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 language | English |
|---|---|
| Pages (from-to) | 5913-5924 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 25 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 01-10-2019 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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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 journal › Article
TY - JOUR
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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85072827982&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0113
DO - 10.1158/1078-0432.CCR-19-0113
M3 - Article
C2 - 31296530
AN - SCOPUS:85072827982
VL - 25
SP - 5913
EP - 5924
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -