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Usefulness of Current Candidate Genetic Markers to Identify Childhood Cancer Patients at Risk for Platinum-Induced Ototoxicity: Results of the European PanCareLIFE Cohort Study

39 Pages Posted: 23 Apr 2020

See all articles by Thorsten Langer

Thorsten Langer

University of Leipzig - Department of Pediatric Oncology and Hematology

Eva Clemens

Princess Máxima Center for Pediatric Oncology

Linda Broer

Erasmus University Rotterdam (EUR) - Department of Internal Medicine

Lara Maier

Ulm University - Institute of Pharmacology of Natural Products and Clinical Pharmacology

Andre G. Uitterlinden

Erasmus University Rotterdam (EUR), Medical Center, Department of Internal Medicine ; Erasmus University Rotterdam (EUR), Medical Center, Department of Epidemiology

Andrica C. H. de Vries

Princess Máxima Center for Pediatric Oncology

Martine van Grotel

Princess Máxima Center for Pediatric Oncology

Saskia F.M. Pluijm

Princess Máxima Center for Pediatric Oncology

Harald Binder

Johannes Gutenberg University Mainz - University Medical Center

Benjamin Mayer

Ulm University - Institute of Epidemiology and Medical Biometry

Annika von dem Knesebeck

University of Leipzig - Department of Pediatric Oncology and Hematology

Julianne Byrne

Boyne Research Institute

Eline van Dulmen-den Broeder

Princess Máxima Center for Pediatric Oncology

Marco Crocco

IRCCS Istituto Giannina Gaslini - Department of Neurooncology

Desiree Grabow

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Peter Kaatsch

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Melanie Kaiser

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Claudia Spix

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Line Kenborg

Danish Cancer Society Research Centre - Childhood Cancer Research Group

Jeanette Falck Winther

Danish Cancer Society Research Centre - Childhood Cancer Research Group; Aarhus University - Department of Clinical Medicine

Catherine Rechnitzer

University of Copenhagen - Department of Pediatrics and Adolescent Medicine

Henrik Hasle

Aarhus University - Department of Pediatrics

Tomas Kepak

University Hospital Brno

Anne-Lotte F. van der Kooi

Princess Máxima Center for Pediatric Oncology

Leontien C. Kremer

Princess Máxima Center for Pediatric Oncology

Jarmila Kruseova

Motol University Hospital - Department of Children Hemato-Oncology

Stefan Bielack

Stuttgart Cancer Center - Department of Pediatric Oncology, Hematology, Immunology

Benjamin Sorg

Stuttgart Cancer Center - Department of Pediatric Oncology, Hematology, Immunology

Stefanie Hecker-Nolting

Stuttgart Cancer Center - Department of Pediatric Oncology, Hematology, Immunology

Claudia E. Kuehni

University of Bern - Institute of Social and Preventive Medicine

Marc Ansari

University of Geneva - Department of Pediatrics, Oncology and Hematology Unit

Martin Kompis

University of Bern - Department of Otolaryngology, Head and Neck Surgery

Heleen van der Pal

Princess Máxima Center for Pediatric Oncology

Ross Parfitt

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Dirk Deuster

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Peter Matulat

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Amelie Tillmanns

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Wim J. E. Tissing

Princess Máxima Center for Pediatric Oncology

Jörn D. Beck

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg - Hospital for Children and Adolescents

Susanne Elsner

University of Lubeck - Institute of Social Medicine & Epidemiology

Antoinette am Zehnhoff-Dinnesen

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Marry M. van den Heuvel-Eibrink

Princess Máxima Center for Pediatric Oncology

Oliver Zolk

University of Leipzig - Department of Pediatric Oncology and Hematology

PanCareLIFE Consortium Group

Independent

More...

Abstract

Background Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in the FDA drug label and a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers.  

Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, andACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined.

Findings: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at start of platinum treatment, cranial radiation, and the interaction term [platinum compound]*[cumulative dose of cisplatin]. Meta-analysis confirmed an allelic association of SLC22A2 rs316019 with cisplatin ototoxicity (odds ratio 1.46, 95% CI 1.10–1.95, p=0.009). Predictive performance of the genetic markers was poor, compared with the clinical risk factors.  

