PMID- 28723497
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240326
IS  - 2405-4569 (Electronic)
IS  - 2405-4569 (Linking)
VI  - 2
IP  - 6
DP  - 2016 Dec 15
TI  - Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic 
      Renal Cell Carcinoma.
PG  - 633-639
LID - S2405-4569(16)30019-0 [pii]
LID - 10.1016/j.euf.2016.03.017 [doi]
AB  - 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.
CI  - Copyright (c) 2016 European Association of Urology. Published by Elsevier B.V. All 
      rights reserved.
FAU - de Velasco, Guillermo
AU  - de Velasco G
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Gray, Kathryn P
AU  - Gray KP
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 
      Biostatistics and Computational Biology, Harvard School of Public Health, Boston, 
      MA, USA.
FAU - Hamieh, Lana
AU  - Hamieh L
AD  - Division of Pulmonary Medicine, Brigham and Women's Hospital, Boston, MA, USA.
FAU - Urun, Yuksel
AU  - Urun Y
AD  - Department of Medical Oncology, Ankara University School of Medicine, Turkey.
FAU - Carol, Hallie A
AU  - Carol HA
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Fay, Andre P
AU  - Fay AP
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 
      PUCRS School of Medicine, Porto Alegre, Brazil.
FAU - Signoretti, Sabina
AU  - Signoretti S
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 
      Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
AD  - Division of Pulmonary Medicine, Brigham and Women's Hospital, Boston, MA, USA.
FAU - McDermott, David F
AU  - McDermott DF
AD  - Department of Medical Oncology, Beth-Israel Deaconess Medical Center, Boston, MA, 
      USA.
FAU - Freedman, Matthew
AU  - Freedman M
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Pomerantz, Mark M
AU  - Pomerantz MM
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Choueiri, Toni K
AU  - Choueiri TK
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 
      Electronic address: toni_choueiri@dfci.harvard.edu.
LA  - eng
GR  - P50 CA101942/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160423
PL  - Netherlands
TA  - Eur Urol Focus
JT  - European urology focus
JID - 101665661
PMC - PMC5520643
MID - NIHMS774555
OTO - NOTNLM
OT  - Biomarker
OT  - Genomics
OT  - Polymorphisms
OT  - Renal cell carcinoma
OT  - Single-nucleotide polymorphism
OT  - Targeted therapy
EDAT- 2017/07/21 06:00
MHDA- 2017/07/21 06:01
PMCR- 2017/12/15
CRDT- 2017/07/21 06:00
PHST- 2016/02/02 00:00 [received]
PHST- 2016/03/04 00:00 [revised]
PHST- 2016/03/26 00:00 [accepted]
PHST- 2017/07/21 06:00 [entrez]
PHST- 2017/07/21 06:00 [pubmed]
PHST- 2017/07/21 06:01 [medline]
PHST- 2017/12/15 00:00 [pmc-release]
AID - S2405-4569(16)30019-0 [pii]
AID - 10.1016/j.euf.2016.03.017 [doi]
PST - ppublish
SO  - Eur Urol Focus. 2016 Dec 15;2(6):633-639. doi: 10.1016/j.euf.2016.03.017. Epub 
      2016 Apr 23.