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Grant Details

Grant Number: 2R01CA157823-07A1 Interpret this number
Primary Investigator: Travis, Lois
Organization: Indiana Univ-Purdue Univ At Indianapolis
Project Title: Genetic Susceptibility and Biomarkers of Platinum-Related Toxicities
Fiscal Year: 2020


Abstract

ABSTRACT Platinum compounds are the most widely used group of cytotoxic drugs worldwide. Each year more than 5.8 million patients are diagnosed with a cancer for which first-line therapy can potentially include platinating agents. Despite over 30 years of use, there are few means of identifying patients at risk for platinum-induced ototoxicity or neuropathy who might be offered alternative therapy or reduced-dose regimens. For patients who must receive platinum, there are no approved preventive measures and few therapies for these toxicities. To help fill these important gaps, in our initial project period, we established the first well-characterized clinical cohort of over 2,000 testicular cancer survivors (TCS) cured with homogeneous cisplatin-based chemotherapy (without other ototoxic/neuropathic drugs) and made inroads into the genetics of ototoxicity and neuropathy. Our initial project period was highly productive. We published 16 manuscripts (3 in the Journal of Clinical Oncology), plus 3 others under review. Our baseline, cross-sectional results showed that 80% of our patients had hearing loss on audiometric testing, with 1 in 5 classified as severe-to-profound (a level at which hearing aids are recommended); 56% had neuropathy; and 40% had tinnitus. We found that a SNP in deafness gene WFS1 that was related to hearing loss (P=1.4x10-8) also showed a significant interaction with cisplatin dose, thus having potential clinical impact to predict susceptibility. At a young median age (37 years), 38% of TCS already had ≥3 adverse health outcomes (range 1-11). Given this early burden, critical unanswered questions remain and will be addressed in the next grant cycle: (1) characterization of the longitudinal trajectory of platinum toxicities, including the role of comorbidities, modifiable risk factors, and residual serum platinum levels; (2) the impact of toxicities on health-related quality of life and patient functioning; and (3) further elucidation of the role of genetic variation in platinum toxicities to identify high-risk subgroups. Our aims are: Aim 1. Characterize the longitudinal trajectory of platinum-related ototoxicity and neuropathy, repeating audiometry, and expanding data collection for the first time to include a comprehensive set of physical and psychosocial domains to inform the eventual development of evidence-based guidelines for TCS follow-up; Aim 2. Evaluate for the first time the impact of cisplatin-related hearing loss, tinnitus and neuropathy and their severity on physical, emotional and social patient functioning; Aim 3. Identify additional genetic variation that predisposes patients to platinum-related ototoxicity and neuropathy and that influences residual serum platinum levels through genotyping and whole exome sequencing. IMPACT: Findings derived from our unique clinical cohort will provide the first comprehensive, longitudinal assessment of multiple platinum-related toxicities in any large, homogenously treated cohort of adult-onset cancer survivors and help inform the eventual development of evidence-based guidelines for TCS follow- up. Our findings will also provide the basis for the development of preventive and interventional strategies for cisplatin- related toxicities associated not only with significant impairment of quality of life, but substantial morbidity.



Publications

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.
Authors: Trendowski M.R. , El-Charif O. , Ratain M.J. , Monahan P. , Mu Z. , Wheeler H.E. , Dinh P.C. , Feldman D.R. , Ardeshir-Rouhani-Fard S. , Hamilton R.J. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-10-01; 25(19), p. 5913-5924.
EPub date: 2019-07-11.
PMID: 31296530
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Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms.
Authors: El Charif O. , Mapes B. , Trendowski M.R. , Wheeler H.E. , Wing C. , Dinh P.C. , Frisina R.D. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-07-01; 25(13), p. 4104-4116.
EPub date: 2019-04-05.
PMID: 30952644
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Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors.
Authors: Abu Zaid M. , Dinh P.C. , Monahan P.O. , Fung C. , El-Charif O. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , Cook R. , et al. .
Source: Journal of the National Comprehensive Cancer Network : JNCCN, 2019-05-01; 17(5), p. 459-468.
PMID: 31085753
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Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities.
Authors: Trendowski M.R. , El Charif O. , Dinh P.C. , Travis L.B. , Dolan M.E. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-02-15; 25(4), p. 1147-1155.
EPub date: 2018-10-10.
PMID: 30305294
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Predicting Cardiovascular Disease Among Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy: Application of the Framingham Risk Score.
Authors: Feldman D.R. , Ardeshir-Rouhani-Fard S. , Monahan P. , Sesso H.D. , Fung C. , Williams A.M. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , Cook R. , et al. .
Source: Clinical genitourinary cancer, 2018 08; 16(4), p. e761-e769.
EPub date: 2018-02-05.
PMID: 29534941
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Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation.
Authors: Gamazon E.R. , Segrè A.V. , van de Bunt M. , Wen X. , Xi H.S. , Hormozdiari F. , Ongen H. , Konkashbaev A. , Derks E.M. , Aguet F. , et al. .
Source: Nature genetics, 2018 07; 50(7), p. 956-967.
EPub date: 2018-06-28.
PMID: 29955180
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Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study.
Authors: Kerns S.L. , Fung C. , Monahan P.O. , Ardeshir-Rouhani-Fard S. , Abu Zaid M.I. , Williams A.M. , Stump T.E. , Sesso H.D. , Feldman D.R. , Hamilton R.J. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018-05-20; 36(15), p. 1505-1512.
EPub date: 2018-04-04.
PMID: 29617189
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Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors.
Authors: Zaid M.A. , Gathirua-Mwangi W.G. , Fung C. , Monahan P.O. , El-Charif O. , Williams A.M. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , et al. .
Source: Journal of the National Comprehensive Cancer Network : JNCCN, 2018 03; 16(3), p. 257-265.
PMID: 29523664
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Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma.
Authors: Gamazon E.R. , Trendowski M.R. , Wen Y. , Wing C. , Delaney S.M. , Huh W. , Wong S. , Cox N.J. , Dolan M.E. .
Source: Scientific reports, 2018-01-15; 8(1), p. 733.
EPub date: 2018-01-15.
PMID: 29335598
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Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Authors: Dolan M.E. , El Charif O. , Wheeler H.E. , Gamazon E.R. , Ardeshir-Rouhani-Fard S. , Monahan P. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2017-10-01; 23(19), p. 5757-5768.
EPub date: 2017-06-13.
PMID: 28611204
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Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality.
Authors: Mapes B. , El Charif O. , Al-Sawwaf S. , Dolan M.E. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2017-08-01; 23(15), p. 4010-4019.
EPub date: 2017-04-25.
PMID: 28442506
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Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy.
Authors: Wing C. , Komatsu M. , Delaney S.M. , Krause M. , Wheeler H.E. , Dolan M.E. .
Source: Stem cell research, 2017 07; 22, p. 79-88.
EPub date: 2017-06-15.
PMID: 28645005
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Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.
Authors: Wheeler H.E. , Gamazon E.R. , Frisina R.D. , Perez-Cervantes C. , El Charif O. , Mapes B. , Fossa S.D. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2017-07-01; 23(13), p. 3325-3333.
EPub date: 2016-12-30.
PMID: 28039263
Related Citations

