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Epidemiology
Cohort profile
Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort
  1. Yuehan Wang1,
  2. Leontien C M Kremer1,2,3,
  3. Flora E van Leeuwen4,
  4. Gregory T Armstrong5,
  5. Wendy Leisenring6,
  6. Florent de Vathaire7,
  7. Melissa M Hudson5,
  8. Claudia E Kuehni8,9,
  9. Michael A Arnold10,11,
  10. Nadia Haddy7,
  11. Charlotte Demoor-Goldschmidt7,12,13,14,
  12. Ibrahima Diallo7,
  13. Rebecca M Howell15,
  14. Matthew J Ehrhardt5,
  15. Chaya S Moskowitz16,
  16. Joseph P Neglia17,
  17. Helena J H van der Pal1,
  18. Leslie L Robison5,
  19. Michael Schaapveld4,
  20. Lucie M Turcotte17,
  21. Nicolas Waespe8,9,18,
  22. Cécile M Ronckers1,19,
  23. Jop C Teepen1
  24. For the International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer
    1. 1Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
    2. 2University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands
    3. 3Emma Children's Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands
    4. 4Netherlands Cancer Institute, Amsterdam, Netherlands
    5. 5St Jude Children's Research Hospital, Memphis, Tennessee, USA
    6. 6Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    7. 7Radiation Epidemiology Team, INSERM U1018, Gustave Roussy, Villejuif, France
    8. 8Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
    9. 9Pediatric Hematology and Oncology, University Children's Hospital Bern, University of Bern, Bern, Switzerland
    10. 10Department of Pathology and Laboratory Medicine, Children’s Hospital Colorado, Aurora, Colorado, USA
    11. 11Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
    12. 12Department of Pediatric Hematology and Oncology, University-Hospital of Angers, Angers, France
    13. 13Radiotherapy department, Francois Baclesse center, Caen, France
    14. 14Supportive care department, Francois Baclesse center, Caen, France
    15. 15University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
    16. 16Memorial Sloan Kettering Cancer Center, New York, New York, USA
    17. 17University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota, USA
    18. 18CANSEARCH research platform in pediatric oncology and hematology, University of Geneva, Geneva, Switzerland
    19. 19Department of Health Services Research, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
    1. Correspondence to Dr Jop C Teepen; J.C.Teepen{at}prinsesmaximacentrum.nl

    Abstract

    Purpose The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age.

    Participants The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis.

    Findings to date This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts’ follow-up started 1951–1981 and ended 2013–2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0–32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5–11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0–40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively.

    Future plans The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future.

    • EPIDEMIOLOGY
    • Paediatric oncology
    • Paediatric radiotherapy
    • STATISTICS & RESEARCH METHODS

    Data availability statement

    Data are available on reasonable request. 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 pseudonymised data is 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 JCT (J.C.Teepen@prinsesmaximacentrum.nl), which will be considered by the consortium.

    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2022-065910

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      STRENGTHS AND LIMITATIONS OF THIS STUDY

      • This study represents the largest cohort of childhood/adolescent cancer survivors with detailed information on treatment and subsequent breast cancer occurrences.

      • Pooling individual patient observations from eligible cohorts worldwide will improve statistical power for the identification of risks of subsequent breast cancer associated with specific treatments, for which power was insufficient in the individual cohorts.

      • The heterogeneity of treatment exposure, in particular related to variation in treatment combinations across countries, creates a better possibility to disentangle single treatment exposures in the pooling effort.

      • The participants in our study were recruited exclusively from North American and European cohorts, predominantly consisting of individuals of European ancestry. The homogeneity of our sample in this respect may limit the generalisability of the results to other populations.

      Introduction

      Although cancer remains a leading cause of death for children worldwide,1 the long-term survival of childhood, adolescent and young adult patients with cancer has improved remarkably due to progress in treatment over the past decades in resource-rich countries.2 3 However, childhood/adolescent cancer survivors experience impaired long-term health due to adverse effects of previous cancer treatments.4 5 These chronic health conditions vary in association with the cancer type and specific treatments, and other patient characteristics that are independent of the prior disease.6

      Breast cancer represents one of the most common subsequent malignant neoplasms among survivors of childhood/adolescent cancer,7 which also causes increased mortality.8 Breast cancer is a long-recognised late adverse effect among women exposed to ionising radiation at a young age, especially with chest-directed radiation.9 Moreover, recent work from various groups provides compelling evidence to suggest that certain chemotherapeutic agents may also increase the risk for subsequent breast cancer.10–12 However, individual studies have often been underpowered to fully explore potentially associated covariates. Therefore, pooling cohorts to expand knowledge of the risk and risk factors for subsequent breast cancer associated with prior treatments is of great importance to both physicians and survivors. For other types of subsequent malignancies, such efforts are available13–15 or are less likely to render a clear benefit owing to small numbers of cases even after pooling.16–19 These may be targeted in the future, though, when more person-years have accrued.

