12 september 2023: Bron: Nature

Uit groot internationaal onderzoek onder leiding van prof. dr. Leontien Kremer en collega's blijkt dat kinderen die in hun kindertijd behandeld zijn voor kanker met chemotherapie en / of radiotherapie / bestraling en die minimaal 5 jaar hebben overleefd het risico op ontwikkelen van borstkanker voor hun 40e jaar 6x tot 13x hoger is in vergelijking met het bevolkingsrisico.
Vooral de chemo doxorubicine en daarnaast radiotherapie / bestraling op de borst werden vaak gevonden als oorzaak van ontstaan van borstkanker later als de kinderen volwassenen waren.
De kinderen waren in hun kindertijd voornamelijk behandeld voor vormen van leukemie en lymfklierkanker.

Drie op de vier kinderen met kanker worden met succes behandeld en overleven de ziekte. Maar de behandeling, die vaak bestaat uit een combinatie van chirurgie, chemotherapie en bestraling, kan bij sommige overlevenden ernstige bijwerkingen en late effecten veroorzaken. Een van die late effecten is het ontwikkelen van een tweede vorm van kanker op volwassen leeftijd.

Yuehan Wang en collega's keken naar de medische dossiers van bijna 18.000 overlevenden van kinderkanker die tussen 1946 en 2012 werden behandeld in Nederland, Frankrijk, de Verenigde Staten en Zwitserland. De onderzoeksresultaten zijn gepubliceerd in Nature Medicine. Yuehan Wang promoveerde op deze studie onder leiding van kinderarts prof. dr. Leontien Kremer.

In uitgebreide gegevenstabel 2 wordt het risico op borstkanker bij behandeling met doxorubicine en radiotherapie van de borstkas weergegeven.

Higher breast cancer risk after certain forms of childhood cancer treatment

Higher breast cancer risk after certain forms of childhood cancer treatment

Cumulative incidence of subsequent breast cancer in female 5-year childhood cancer survivors by cu.......

Uit het studierapport vertaald:

Vergeleken met de algemene vrouwelijke bevolking was het risico op invasieve borstkanker het hoogst in de overlevende groep die een cumulatieve dosis doxorubicine ≥200 mg m−2 en radiotherapie op de borst kreeg (gestandaardiseerde incidentieratio (SIR): 17,5, 95% betrouwbaarheidsinterval ( BI): 13,3–22,6; mediane bereikte leeftijd 36,1 jaar),
gevolgd door de cumulatieve dosis doxorubicine <200 mg m² en radiotherapiegroep op de borst (SIR: 13,9; 95%: BI: 9,7–19,2; mediane bereikte leeftijd 33,8 jaar),
vervolgens door de groep met alleen radiotherapie op de borst zonder doxorubicine (SIR: 10,7, 95%: BI 9,4–12,1; mediaan bereikte leeftijd 38,4 jaar),
vervolgens door de cumulatieve dosis doxorubicine ≥200 mg m−2 zonder borstkas radiotherapiegroep (SIR: 5,6, 95% BI: 4,5–6,9; mediaan bereikte leeftijd 36,5 jaar),
vervolgens met de cumulatieve dosis doxorubicine <200 mg m−2 zonder radiotherapiegroep op de borst (SIR: 3,2, 95% BI: 1,9 -5,1; mediaan bereikte leeftijd 28,9 jaar)
en ten slotte door de groep die noch doxorubicine noch radiotherapie op de borst kreeg (SIR: 1,7, 95% BI: 1,4-2,1; mediaan bereikte leeftijd 32,8 jaar).
Het hoogste excess absolute risico (EAR) werd waargenomen in de cumulatieve doxorubicinedosis ≥200 mg m−2 en de groep met radiotherapie op de borst, met 5,0 extra gevallen per 1.000 persoonsjaren.

