Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy

Matthew R. Trendowski, Omar El-Charif, Mark J. Ratain, Patrick Monahan, Zepeng Mu, Heather E. Wheeler, Paul C. Dinh, Darren R. Feldman, Shirin Ardeshir-Rouhani-Fard, Robert J. Hamilton, David J. Vaughn, Chunkit Fung, Christian Kollmannsberger, Taisei Mushiroda, Michiaki Kubo, Robyn Hannigan, Frederick Strathmann, Lawrence H. Einhorn, Sophie D. Fossa, Lois B. TravisM. Eileen Dolan

Research output: Contribution to journalArticle

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/m2 cisplatin 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 biexponential 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 platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P ¼ 2.13 103). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P ¼ 6.58 103). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low ¼ 1.46; P ¼ 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low ¼ 1.68, P ¼ 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P ¼ 4.6 108, 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.

Original languageEnglish (US)
Pages (from-to)5913-5924
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2019

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Platinum
Cisplatin
Genome
Drug Therapy
Serum
Genome-Wide Association Study
Testicular Neoplasms
Single Nucleotide Polymorphism
Survivors
Raynaud Disease
Tinnitus
Luteinizing Hormone
Creatinine
Reference Values
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Trendowski, M. R., El-Charif, O., Ratain, M. J., Monahan, P., Mu, Z., Wheeler, H. E., ... Eileen Dolan, M. (2019). Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy. Clinical Cancer Research, 25(19), 5913-5924. https://doi.org/10.1158/1078-0432.CCR-19-0113

Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy. / Trendowski, Matthew R.; El-Charif, Omar; Ratain, Mark J.; Monahan, Patrick; Mu, Zepeng; Wheeler, Heather E.; Dinh, Paul C.; Feldman, Darren R.; Ardeshir-Rouhani-Fard, Shirin; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Hannigan, Robyn; Strathmann, Frederick; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Eileen Dolan, M.

In: Clinical Cancer Research, Vol. 25, No. 19, 01.10.2019, p. 5913-5924.

Research output: Contribution to journalArticle

Trendowski, MR, El-Charif, O, Ratain, MJ, Monahan, P, Mu, Z, Wheeler, HE, Dinh, PC, Feldman, DR, Ardeshir-Rouhani-Fard, S, Hamilton, RJ, Vaughn, DJ, Fung, C, Kollmannsberger, C, Mushiroda, T, Kubo, M, Hannigan, R, Strathmann, F, Einhorn, LH, Fossa, SD, Travis, LB & Eileen Dolan, M 2019, 'Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy', Clinical Cancer Research, vol. 25, no. 19, pp. 5913-5924. https://doi.org/10.1158/1078-0432.CCR-19-0113
Trendowski, Matthew R. ; El-Charif, Omar ; Ratain, Mark J. ; Monahan, Patrick ; Mu, Zepeng ; Wheeler, Heather E. ; Dinh, Paul C. ; Feldman, Darren R. ; Ardeshir-Rouhani-Fard, Shirin ; Hamilton, Robert J. ; Vaughn, David J. ; Fung, Chunkit ; Kollmannsberger, Christian ; Mushiroda, Taisei ; Kubo, Michiaki ; Hannigan, Robyn ; Strathmann, Frederick ; Einhorn, Lawrence H. ; Fossa, Sophie D. ; Travis, Lois B. ; Eileen Dolan, M. / Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 19. pp. 5913-5924.
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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/m2 cisplatin 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 biexponential 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 platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P ¼ 2.13 103). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P ¼ 6.58 103). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low ¼ 1.46; P ¼ 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low ¼ 1.68, P ¼ 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P ¼ 4.6 108, 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.",
author = "Trendowski, {Matthew R.} and Omar El-Charif and Ratain, {Mark J.} and Patrick Monahan and Zepeng Mu and Wheeler, {Heather E.} and Dinh, {Paul C.} and Feldman, {Darren R.} and Shirin Ardeshir-Rouhani-Fard and Hamilton, {Robert J.} and Vaughn, {David J.} and Chunkit Fung and Christian Kollmannsberger and Taisei Mushiroda and Michiaki Kubo and Robyn Hannigan and Frederick Strathmann and Einhorn, {Lawrence H.} and Fossa, {Sophie D.} and Travis, {Lois B.} and {Eileen Dolan}, M.",
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T1 - Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy

AU - Trendowski, Matthew R.

AU - El-Charif, Omar

AU - Ratain, Mark J.

AU - Monahan, Patrick

AU - Mu, Zepeng

AU - Wheeler, Heather E.

AU - Dinh, Paul C.

AU - Feldman, Darren R.

AU - Ardeshir-Rouhani-Fard, Shirin

AU - Hamilton, Robert J.

AU - Vaughn, David J.

AU - Fung, Chunkit

AU - Kollmannsberger, Christian

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Hannigan, Robyn

AU - Strathmann, Frederick

AU - Einhorn, Lawrence H.

AU - Fossa, Sophie D.

AU - Travis, Lois B.

AU - Eileen Dolan, M.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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/m2 cisplatin 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 biexponential 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 platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P ¼ 2.13 103). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P ¼ 6.58 103). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low ¼ 1.46; P ¼ 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low ¼ 1.68, P ¼ 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P ¼ 4.6 108, 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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