability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classic pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied.MethodsBased on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional variants in 806 drug-related genes, including 628 known drug targets. We further computed the likelihood of 1236 FDA-approved drugs to be affected by functional variants in their targets in the whole ExAC population as well as different geographic sub-populations.ResultsWe find that most genetic variants in drug-related genes are very rare (f < 0.1%) and thus will likely not be observed in clinical trials. Furthermore, we show that patient risk varies for many drugs and with respect to geographic ancestry. A focused analysis of oncological drug targets indicates that the probability of a patient carrying germline variants in oncological drug targets is, at 44%, high enough to suggest that not only somatic alterations but also germline variants carried over into the tumor genome could affect the response to antineoplastic agents.ConclusionsThis study indicates that even though many variants are very rare and thus likely not observed in clinical trials, four in five patients are likely to carry a variant with possibly functional effects in a target for commonly prescribed drugs. Such variants could potentially alter drug efficacy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0502-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Genetic variation in human drug-related genes

et al. 2017

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“…For example, TRAK1 (trafficking kinesin protein 1) gene has been identified as a favorable prognostic marker, since its low level expression was associated with poorer survival ( 52 ). Polymorphisms in CYP3A5 (a cytochrome P450 family member) can define a subset of BCa patients who better respond to cabazitaxel and temsirolimus, in terms of lower toxicity and higher efficacy ( 53 , 54 ).…”

Section: Emerging Bca Biomarkers Identified By the Wgcna Methodsmentioning

confidence: 99%

Emerging Biomarkers in Bladder Cancer Identified by Network Analysis of Transcriptomic Data

Giulietti¹,

Occhipinti²,

Righetti³

et al. 2018

Front. Oncol.

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Bladder cancer is a very common malignancy. Although new treatment strategies have been developed, the identification of new therapeutic targets and reliable diagnostic/prognostic biomarkers for bladder cancer remains a priority. Generally, they are found among differentially expressed genes between patients and healthy subjects or among patients with different tumor stages. However, the classical approach includes processing these data taking into consideration only the expression of each single gene regardless of the expression of other genes. These complex gene interaction networks can be revealed by a recently developed systems biology approach called Weighted Gene Co-expression Network Analysis (WGCNA). It takes into account the expression of all genes assessed in an experiment in order to reveal the clusters of co-expressed genes (modules) that, very probably, are also co-regulated. If some genes are co-expressed in controls but not in pathological samples, it can be hypothesized that a regulatory mechanism was altered and that it could be the cause or the effect of the disease. Therefore, genes within these modules could play a role in cancer and thus be considered as potential therapeutic targets or diagnostic/prognostic biomarkers. Here, we have reviewed all the studies where WGCNA has been applied to gene expression data from bladder cancer patients. We have shown the importance of this new approach in identifying candidate biomarkers and therapeutic targets. They include both genes and miRNAs and some of them have already been identified in the literature to have a role in bladder cancer initiation, progression, metastasis, and patient survival.

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“…In previous research investigating these SNPs, female CYP3A4*22 carriers were found to be at increased risk of grade 3-4 toxicity during docetaxel treatment and of neurotoxicity during paclitaxel treatment [12,13]. In patients with advanced urothelial cell carcinoma (UCC) treated with cabazitaxel, CYP3A5*1 has been associated with a reduced risk of gastrointestinal toxicity and a shorter progression-free survival (PFS) [14]. Additionally, genetic polymorphisms in CYP3A4 and CYP3A5 have been associated with an increased docetaxel clearance [15].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, genetic polymorphisms in CYP3A4 and CYP3A5 have been associated with an increased docetaxel clearance [15]. ABCB1 polymorphisms were found to be related to increased grade 3-4 toxicity [14]. SNPs in SLCO1B1 and SLCO1B3 were not shown to be associated in pharmacokinetic differences in docetaxel in European population [16,17].…”

Section: Introductionmentioning

confidence: 99%

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The influence of single-nucleotide polymorphisms on overall survival and toxicity in cabazitaxel-treated patients with metastatic castration-resistant prostate cancer

Belderbos

Singh

Agema

et al. 2020

Cancer Chemother Pharmacol

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Purpose Cabazitaxel, used in patients with metastatic castration-resistant prostate cancer (mCRPC), is associated with adverse events which may require dose reductions or discontinuation of treatment. We investigated the potential association of single-nucleotide polymorphisms (SNPs) in genes encoding drug transporters and drug-metabolizing enzymes with cabazitaxel toxicity, overall survival (OS) and pharmacokinetics (PK). Methods A total of 128 cabazitaxel-treated mCRPC patients, of whom prospectively collected data on toxicity and OS were available and 24 mCRPC patients with available cabazitaxel PK measurements, were genotyped using genomic DNA obtained from EDTA blood. The SLCO1B1 (388A > G; *1B; rs2306283 and 521 T > C; *5; rs4149056 and haplotype SLCO1B1*15), SLCO1B3 (334 T > G; rs4149117), CYP3A4 (*22; rs35599367), CYP3A5 (*3; rs776746), ABCB1 (3435C > T; rs1045642), and TUBB1 (57 + 87A > C; rs463312) SNPs were tested for their association with clinical and PK parameters by univariate/ multivariate logistic regression, log-rank test, or Kruskal-Wallis test. Results The SLCO1B1*15 haplotype was significantly associated with a lower incidence of leukopenia and neutropenia (p = 0.020 and p = 0.028, respectively). Patients harboring a homozygous variant for SLCO1B1*1B experienced higher rate ≥ grade 3 (p = 0.042). None of the SNPs were associated with pharmacokinetics or OS. Conclusions In this study, SLCO1B1 (SLCO1B1*15 and SLCO1B1*1B) was associated with cabazitaxel-induced adverse events in mCRPC patients. As the associations were opposite to previous studies in other drugs and contradicted an underlying pharmacokinetic rationale, these findings are likely to be false-positive and would ideally be validated with even larger (pharmacokinetic) cohorts.

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SNPs Associated with Activity and Toxicity of Cabazitaxel in Patients with Advanced Urothelial Cell Carcinoma

Abstract: Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

Cited by 8 publications

References 31 publications

Genetic variation in human drug-related genes

Genetic variation in human drug-related genes

Emerging Biomarkers in Bladder Cancer Identified by Network Analysis of Transcriptomic Data

The influence of single-nucleotide polymorphisms on overall survival and toxicity in cabazitaxel-treated patients with metastatic castration-resistant prostate cancer

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