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Clin Cancer Res. 2019 Jul 11. pii: clincanres.0113.2019. doi: 10.1158/1078-0432.CCR-19-0113. [Epub ahead of print]

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Author information

1
Medicine, University of Chicago.
2
Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, Comprehensive Cancer Center, University of Chicago.
3
Biostatistics, Indiana University Indianapolis.
4
Biological Sciences Division, University of Chicagoo.
5
Biology, Loyola University Chicago.
6
Simon Cancer Center, Indiana University - Purdue University Indianapolis.
7
Medicine, Memorial Sloan Kettering Cancer Center.
8
Epidemiology, Indiana University Bloomington.
9
Department of Surgery, Princess Margaret Cancer Center, University of Toronto.
10
Hematology-Oncology, University of Pennsylvania.
11
Medicine, University of Rochester.
12
Vancouver Centre, BC Cancer - Vancouver Centre.
13
Center for Integrative Medical Sciences, RIKEN.
14
Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences.
15
University of Massachusetts Boston.
16
R&D, NMS Labs.
17
Div of Oncology/Hematology, Indiana University Hospital N582.
18
National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital.
19
University of Indiana.
20
Medicine, University of Chicago edolan@medicine.bsd.uchicago.edu.

Abstract

PURPOSE:

Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels.

EXPERIMENTAL DESIGN:

Eligible TCS given 300 or 400 (±15) mg/m2cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a bi-exponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model.

RESULTS:

Serum platinumlevels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13x10-3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58x10-3). Patients with high residual platinum levels experienced greater Raynaud's phenomenon than those with medium or low levels (age-adjusted ORhigh/low =1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low= 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6x10-8, a SNP intronic to MYH14) Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

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