In de Volkskrant online wordt deze studie ook beschreven en in dat artikel (staat achter een betaalmuur maar hier een screenshot van het artikel) pleiten verschillende artsen om kinderen die hun kanker hebben overleefd al vroeg jaarlijks te screenen.

Screening op borstkanker:

Vanaf vijf jaar na de diagnose bezoeken kinderen en volwassenen die behandeld zijn voor kinderkanker de LATER-polikliniek van het Prinses Máxima Centrum. Daar worden ze gecontroleerd op mogelijke late effecten van de behandeling, waaronder het ontwikkelen van een tweede vorm van kanker.
Op basis van de nieuwe resultaten pleiten de onderzoekers voor verruiming van de richtlijnen voor borstkankerscreening bij overlevenden van kinderkanker.

Yuehan Wang, lid van de Kremergroep van het Prinses Máxima Centrum voor kinderoncologie, werkte aan het onderzoek als onderdeel van haar PhD. onderzoek. Zij vertelt: “Antracyclines vormen nog steeds een belangrijk onderdeel van de behandeling van ruim de helft van de kinderen met kanker. De dosis die nu wordt voorgeschreven is gemiddeld veel lager dan vroeger, maar er zijn nog steeds kinderen die hiervan een hoge dosis nodig hebben."

“We weten al een tijdje dat antracyclines schadelijk kunnen zijn voor het hart, dus het belang van het laag houden van de dosis van dit soort chemotherapie was al duidelijk. Het ontwikkelen van een tweede kanker is een zeldzaam maar ernstig laat effect van de behandeling van kinderkanker. De resultaten onderstrepen de noodzaak om de dosis doxorubicine bij kinderen waar mogelijk te verlagen."

Prof. dr. Leontien Kremer, onderzoeksgroepleider bij het Prinses Máxima Centrum voor kinderoncologie, die het onderzoek leidde, zegt: “We werken er hard aan om de behandeling van kinderen met kanker effectiever te maken en de kwaliteit van leven tijdens en na de behandeling te verbeteren. In ons onderzoek zagen we dat het merendeel van de overlevenden gelukkig niet op jonge leeftijd borstkanker krijgt. Maar een aantal patiëntengroepen heeft wel een hoger risico op het ontwikkelen van borstkanker."

“Vrouwen die als kind radiotherapie / bestraling op de borst kregen, worden vanaf 25-jarige leeftijd gescreend op borstkanker, omdat al bekend was dat zij een verhoogd risico lopen. Op basis van deze nieuwe resultaten streven wij ernaar de internationale richtlijnen voor borstkankerscreening uit te breiden, zodat ook vrouwen die een hoge dosis doxorubicine kregen vroegtijdig worden gescreend."

Het volledige studierapport is gratis in te zien of te downloaden op de website van Nasture. Klik op de titel van het abstract voor het volledige studierapport:

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer

Nature Medicine (2023)Cite this article

24 Altmetric
Metricsdetails

Abstract

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m−2: 1.24, 95% confidence interval (CI): 1.18–1.31), with more than twofold increased risk for survivors treated with ≥200 mg m−2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200–299 mg m−2, HR: 2.33 for 300–399 mg m−2 and HR: 2.78 for ≥400 mg m−2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59–6.63). For patients treated with or without chest irradiation, HRs per 100 mg m−2 of doxorubicin were 1.11 (95% CI: 1.02–1.21) and 1.26 (95% CI: 1.17–1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m−2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer database is not an open-access database due to ethical and data protection constraints. The pseudonymized data are managed by the Princess Máxima Center for Pediatric Oncology in the Netherlands and cannot be shared with investigators outside the institute without consent from all involved parties. However, potential collaborators are welcome to submit proposals to J.C.T. (j.c.teepen@prinsesmaximacentrum.nl), which will be considered by the consortium. The consortium will come up with a decision about submitted proposals within 3 months after application. The country-specific female breast cancer rates of the Cancer Incidence in Five Continents database were used as the general female population in our study. These data are publicly available: https://ci5.iarc.fr/.