      Clinical practice guidelines for providers have been developed to promote optimal health-related outcomes by screening survivors.20 21 In 2010, the International Late Effects of Childhood Cancer Guideline Harmonisation Group (IGHG) was established (https://www.ighg.org/) to harmonise the guidelines available worldwide, according to a common methodology.22 In 2012, the IGHG formulated recommendations for breast cancer surveillance among high-risk groups,23 to which an update was recently published.24 As part of the harmonisation methodology,22 the expert group identified gaps in knowledge by specifying clinical questions for which empirical evidence was deemed insufficient to affect or alter recommendations for clinical practice.23 24 For this reason, we established the International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer funded by the Children Cancer Free Foundation (KiKa, Grant No. 325), to conduct individual patient data analyses. Initially, the consortium aimed to address three knowledge gaps regarding subsequent breast cancer identified in the IGHG breast cancer guidelines23 24: (1) to explore the effects of prescribed radiation dose and radiation field, as a proxy for exposed tissue volume, on the risk of subsequent breast cancer; (2) to examine the role of anthracyclines and the contributions of single anthracycline drugs regarding risk of subsequent breast cancer and (3) to evaluate whether relative and absolute excess risks of subsequent breast cancer remain increased across lifespan, especially after age 50 years.

      Knowledge gap #1: radiotherapy threshold associated with subsequent breast cancer

      Substantial evidence demonstrates a linear dose–response relationship between radiotherapy dose exposure to the chest and the risk of subsequent breast cancer, based largely on doses of exposure ≥10 Gy.25 26 However, less is known about the risk of subsequent breast cancer among female survivors exposed to lower doses of chest-directed or stray radiation in combination with radiation-exposed tissue volumes in the chest.23 24 27 This is especially relevant as contemporary cancer treatments use lower doses and smaller radiation volumes than cancer treatments from earlier years. In addition, there is a paucity of radiation dose-volume data in long-term observational studies for childhood/adolescent cancer survivors for follow-up periods exceeding a decade. It is important to establish more precise subsequent breast cancer risk estimates for lower doses of radiotherapy exposure to the chest because women with very low dose ionising radiation exposure in other circumstances (eg, diagnostic radiation) have experienced an elevated risk of subsequent breast cancers.9 Furthermore, the Childhood Cancer Survivor Study (CCSS) evaluated parameters/characteristics of radiotherapy beyond cumulative radiation dose that may affect subsequent breast cancer risk. Specifically, women treated with lower dose radiotherapy to the whole volume of breast tissue (eg, whole lung irradiation, median delivered dose, 14 Gy; range, 2–20 Gy) appeared to have excess risk of breast cancer; standardised incidence ratio (SIR), 43.6; 95% CI 27.2 to 70.3). This exceeds the reported risk for females treated with high dose radiotherapy exposures to only part of the breast tissue (eg, mantle irradiation, median delivered dose 40 Gy; range, 5–54 Gy; SIR, 24.2; 95% CI 20.7 to 28.3).27 Consequently, evaluation of the combined effects of radiation dose and radiation field, as an indicator of radiation-exposed tissue volume, in an adequately sized sample is essential to confirm and further specify this finding.

      Knowledge gap #2: association between anthracycline chemotherapy and subsequent breast cancer

