Cancer Medicine (Aug 2023)
Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival
- Anna Morra,
- Maartje A. C. Schreurs,
- Irene L. Andrulis,
- Hoda Anton‐Culver,
- Annelie Augustinsson,
- Matthias W. Beckmann,
- Sabine Behrens,
- Stig E. Bojesen,
- Manjeet K. Bolla,
- Hiltrud Brauch,
- Annegien Broeks,
- Saundra S. Buys,
- Nicola J. Camp,
- Jose E. Castelao,
- Melissa H. Cessna,
- Jenny Chang‐Claude,
- Wendy K. Chung,
- NBCS Collaborators,
- Sarah V. Colonna,
- Fergus J. Couch,
- Angela Cox,
- Simon S. Cross,
- Kamila Czene,
- Mary B. Daly,
- Joe Dennis,
- Peter Devilee,
- Thilo Dörk,
- Alison M. Dunning,
- Miriam Dwek,
- Douglas F. Easton,
- Diana M. Eccles,
- Mikael Eriksson,
- D. Gareth Evans,
- Peter A. Fasching,
- Tanja N. Fehm,
- Jonine D. Figueroa,
- Henrik Flyger,
- Marike Gabrielson,
- Manuela Gago‐Dominguez,
- Montserrat García‐Closas,
- José A. García‐Sáenz,
- Jeanine Genkinger,
- Felix Grassmann,
- Melanie Gündert,
- Eric Hahnen,
- Christopher A. Haiman,
- Ute Hamann,
- Patricia A. Harrington,
- Jaana M. Hartikainen,
- Reiner Hoppe,
- John L. Hopper,
- Richard S. Houlston,
- Anthony Howell,
- ABCTB Investigators,
- kConFab Investigators,
- Anna Jakubowska,
- Wolfgang Janni,
- Helena Jernström,
- Esther M. John,
- Nichola Johnson,
- Michael E. Jones,
- Vessela N. Kristensen,
- Allison W. Kurian,
- Diether Lambrechts,
- Loic Le Marchand,
- Annika Lindblom,
- Jan Lubiński,
- Michael P. Lux,
- Arto Mannermaa,
- Dimitrios Mavroudis,
- Anna Marie Mulligan,
- Taru A. Muranen,
- Heli Nevanlinna,
- Ines Nevelsteen,
- Patrick Neven,
- William G. Newman,
- Nadia Obi,
- Kenneth Offit,
- Andrew F. Olshan,
- Tjoung‐Won Park‐Simon,
- Alpa V. Patel,
- Paolo Peterlongo,
- Kelly‐Anne Phillips,
- Dijana Plaseska‐Karanfilska,
- Eric C. Polley,
- Nadege Presneau,
- Katri Pylkäs,
- Brigitte Rack,
- Paolo Radice,
- Muhammad U. Rashid,
- Valerie Rhenius,
- Mark Robson,
- Atocha Romero,
- Emmanouil Saloustros,
- Elinor J. Sawyer,
- Rita K. Schmutzler,
- Sabine Schuetze,
- Christopher Scott,
- Mitul Shah,
- Snezhana Smichkoska,
- Melissa C. Southey,
- William J. Tapper,
- Lauren R. Teras,
- Rob A. E. M. Tollenaar,
- Katarzyna Tomczyk,
- Ian Tomlinson,
- Melissa A. Troester,
- Celine M. Vachon,
- Elke M. vanVeen,
- Qin Wang,
- Camilla Wendt,
- Hans Wildiers,
- Robert Winqvist,
- Argyrios Ziogas,
- Per Hall,
- Paul D. P. Pharoah,
- Muriel A. Adank,
- Antoinette Hollestelle,
- Marjanka K. Schmidt,
- Maartje J. Hooning
Affiliations
- Anna Morra
- Division of Molecular Pathology The Netherlands Cancer Institute Amsterdam the Netherlands
- Maartje A. C. Schreurs
- Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam the Netherlands
- Irene L. Andrulis
- Fred A. Litwin Center for Cancer Genetics Lunenfeld‐Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada
- Hoda Anton‐Culver
- Department of Medicine, Genetic Epidemiology Research Institute University of California Irvine Irvine California USA
- Annelie Augustinsson
- Oncology, Clinical Sciences in Lund Lund University Lund Sweden
- Matthias W. Beckmann
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen‐EMN, Friedrich‐Alexander University Erlangen‐Nuremberg University Hospital Erlangen Erlangen Germany
- Sabine Behrens
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ) Heidelberg Germany
- Stig E. Bojesen
- Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark
- Manjeet K. Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care University of Cambridge Cambridge UK
- Hiltrud Brauch
- Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology Stuttgart Germany
- Annegien Broeks
- Division of Molecular Pathology The Netherlands Cancer Institute Amsterdam the Netherlands
- Saundra S. Buys
- Department of Internal Medicine and Huntsman Cancer Institute University of Utah Salt Lake City Utah USA
- Nicola J. Camp
- Department of Internal Medicine and Huntsman Cancer Institute University of Utah Salt Lake City Utah USA
- Jose E. Castelao
- Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS) Xerencia de Xestion Integrada de Vigo‐SERGAS Vigo Spain
- Melissa H. Cessna
- Intermountain Healthcare Salt Lake City Utah USA
- Jenny Chang‐Claude
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ) Heidelberg Germany
- Wendy K. Chung
- Departments of Pediatrics and Medicine Columbia University New York New York USA
- NBCS Collaborators
- Department of Cancer Genetics, Institute for Cancer Research Oslo University Hospital‐Radiumhospitalet Oslo Norway
- Sarah V. Colonna
- Department of Internal Medicine and Huntsman Cancer Institute University of Utah Salt Lake City Utah USA
- Fergus J. Couch
- Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA
- Angela Cox
- Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA) University of Sheffield Sheffield UK
- Simon S. Cross
- Department of Neuroscience, Academic Unit of Pathology University of Sheffield Sheffield UK
- Kamila Czene
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Mary B. Daly
- Department of Clinical Genetics Fox Chase Cancer Center Philadelphia Pennsylvania USA
- Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care University of Cambridge Cambridge UK
- Peter Devilee
- Department of Pathology Leiden University Medical Center Leiden the Netherlands