Code availability

The statistical code for our main analyses is available at https://github.com/yuehanwanggitub/IPDanthracyclines.git.

References

Meadows, A. T. et al. Second neoplasms in survivors of childhood cancer: findings from the childhood cancer survivor study cohort. J. Clin. Oncol. 27, 2356–2362 (2009).

Article PubMed PubMed Central Google Scholar
Reulen, R. C. et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304, 172–179 (2010).

Article CAS PubMed Google Scholar
Armstrong, G. T. et al. Reduction in late mortality among 5-year survivors of childhood cancer. N. Engl. J. Med. 374, 833–842 (2016).

Article CAS PubMed PubMed Central Google Scholar
Yeh, J. M. et al. Life expectancy of adult survivors of childhood cancer over 3 decades. JAMA Oncol. 6, 350–357 (2020).

Article PubMed Google Scholar
Bhatia, S. et al. Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N. Engl. J. Med. 334, 745–751 (1996).

Article CAS PubMed Google Scholar
Moskowitz, C. S. et al. Breast cancer after chest radiation therapy for childhood cancer. J. Clin. Oncol. 32, 2217–2223 (2014).

Article PubMed PubMed Central Google Scholar
Henderson, T. O. et al. Association of changes in cancer therapy over 3 decades with risk of subsequent breast cancer among female childhood cancer survivors: a report from the childhood cancer survivor study (CCSS). JAMA Oncol. 8, 1765–1774 (2022).

Article PubMed Google Scholar
Mulder, R. L. et al. Updated breast cancer surveillance recommendations for female survivors of childhood, adolescent, and young adult cancer from the international guideline harmonization group. J. Clin. Oncol. 38, 4194–4207 (2020).

Article CAS PubMed PubMed Central Google Scholar
Ren, W., Chen, M., Qiao, Y. & Zhao, F. Global guidelines for breast cancer screening: a systematic review. Breast 64, 85–99 (2022).

Article PubMed PubMed Central Google Scholar
Turcotte, L. M. et al. Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970–2015. JAMA 317, 814–824 (2017).

Article PubMed PubMed Central Google Scholar
Henderson, T. O. et al. Breast cancer risk in childhood cancer survivors without a history of chest radiotherapy: a report from the childhood cancer survivor study. J. Clin. Oncol. 34, 910–918 (2016).

Article CAS PubMed Google Scholar
Teepen, J. C. et al. Long-term risk of subsequent malignant neoplasms after treatment of childhood cancer in the DCOG LATER study cohort: role of chemotherapy. J. Clin. Oncol. 35, 2288–2298 (2017).

Article CAS PubMed Google Scholar
Ehrhardt, M. J. et al. Subsequent breast cancer in female childhood cancer survivors in the St Jude Lifetime Cohort Study (SJLIFE). J. Clin. Oncol. 37, 1647–1656 (2019).

Article CAS PubMed PubMed Central Google Scholar
Veiga, L. H. et al. Association of breast cancer risk after childhood cancer with radiation dose to the breast and anthracycline use: a report from the childhood cancer survivor study. JAMA Pediatr. 173, 1171–1179 (2019).

Article PubMed PubMed Central Google Scholar
Turcotte, L. M. et al. Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort. J. Clin. Oncol. 37, 3310–3319 (2019).

Article CAS PubMed PubMed Central Google Scholar
Inskip, P. D. et al. Radiation dose and breast cancer risk in the childhood cancer survivor study. J. Clin. Oncol. 27, 3901–3907 (2009).

Article PubMed PubMed Central Google Scholar
van der Zanden, S. Y., Qiao, X. & Neefjes, J. New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 288, 6095–6111 (2021).

Article PubMed Google Scholar
Bucclarelli, E. Mammary tumor induction in male and female Sprague-Dawley rats by adriamycin and daunomycin. J. Natl Cancer Inst. 66, 81–84 (1981).