Interpretation: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, our study cannot recommend the use of any of the investigated genetic markers to guide the management and prevention of cisplatin-induced hearing loss. The study results will require a revision of the pharmacogenetic guideline and the FDA drug label.   

Funding Statement: This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 602030. CEK was funded by the Swiss Cancer Research Foundation (grant no. 4157-02-2017), the Swiss Cancer League (grant no. 3412-02-2014), the Bernese Cancer League, and the Lung League Bern. JFW received supplementary funding from the Danish Childhood Cancer Foundation and Soroptimist International Helsingør, Denmark.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: The PanCareLIFE study has been approved by the local ethics committees: Kantonale Ethikkommission Bern, 362/2015; Comitate Etico Regionale, 507REG2014; Ethical Committee University Hospital Brno, June 11, 2016; Ethics Committee Fakultni Nemocnice v Motole, Prague; De Videnskabsetiske Komiteer Region Hovedstaden, H-1- 2014-125; Ethikkommission Medizinische Universität Graz, 27-015 ex 14/15; Ethikkommission der Universität Ulm, 160/17; Ethikkommission der Universität zu Lübeck, 14/181; Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität Münster, 2014-619; Medische Ethische Toetsings Commissie Erasmus MC; Medisch Ethische Toetsingscommissie, 2015_202. The informed consent of the patient (if adult) or his/her legal representative has been obtained.

Keywords: Cancer survivors; childhood cancer; antineoplastic drugs; cisplatin: carboplati; druginduced ototoxicity; adverse drug reaction; Pharmacogenetics; genetic markers; multicenter cohort study

Suggested Citation

Langer, Thorsten and Clemens, Eva and Broer, Linda and Maier, Lara and Uitterlinden, Andre G. and de Vries, Andrica C. H. and van Grotel, Martine and Pluijm, Saskia F.M. and Binder, Harald and Mayer, Benjamin and von dem Knesebeck, Annika and Byrne, Julianne and van Dulmen-den Broeder, Eline and Crocco, Marco and Grabow, Desiree and Kaatsch, Peter and Kaiser, Melanie and Spix, Claudia and Kenborg, Line and Winther, Jeanette Falck and Rechnitzer, Catherine and Hasle, Henrik and Kepak, Tomas and van der Kooi, Anne-Lotte F. and Kremer, Leontien C. and Kruseova, Jarmila and Bielack, Stefan and Sorg, Benjamin and Hecker-Nolting, Stefanie and Kuehni, Claudia E. and Ansari, Marc and Kompis, Martin and van der Pal, Heleen and Parfitt, Ross and Deuster, Dirk and Matulat, Peter and Tillmanns, Amelie and Tissing, Wim J. E. and Beck, Jörn D. and Elsner, Susanne and am Zehnhoff-Dinnesen, Antoinette and van den Heuvel-Eibrink, Marry M. and Zolk, Oliver and Group, PanCareLIFE Consortium, Usefulness of Current Candidate Genetic Markers to Identify Childhood Cancer Patients at Risk for Platinum-Induced Ototoxicity: Results of the European PanCareLIFE Cohort Study (3/10/2020). Available at SSRN: https://ssrn.com/abstract=3552808 or http://dx.doi.org/10.2139/ssrn.3552808

Thorsten Langer (Contact Author)

University of Leipzig - Department of Pediatric Oncology and Hematology

Lübeck
Germany

Eva Clemens

Princess Máxima Center for Pediatric Oncology

Netherlands

Linda Broer

Erasmus University Rotterdam (EUR) - Department of Internal Medicine

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Lara Maier

Ulm University - Institute of Pharmacology of Natural Products and Clinical Pharmacology

Ulm
Germany

Andre G. Uitterlinden

Erasmus University Rotterdam (EUR), Medical Center, Department of Internal Medicine

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Erasmus University Rotterdam (EUR), Medical Center, Department of Epidemiology