- Thilo Dörk
- Gynaecology Research Unit Hannover Medical School Hannover Germany
- Alison M. Dunning
- Department of Oncology, Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Miriam Dwek
- School of Life Sciences University of Westminster London UK
- Douglas F. Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care University of Cambridge Cambridge UK
- Diana M. Eccles
- Faculty of Medicine University of Southampton Southampton UK
- Mikael Eriksson
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- D. Gareth Evans
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester Manchester Academic Health Science Centre Manchester UK
- Peter A. Fasching
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen‐EMN, Friedrich‐Alexander University Erlangen‐Nuremberg University Hospital Erlangen Erlangen Germany
- Tanja N. Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf Heinrich‐Heine University Düsseldorf Düsseldorf Germany
- Jonine D. Figueroa
- Usher Institute of Population Health Sciences and Informatics The University of Edinburgh Edinburgh UK
- Henrik Flyger
- Department of Breast Surgery, Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark
- Marike Gabrielson
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Manuela Gago‐Dominguez
- Cancer Genetics and Epidemiology Group, SERGAS, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation Complejo Hospitalario Universitario de Santiago Santiago de Compostela Spain
- Montserrat García‐Closas
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute National Institutes of Health Bethesda Maryland USA
- José A. García‐Sáenz
- Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC) Centro Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid Spain
- Jeanine Genkinger
- Department of Epidemiology, Mailman School of Public Health Columbia University New York New York USA
- Felix Grassmann
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Melanie Gündert
- Molecular Epidemiology Group, C080 German Cancer Research Center (DKFZ) Heidelberg Germany
- Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany
- Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine University of Southern California Los Angeles California USA
- Ute Hamann
- Molecular Genetics of Breast Cancer German Cancer Research Center (DKFZ) Heidelberg Germany
- Patricia A. Harrington
- Department of Oncology, Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Jaana M. Hartikainen
- Translational Cancer Research Area University of Eastern Finland Kuopio Finland
- Reiner Hoppe
- Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology Stuttgart Germany
- John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia
- Richard S. Houlston
- Division of Genetics and Epidemiology The Institute of Cancer Research London UK
- Anthony Howell
- Division of Cancer Sciences University of Manchester Manchester UK
- ABCTB Investigators
- Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research University of Sydney Sydney New South Wales Australia
- kConFab Investigators
- Research Department Peter MacCallum Cancer Center Melbourne Victoria Australia
- Anna Jakubowska
- Department of Genetics and Pathology, International Hereditary Cancer Center Pomeranian Medical University Szczecin Poland
- Wolfgang Janni
- Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany
- Helena Jernström
- Oncology, Clinical Sciences in Lund Lund University Lund Sweden
- Esther M. John
- Department of Epidemiology and Population Health Stanford University School of Medicine Stanford California USA
- Nichola Johnson
- The Breast Cancer Now Toby Robins Research Centre The Institute of Cancer Research London UK
- Michael E. Jones
- Division of Genetics and Epidemiology The Institute of Cancer Research London UK
- Vessela N. Kristensen
- Faculty of Medicine, Institute of Clinical Medicine University of Oslo Oslo Norway
- Allison W. Kurian
- Department of Epidemiology and Population Health Stanford University School of Medicine Stanford California USA
- Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics KU Leuven Leuven Belgium
- Loic Le Marchand
- Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii USA
- Annika Lindblom
- Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
- Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center Pomeranian Medical University Szczecin Poland
- Michael P. Lux
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen‐EMN, Friedrich‐Alexander University Erlangen‐Nuremberg University Hospital Erlangen Erlangen Germany
- Arto Mannermaa
- Translational Cancer Research Area University of Eastern Finland Kuopio Finland
- Dimitrios Mavroudis
- Department of Medical Oncology University Hospital of Heraklion Heraklion Greece
- Anna Marie Mulligan
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
- Taru A. Muranen
- Department of Obstetrics and Gynecology, Helsinki University Hospital University of Helsinki Helsinki Finland
- Heli Nevanlinna
- Department of Obstetrics and Gynecology, Helsinki University Hospital University of Helsinki Helsinki Finland
- Ines Nevelsteen
- Department of Oncology, Leuven Multidisciplinary Breast Center, University Hospitals Leuven Leuven Cancer Institute Leuven Belgium