CAS PubMed Google Scholar
Solcia, E., Ballerini, L., Bellini, O., Sala, L. & Bertazzoli, C. Mammary tumors induced in rats by adriamycin and daunomycin. Cancer Res. 38, 1444–1446 (1978).

CAS PubMed Google Scholar
Buckley, J. D. et al. Remission induction in children with acute non-lymphocytic leukemia using cytosine arabinoside and doxorubicin or daunorubicin: a report from the Childrens Cancer Study Group. Med. Pediatr. Oncol. 17, 382–390 (1989).

Article CAS PubMed Google Scholar
Kaspers, G. L. et al. In vitro cytotoxicity of mitoxantrone, daunorubicin and doxorubicin in untreated childhood acute leukemia. Leukemia 8, 24–29 (1994).

CAS PubMed Google Scholar
Qiao, X. et al. Uncoupling DNA damage from chromatin damage to detoxify doxorubicin. Proc. Natl Acad. Sci. USA 117, 15182–15192 (2020).

Article CAS PubMed PubMed Central Google Scholar
Erdmann, F. et al. Childhood cancer: survival, treatment modalities, late effects and improvements over time. Cancer Epidemiol. 71, 101733 (2021).

Article PubMed Google Scholar
Lown, E. A. et al. Patterns and predictors of clustered risky health behaviors among adult survivors of childhood cancer: a report from the childhood cancer survivor study. Cancer 122, 2747–2756 (2016).

Article PubMed Google Scholar
Wang, Y. et al. Cohort profile: risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort. BMJ Open 12, e065910 (2022).

Article PubMed PubMed Central Google Scholar
Green, D. M. et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the childhood cancer survivor study. Pediatr. Blood Cancer 61, 53–67 (2014).

Article CAS PubMed Google Scholar
Bray, F. et al. Cancer Incidence in Five Continents (Electronic Version) Vol. 11 (International Agency for Research on Cancer, 2017).
Binder-Foucard, F. et al. Cancer incidence and mortality in France over the 1980–2012 period: solid tumors. Rev. Epidemiol. Sante Publique 62, 95–108 (2014).

Article CAS PubMed Google Scholar
Defossez, G. et al. Cancer incidence and mortality trends in France over 1990–2018 for solid tumors: the sex gap is narrowing. BMC Cancer 21, 726 (2021).

Article CAS PubMed PubMed Central Google Scholar
Ménégoz, F. et al. Cancer incidence and mortality in France in 1975–95. Eur. J. Cancer Prev. 6, 442–466 (1997).

Article PubMed Google Scholar
Yasui, Y. et al. A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers. Am. J. Epidemiol. 158, 1108–1113 (2003).

Article PubMed Google Scholar
Swerdlow, A. J. et al. Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin’s lymphoma in England and Wales: a National Cohort Study. J. Clin. Oncol. 30, 2745–2752 (2012).

Article PubMed Google Scholar
Moskowitz, C. S. et al. Radiation-associated breast cancer and gonadal hormone exposure: a report from the childhood cancer survivor study. Br. J. Cancer 117, 290–299 (2017).

Article CAS PubMed PubMed Central Google Scholar
Rod, N. H., Lange, T., Andersen, I., Marott, J. L. & Diderichsen, F. Additive interaction in survival analysis: use of the additive hazards model. Epidemiology 23, 733–737 (2012).

