Elsevier

European Urology Focus

Volume 2, Issue 6, 15 December 2016, Pages 633-639
European Urology Focus

Platinum Priority – Kidney Cancer
Editorial by Jesus Garcia-Donas, Sandra Falagan and Juan Francisco Rodriguez-Moreno on pp. 640–641 of this issue
Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma

https://doi.org/10.1016/j.euf.2016.03.017Get rights and content

Abstract

Background

Targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity.

Objective

To investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs).

Design, setting, and participants

Germline DNA was extracted from blood or normal kidney tissue from mRCC patients of Caucasian ethnicity in two cohorts treated with either sunitinib (n = 159) or mTOR inhibitors (n = 62). Six SNPs in three candidate genes (CYP3A4: rs2242480, rs4646437, and rs2246709; CYP3A5: rs15524; and ABCB1: rs2032582 and rs1045642) were analyzed.

Outcome measurements and statistical analysis

Primary endpoints were grade ≥3 AEs for all patients; grade ≥3 hypertension in the sunitinib cohort, and any grade pneumonitis in the mTOR inhibitors cohort. A logistic regression model was used to assess the association between SNPs and AEs, with adjustment for relevant clinical factors.

Results and limitations

In total, 221 samples were successfully genotyped for the selected SNPs. In the sunitinib cohort, the CYP3A4 rs464637 AG variant was associated with a lower risk of high-grade AEs (odds ratio 0.27, 95% confidence interval 0.08–0.88; p = 0.03), but no SNPs were associated with hypertension. In the mTOR inhibitor cohort, none of the selected SNPs was associated with analyzed toxicities.

Conclusions

We observed an association between CYP3A4 polymorphisms and toxicity outcomes in mRCC patients treated with sunitinib, but not with everolimus or temsirolimus. Our findings are exploratory in nature, and further validation in independent and larger cohorts is needed.

Patient summary

We found that variants of CYP3A4, a gene involved in drug metabolism, are associated with sunitinib toxicity. This information may help in better selection of patients for targeted therapies in metastatic renal cell carcinoma.

Introduction

The introduction of targeted therapy (TT) in the management of metastatic renal cell carcinoma (mRCC) has led to improved outcomes at the expense of side effects associated with treatment [1]. Since mRCC remains an incurable disease, quality of life (QoL) is an important consideration for patients. During the last decade, two different types of TT agents have been used for the treatment of mRCC: vascular endothelial growth factor-TT (VEGF-TT), mainly TKIs (tyrosine kinase inhibitors); and mTOR inhibitors. These drugs are generally well tolerated, but major toxicities frequently arise. Some series show that up to 50% of patients can develop grade ≥3 toxicities, and a significant number experience adverse events (AEs) leading to treatment interruption, dose reduction, and drug discontinuation [2]. Therefore, individual variability in drug efficacy resulting in therapeutic failure is an important issue. Identification of genomic variants may aid in the development of strategies for patient selection that could lead to improved adherence to treatment and better QoL. Moreover, pharmacogenomics may reduce costs and improve optimal drug development [3].

The mechanism underlying TT toxicity is complex and not entirely understood [4]. While fatigue/asthenia, rash, and diarrhea are common to both sunitinib and mTOR inhibitors, other AEs are class-specific [1], [2]. For example, sunitinib is associated with higher incidence of hypertension and hand-foot syndrome, while higher incidence of infections, pneumonitis, hypercholesterolemia, and hyperglycemia has been observed for mTOR inhibitors [2].

Clinical determinants of TT toxicity, such as age, female gender, and low body-surface area, only partly explain the interindividual variability in drug toxicity [5]. Patients with similar clinical characteristics may exhibit wide variability in tolerability for the same drug according to their genetic background [6]. Single-nucleotide polymorphisms (SNPs) in the pharmacokinetic (PK) and pharmacodynamic (PD) pathways for TT agents have been postulated as a complementary explanation for this heterogeneous toxicity [3]. Not all TTs in the same class have the same toxicity profiles, and SNPs may contribute to shape these differences [7]. Sunitinib and mTOR inhibitors are significantly metabolized by cytochrome P450 proteins, predominantly CYP3A4, leading to variation in serum concentrations of the drugs [8], [9]. Similarly, concentrations may differ according to polymorphisms in transporters such as ABCB1 [10]. Therefore, SNPs of genes involved in drug PK pathways affect the frequency and severity of drug toxicities in mRCC [11], [12]. However, no individual SNP is currently used as a risk factor for TT toxicity in mRCC.

The aim of our study was to assess the association between six SNPs in three core genes implicated in the metabolic and transport pathways for sunitinib and mTOR inhibitors and the risk of grade ≥3 AEs and class-specific AEs such as hypertension in the sunitinib cohort and pneumonitis in the mTOR inhibitor cohort.

Section snippets

Patients

The cohort comprised 221 mRCC patients who received at least one cycle (4 wk on treatment) of sunitinib or mTOR inhibitors as TT at the Dana-Farber/Harvard Cancer Center (DF/HCC) between January 2005 and December 2011 and for whom genotyping was successful. Patients were exclusively of Caucasian ethnicity to ensure no admixture due to ancestry [13]. All patients provided written informed consent. The institutional review board for DF/HCC approved the study. Clinical data were ascertained from

Results

DNA was extracted and successfully genotyped for 221 patients with mRCC who received either sunitinib (n = 159) or temsirolimus or everolimus as an mTOR inhibitor (n = 62). All patients were Caucasian, and 81% had clear-cell RCC (Table 1).

Discussion

We hypothesized that variability in drug toxicity has a heritable component. We interrogated inherited variants for key genes involved in drug metabolism to develop a genetic risk profile. An accurate profile could facilitate individualization of treatment and minimization of toxicity [15]. In our series, in line with published data, most mRCC patients receiving TT experienced side effects, and up to 50% developed grade ≥3 toxicity [16]. Since TT is a noncurative therapy for mRCC and QoL is an

Conclusions

We found a statistically significant association between CYP3A4 rs4646437 polymorphism and high-grade toxicity in patients treated with sunitinib, whereby patients with the AG variant experienced a lower number of high-grade AEs. Testing for associations between genetic polymorphisms and toxicity is feasible and could potentially guide clinicians in selecting optimal personalized therapies for their patients, rather than using a “one size fits all” approach. This is particularly important in

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