Rotterdam
Netherlands

Andrica C. H. De Vries

Princess Máxima Center for Pediatric Oncology

Heidelberglaan 25
3584 CS Utrecht
Germany

Martine Van Grotel

Princess Máxima Center for Pediatric Oncology

Netherlands

Saskia F.M. Pluijm

Princess Máxima Center for Pediatric Oncology

Heidelberglaan 25
3584 CS Utrecht
Germany

Harald Binder

Johannes Gutenberg University Mainz - University Medical Center ( email )

Langenbeckstrasse 1
International Office Building 301
Mainz, D-55099
Germany

Benjamin Mayer

Ulm University - Institute of Epidemiology and Medical Biometry

Ulm
Germany

Annika Von dem Knesebeck

University of Leipzig - Department of Pediatric Oncology and Hematology

Lübeck
Germany

Julianne Byrne

Boyne Research Institute

Drogheda
Ireland

Eline Van Dulmen-den Broeder

Princess Máxima Center for Pediatric Oncology

Heidelberglaan 25
3584 CS Utrecht
Germany

Marco Crocco

IRCCS Istituto Giannina Gaslini - Department of Neurooncology

Genova
Italy

Desiree Grabow

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Mainz
Germany

Peter Kaatsch

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Mainz
Germany

Melanie Kaiser

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Mainz
Germany

Claudia Spix

Johannes Gutenberg University Mainz - German Childhood Cancer Registry

Mainz
Germany

Line Kenborg

Danish Cancer Society Research Centre - Childhood Cancer Research Group

2100 Copenhagen
Denmark

Jeanette Falck Winther

Danish Cancer Society Research Centre - Childhood Cancer Research Group

2100 Copenhagen
Denmark

Aarhus University - Department of Clinical Medicine

Denmark

Catherine Rechnitzer

University of Copenhagen - Department of Pediatrics and Adolescent Medicine

Copenhagen
Denmark

Henrik Hasle

Aarhus University - Department of Pediatrics

Aarhus
Denmark

Tomas Kepak

University Hospital Brno

Brno
Czech Republic

Anne-Lotte F. Van der Kooi

Princess Máxima Center for Pediatric Oncology

Netherlands

Leontien C. Kremer

Princess Máxima Center for Pediatric Oncology

Heidelberglaan 25
3584 CS Utrecht
Germany

Jarmila Kruseova

Motol University Hospital - Department of Children Hemato-Oncology

Prague
Czech Republic

Stefan Bielack

Stuttgart Cancer Center - Department of Pediatric Oncology, Hematology, Immunology

Stuttgart
Germany

Benjamin Sorg

Stuttgart Cancer Center - Department of Pediatric Oncology, Hematology, Immunology

Stuttgart
Germany

Stefanie Hecker-Nolting

Stuttgart Cancer Center - Department of Pediatric Oncology, Hematology, Immunology

Stuttgart
Germany

Claudia E. Kuehni

University of Bern - Institute of Social and Preventive Medicine

Bern
Switzerland

Marc Ansari

University of Geneva - Department of Pediatrics, Oncology and Hematology Unit

Geneva
Switzerland

Martin Kompis

University of Bern - Department of Otolaryngology, Head and Neck Surgery

Bern
Switzerland

Heleen van der Pal

Princess Máxima Center for Pediatric Oncology

Heidelberglaan 25
3584 CS Utrecht
Germany

Ross Parfitt

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Munster
Germany

Dirk Deuster

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Munster
Germany

Peter Matulat

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Munster
Germany

Amelie Tillmanns

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Munster
Germany

Wim J. E. Tissing

Princess Máxima Center for Pediatric Oncology

Heidelberglaan 25
3584 CS Utrecht
Germany

Jörn D. Beck

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg - Hospital for Children and Adolescents

Erlangen
Germany

Susanne Elsner

University of Lubeck - Institute of Social Medicine & Epidemiology

Lübeck
Germany

Antoinette Am Zehnhoff-Dinnesen

Westphalian Wilhelm University - Department of Phoniatrics and Pedaudiology

Munster
Germany

Marry M. Van den Heuvel-Eibrink

Princess Máxima Center for Pediatric Oncology

Netherlands

Oliver Zolk

University of Leipzig - Department of Pediatric Oncology and Hematology ( email )

Lübeck
Germany