Article PubMed Google Scholar

Download references

Acknowledgements

This work was supported by the Children Cancer Free Foundation (KiKa; grant 325 title: risk factors for female breast cancer after treatment for childhood and adolescent cancer: individual patient data analyses of an internationally pooled cohort) to C.M.R., F.E.v.L., L.C.M.K. (principal investigators). The CCSS and SJLIFE cohorts are supported by the National Cancer Institute (CA55727 to G.T.A. (principal investigator) and CA195547 to M.M.H. and K.K.N. (principal investigators)) as well as support to St. Jude Children’s Research Hospital also provided by the Cancer Center Support (CORE) grant (CA21765 to C.R. (principal investigator)) and the American Lebanese-Syrian Associated Charities (ALSAC). The NWTSG was supported by the National Cancer Institute (CA054498 to N.E.B. and W.L. (principal investigator)). The DCCSS-LATER is supported by the Dutch Cancer Society (DCOG2011-5027 to C.M.R., F.E.v.L. and W.T. (principal investigators) and UVA2012-5517 to C.M.R. and L.C.M.K. (principal investigators)). The FCCSS is funded by the Fondation ARC (PopHARC Grant to F.d.V. (principal investigator)), the Agence Nationale pour la Recherche Médicale (ANR, Hope-Epi Grant to F.d.V. (principal investigator)), and the Gustave Roussy Foundation (Pediatric Program ‘Guérir le Cancer de l’Enfant’ to F.d.V. (principal investigator)). The SCCSS has been supported by the Swiss Cancer League and the Swiss Cancer Research foundation (KFS-02783-02-2011, KLS-3412-02-2014, KFS-4157-02-2017, KLS/KFS-4825-01-2019, KFS-4722-02-2019, KFS-5027-02-2020, KFS-5302-02-2021 and KLS-5432-08-2021 to C.E.K. (principal investigator)), Kinderkrebs Schweiz (www.kinderkrebs-schweiz.ch) and Kinderkrebshilfe Schweiz (www.kinderkrebshilfe.ch). The Dutch Hodgkin Late Effects cohort has been supported by the Dutch Cancer Society (NKI 2010-4720 to F.E.v.L. (principal investigator)).

Author information

Authors and Affiliations

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

Yuehan Wang, Cécile M. Ronckers, Helena J. H. van der Pal, Leontien C. M. Kremer, Jop C. Teepen, Helena J. H. van der Pal & Geert O. Janssens
Department of Health Services Research, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany

Cécile M. Ronckers
Division of Childhood Cancer Epidemiology (EpiKiK), Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

Cécile M. Ronckers
Netherlands Cancer Institute, Amsterdam, The Netherlands

Flora E. van Leeuwen, Michael Schaapveld & Flora E. van Leeuwen
Memorial Sloan Kettering Cancer Center, New York City, NY, USA

Chaya S. Moskowitz
Fred Hutchinson Cancer Center, Seattle, WA, USA

Wendy Leisenring & K. Scott Baker
St. Jude Children’s Research Hospital, Memphis, TN, USA

Gregory T. Armstrong, Melissa M. Hudson, Daniel M. Green, Matthew J. Ehrhardt & Leslie L. Robison
Radiation Epidemiology Team, INSERM U1018, Gustave Roussy, Université Paris-Saclay, Villejuif, France

Florent de Vathaire, Charlotte Demoor-Goldschmidt, Florent de Vathaire, Nadia Haddy & Ibrahima Diallo
Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

Claudia E. Kuehni & Nicolas Waespe
Pediatric Hematology and Oncology, University Children’s Hospital Bern, University of Bern, Bern, Switzerland

Claudia E. Kuehni & Nicolas Waespe
Department of Pathology and Laboratory Medicine, Children’s Hospital Colorado, Aurora, CO, USA

Michael A. Arnold
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Michael A. Arnold
Department of Pediatric Hematology and Oncology, University-Hospital of Angers, Angers, France

Charlotte Demoor-Goldschmidt
Radiotherapy Department, Francois Baclesse Center, Caen, France

Charlotte Demoor-Goldschmidt
University of Chicago Medicine Comer Children’s Hospital, Chicago, IL, USA

Tara O. Henderson
University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Rebecca M. Howell
University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA

Joseph P. Neglia & Lucie M. Turcotte
Duke University Medical Center, Durham, NC, USA

Kevin C. Oeffinger
CANSEARCH research platform in pediatric oncology and hematology of the University of Geneva, Geneva, Switzerland