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.
Authors: Fung C. , Sesso H.D. , Williams A.M. , Kerns S.L. , Monahan P. , Abu Zaid M. , Feldman D.R. , Hamilton R.J. , Vaughn D.J. , Beard C.J. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017-04-10; 35(11), p. 1211-1222.
EPub date: 2017-02-27.
PMID: 28240972
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High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience.
Authors: Adra N. , Abonour R. , Althouse S.K. , Albany C. , Hanna N.H. , Einhorn L.H. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017-04-01; 35(10), p. 1096-1102.
EPub date: 2016-11-21.
PMID: 27870561
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Increased pancreatic cancer risk following radiotherapy for testicular cancer.
Authors: Hauptmann M. , Børge Johannesen T. , Gilbert E.S. , Stovall M. , van Leeuwen F.E. , Rajaraman P. , Smith S.A. , Weathers R.E. , Aleman B.M. , Andersson M. , et al. .
Source: British journal of cancer, 2016-09-27; 115(7), p. 901-8.
EPub date: 2016-09-06.
PMID: 27599043
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Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer.
Authors: Frisina R.D. , Wheeler H.E. , Fossa S.D. , Kerns S.L. , Fung C. , Sesso H.D. , Monahan P.O. , Feldman D.R. , Hamilton R. , Vaughn D.J. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2016-08-10; 34(23), p. 2712-20.
EPub date: 2016-06-27.
PMID: 27354478
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Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014.
Authors: Adra N. , Althouse S.K. , Liu H. , Brames M.J. , Hanna N.H. , Einhorn L.H. , Albany C. .
Source: Annals of oncology : official journal of the European Society for Medical Oncology, 2016 05; 27(5), p. 875-9.
EPub date: 2016-02-09.
PMID: 26861605
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Novel genetic predictors of venous thromboembolism risk in African Americans.
Authors: Hernandez W. , Gamazon E.R. , Smithberger E. , O'Brien T.J. , Harralson A.F. , Tuck M. , Barbour A. , Kittles R.A. , Cavallari L.H. , Perera M.A. .
Source: Blood, 2016-04-14; 127(15), p. 1923-9.
EPub date: 2016-02-17.
PMID: 26888256
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Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor.
Authors: Adra N. , Sayar H. , Einhorn L.H. .
Source: JAMA oncology, 2016 Mar; 2(3), p. 391-2.
PMID: 26632950
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Chemotherapy-induced peripheral neuropathy: Current status and progress.
Authors: Brewer J.R. , Morrison G. , Dolan M.E. , Fleming G.F. .
Source: Gynecologic oncology, 2016 Jan; 140(1), p. 176-83.
EPub date: 2015-11-07.
PMID: 26556766
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Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study.
Authors: Fung C. , Fossa S.D. , Milano M.T. , Sahasrabudhe D.M. , Peterson D.R. , Travis L.B. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015-10-01; 33(28), p. 3105-15.
EPub date: 2015-08-03.
PMID: 26240226
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Utilization of sperm banking and barriers to its use in testicular cancer patients.
Authors: Sonnenburg D.W. , Brames M.J. , Case-Eads S. , Einhorn L.H. .
Source: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 2015 Sep; 23(9), p. 2763-8.
EPub date: 2015-02-15.
PMID: 25680764
Related Citations

Increased stomach cancer risk following radiotherapy for testicular cancer.
Authors: Hauptmann M. , Fossa S.D. , Stovall M. , van Leeuwen F.E. , Johannesen T.B. , Rajaraman P. , Gilbert E.S. , Smith S.A. , Weathers R.E. , Aleman B.M. , et al. .
Source: British journal of cancer, 2015-01-06; 112(1), p. 44-51.
EPub date: 2014-11-04.
PMID: 25349972
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Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.
Authors: Wheeler H.E. , Wing C. , Delaney S.M. , Komatsu M. , Dolan M.E. .
Source: PloS one, 2015; 10(2), p. e0118020.
EPub date: 2015-02-17.
PMID: 25689802
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Testicular cancer: a reflection on 50 years of discovery.
Authors: Hanna N. , Einhorn L.H. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014-10-01; 32(28), p. 3085-92.
EPub date: 2014-07-14.
PMID: 25024068
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Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics.
Authors: Travis L.B. , Fossa S.D. , Sesso H.D. , Frisina R.D. , Herrmann D.N. , Beard C.J. , Feldman D.R. , Pagliaro L.C. , Miller R.C. , Vaughn D.J. , et al. .
Source: Journal of the National Cancer Institute, 2014-03-12; 106(5), .
EPub date: 2014-03-12.
PMID: 24623533
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Solid tumors after chemotherapy or surgery for testicular nonseminoma: a population-based study.
Authors: Fung C. , Fossa S.D. , Milano M.T. , Oldenburg J. , Travis L.B. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2013-10-20; 31(30), p. 3807-14.
EPub date: 2013-09-16.
PMID: 24043737
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Outcomes in stage I testicular seminoma: a population-based study of 9193 patients.
Authors: Beard C.J. , Travis L.B. , Chen M.H. , Arvold N.D. , Nguyen P.L. , Martin N.E. , Kuban D.A. , Ng A.K. , Hoffman K.E. .
Source: Cancer, 2013-08-01; 119(15), p. 2771-7.
EPub date: 2013-04-30.
PMID: 23633409
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