- Patrick Neven
- Department of Oncology, Leuven Multidisciplinary Breast Center, University Hospitals Leuven Leuven Cancer Institute Leuven Belgium
- William G. Newman
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester Manchester Academic Health Science Centre Manchester UK
- Nadia Obi
- Institute for Medical Biometry and Epidemiology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Kenneth Offit
- Clinical Genetics Research Lab, Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York New York USA
- Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill North Carolina USA
- Tjoung‐Won Park‐Simon
- Gynaecology Research Unit Hannover Medical School Hannover Germany
- Alpa V. Patel
- Department of Population Science American Cancer Society Atlanta Georgia USA
- Paolo Peterlongo
- IFOM ETS ‐ The AIRC Institute of Molecular Oncology, Genome Diagnostics Program Milan Italy
- Kelly‐Anne Phillips
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia
- Dijana Plaseska‐Karanfilska
- Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov' MASA Skopje Republic of North Macedonia
- Eric C. Polley
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences Mayo Clinic Rochester Minnesota USA
- Nadege Presneau
- School of Life Sciences University of Westminster London UK
- Katri Pylkäs
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu University of Oulu Oulu Finland
- Brigitte Rack
- Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany
- Paolo Radice
- Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori “Predictive Medicine: Molecular Bases of Genetic Risk” Milan Italy
- Muhammad U. Rashid
- Molecular Genetics of Breast Cancer German Cancer Research Center (DKFZ) Heidelberg Germany
- Valerie Rhenius
- Department of Oncology, Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Mark Robson
- Clinical Genetics Service, Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
- Atocha Romero
- Medical Oncology Department Hospital Universitario Puerta de Hierro Madrid Spain
- Emmanouil Saloustros
- Department of Oncology University Hospital of Larissa Larissa Greece
- Elinor J. Sawyer
- School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus King's College London London UK
- Rita K. Schmutzler
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany
- Sabine Schuetze
- Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany
- Christopher Scott
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences Mayo Clinic Rochester Minnesota USA
- Mitul Shah
- Department of Oncology, Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK
- Snezhana Smichkoska
- Medical Faculty, University Clinic of Radiotherapy and Oncology Ss. Cyril and Methodius University in Skopje Skopje Republic of North Macedonia
- Melissa C. Southey
- Precision Medicine, School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia
- William J. Tapper
- Faculty of Medicine University of Southampton Southampton UK
- Lauren R. Teras
- Department of Population Science American Cancer Society Atlanta Georgia USA
- Rob A. E. M. Tollenaar
- Department of Surgery Leiden University Medical Center Leiden the Netherlands
- Katarzyna Tomczyk
- The Breast Cancer Now Toby Robins Research Centre The Institute of Cancer Research London UK
- Ian Tomlinson
- Cancer Research Centre The University of Edinburgh Edinburgh UK
- Melissa A. Troester
- Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill North Carolina USA
- Celine M. Vachon
- Division of Epidemiology, Department of Quantitative Health Sciences Mayo Clinic Rochester Minnesota USA
- Elke M. vanVeen
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester Manchester Academic Health Science Centre Manchester UK
- Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care University of Cambridge Cambridge UK
- Camilla Wendt
- Department of Clinical Science and Education, Södersjukhuset Karolinska Institutet Stockholm Sweden
- Hans Wildiers
- Department of Oncology, Leuven Multidisciplinary Breast Center, University Hospitals Leuven Leuven Cancer Institute Leuven Belgium
- Robert Winqvist
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu University of Oulu Oulu Finland
- Argyrios Ziogas
- Department of Medicine, Genetic Epidemiology Research Institute University of California Irvine Irvine California USA
- Per Hall
- Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden
- Paul D. P. Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care University of Cambridge Cambridge UK
- Muriel A. Adank
- Family Cancer Clinic The Netherlands Cancer Institute ‐ Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands
- Antoinette Hollestelle
- Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam the Netherlands
- Marjanka K. Schmidt
- Division of Molecular Pathology The Netherlands Cancer Institute Amsterdam the Netherlands
- Maartje J. Hooning
- Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam the Netherlands
- DOI
- https://doi.org/10.1002/cam4.6272
- Journal volume & issue
-
Vol. 12,
no. 15
pp. 16142 – 16162
Abstract
Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
Keywords
- CHEK2 c.1100delC germline genetic variant
- contralateral breast cancer risk
- radiotherapy
- survival
- systemic treatment