Nicolas Waespe
University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands

Leontien C. M. Kremer
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Amy Berrington de González
Institute of Cancer Research, Sutton, UK

Amy Berrington de González
Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

Miriam R. Conces
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Miriam R. Conces
University of Rochester Medical Center, Rochester, NY, USA

Louis S. Constine
Centre for Childhood Cancer Survivor Studies, University of Birmingham, Birmingham, UK

Mike Hawkins & Raoul Reulen
Radboudumc Center of Expertise for Cancer Survivorship, Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands

Jacqueline J. Loonen
Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

Marloes Louwerens
Department of Radiation Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands

Geert O. Janssens
Danish Cancer Society Research Center, Copenhagen, Denmark

Lene Mellemkjaer
Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark

Jeanette F. Winther
Department of Clinical Medicine, Faculty of Health, Aarhus University and Aarhus University Hospital, Aarhus, Denmark

Jeanette F. Winther

Consortia

The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer

Yuehan Wang
, Cécile M. Ronckers
, Flora E. van Leeuwen
, Chaya S. Moskowitz
, Wendy Leisenring
, Gregory T. Armstrong
, Florent de Vathaire
, Melissa M. Hudson
, Claudia E. Kuehni
, Michael A. Arnold
, Charlotte Demoor-Goldschmidt
, Daniel M. Green
, Tara O. Henderson
, Rebecca M. Howell
, Matthew J. Ehrhardt
, Joseph P. Neglia
, Kevin C. Oeffinger
, Helena J. H. van der Pal
, Leslie L. Robison
, Michael Schaapveld
, Lucie M. Turcotte
, Nicolas Waespe
, Nadia Haddy
, Ibrahima Diallo
, K. Scott Baker
, Amy Berrington de González
, Miriam R. Conces
, Louis S. Constine
, Mike Hawkins
, Jacqueline J. Loonen
, Marloes Louwerens
, Geert O. Janssens
, Lene Mellemkjaer
, Raoul Reulen
, Jeanette F. Winther
, Leontien C. M. Kremer
& Jop C. Teepen

Contributions

Y.W., J.C.T., L.C.M.K., C.M.R. and F.E.v.L. designed and conceptualized the study. J.C.T., L.C.M.K., C.M.R. and F.E.v.L. acquired funding and supervised the project. G.T.A., M.M.H., W.L., F.v.D., L.C.M.K., F.E.v.L. and C.E.K. provided administrative, technical or material support. Y.W., J.C.T., C.S.M. and W.L. performed the statistical analyses. Y.W., J.C.T., L.C.M.K., C.M.R. and F.E.v.L. drafted the manuscript. All authors contributed to data interpretation and manuscript revision and approved the final version for publication.

Corresponding author

Correspondence to Yuehan Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Joachim Schuz, Giuseppe Curigliano and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ming Yang, in collaboration with the Nature Medicine team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Table 1 Demographic and treatment characteristics of female five-year childhood cancer survivors by cumulative doxorubicin dose categories

Full size table

Extended Data Table 2 Standardized incidence ratios, excess absolute risks, and cumulative incidences by treatmentsa

Full size table

Extended Data Table 3 Joint effects of cumulative doxorubicin and daunorubicin doses and other relevant risk factors on subsequent breast cancer among female five-year childhood cancer survivors

Full size table

Extended Data Table 4 Multivariable Cox proportional hazard regression analyses for subsequent breast cancer in female five-year childhood cancer survivors with different chest radiotherapy fields irradiationa

Full size table

Extended Data Table 5 Sensitivity analyses for risk of subsequent breast cancer on subgroups with different treatments or eventsa

Full size table

Extended Data Table 6 Multivariable Cox proportional hazard regression analyses for subsequent breast cancer in female five-year childhood cancer survivors stratified by chest radiotherapy status (yes/no)

Full size table

Supplementary information

Supplementary Information

Supplementary Tables 1–7.

Reporting Summary

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.