      The second gap in knowledge concerns the role of specific anthracycline derivatives and cumulative subsequent breast cancer risk among childhood/adolescent cancer survivors, since anthracyclines have been shown to increase subsequent breast cancer risk.10 11 28 A CCSS investigation showed that female survivors without chest radiotherapy exposure had a fourfold increase in breast cancer risk compared with the general population at a similar age (SIR 4.0; 95% CI 3.0 to 5.3). Alkylating agents and anthracyclines were associated with a dose-dependent increase of breast cancer risk (p values from test for trend were both <0.01).11 In the Dutch Long-term Effects After Childhood Cancer Study (DCCSS LATER), increasing cumulative doxorubicin dose was associated with increasing risk of subsequent breast cancer, with HRs of 1.1 (95% CI 0.4 to 2.9), 2.6 (95% CI 1.1 to 6.5) and 5.8 (95% CI 2.7 to 12.5) for ≤270, 271–443, and >443 mg/m2 doxorubicin dose, respectively (Ptrend<0.001).10 In both, the CCSS and DCCSS LATER reports, the association between anthracyclines and subsequent breast cancer was stronger among survivors of tumour types known to be associated with Li-Fraumeni syndrome, that is, leukaemia, central nervous system tumours and non-Ewing sarcoma. It was postulated that interactions between anthracycline exposure and genes affecting cancer susceptibility in Li-Fraumeni and Li-Fraumeni-like syndromes may contribute to the mechanism underlying anthracycline-related breast cancer risk. A study from St. Jude Lifetime Cohort Study (SJLIFE) using whole-genome sequencing demonstrated that an association between anthracyclines and subsequent breast cancer was still present in models excluding survivors with pathogenic or likely pathogenic mutations known to be associated with breast cancer in the general population.28 This highlights the need for large, pooled studies to better understand this association and to explore clues regarding the potential mechanisms. Others have leveraged the CCSS population to investigate the interaction between radiotherapy exposure to the chest and anthracycline treatment (ie, additive interaction) on subsequent breast cancer risk in survivors.12 To date, it has not been possible to investigate the role of different anthracycline derivatives because most survivors who received anthracyclines were treated with doxorubicin, with small groups exposed to daunorubicin, epirubicine, idarubicin and mitoxantrone.

      Knowledge gap #3: attained age and risk of subsequent breast cancer

      The third gap in knowledge from the IGHG guideline that requires more investigation, concerns the subsequent breast cancer risk among post-menopausal women (eg, ≥50 years23 and ≥60 years24). Among atomic bomb survivors, breast cancer risk remains elevated up to the age of 70.29 Also, in cohorts with young adult cancer survivors, who have typically already reached higher attained ages compared with childhood/adolescent cancer survivor cohorts, breast cancer risk remained elevated in female survivors aged ≥50 years.19 Increasing evidence indicates that childhood/adolescent cancer survivors may remain at elevated risk of developing subsequent neoplasms compared with age-matched peers for as long as five decades after initial cancer treatment.30 31 Others have reported that the effect of age on subsequent breast cancer risk may be substantially influenced by different cancer treatments.19 27 However, the number of childhood/adolescent cancer survivors who have reached postmenopausal ages in the existing studies is too limited to demonstrate whether the risk of subsequent breast cancer remains elevated beyond postmenopausal ages.

      Cohort description

      Study population

      Cohorts of female childhood/adolescent cancer survivors meeting the following criteria were eligible to be included in the pooled study population: a primary cancer diagnosis at <21 years of age, survival ≥5 years from diagnosis, follow-up data on presence and type of subsequent neoplasms, as well as individual detailed accounts of radiotherapy and chemotherapy treatment available for the majority of cohort members. The characteristics of seven cohorts that satisfied these criteria are shown in online supplemental table 1: three cohorts from North America and four from Europe. The cohorts from North America include the CCSS,32 33 the SJLIFE,34 35 and the US National Wilms Tumour Study Group (NWTSG).36 37 The European cohorts consist of the DCCSS LATER,10 the French Childhood Cancer Survivor Study (FCCSS),38 39 the Swiss Childhood Cancer Survivor Study (SCCSS)40 41 and the Dutch Hodgkin Late Effects cohort (DHL).42–44 The included multi-institutional study groups represent long-standing and well-established research infrastructures to study health and well-being among childhood/adolescent cancer survivors. A few specific aspects are mentioned below, as they impact the contribution of the respective study group to this effort. For the SCCSS, data collection on treatment details is ongoing; cohort-wide data is not available yet. Therefore, the SCCSS contributed data from a case-cohort study. The treatment details for survivors in a subcohort of their total cohort and all subsequent breast cancer cases were collected. Similarly, in the NWTSG some aspects of treatment have not been collected for all cohort members. As such, this cohort will be excluded for analyses of chemotherapy treatment dose effects.

      Overlaps between the North American cohorts (CCSS/SJLIFE/NWTSG) and the Dutch cohorts (DCCSS LATER/DHL) were checked, and only unique patients were included. The data was prepared by analysts from the individual studies according to a jointly developed harmonised data protocol, and are stored at the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (see online supplemental table 1 for an overview per data provider).

      Childhood/adolescent cancer diagnosis information and treatment exposures

      For each individual cohort, details on childhood/adolescent cancer diagnosis and treatment were included in the pooled cohort (table 1). For childhood/adolescent cancer diagnosis, the year and month were recorded as well as the ICD-O-3 morphology, behaviour and topography codes. Radiotherapy details included direct in-field exposure (yes/no and cumulative dose) to the following body regions: head/neck, chest, abdomen, pelvis, extremities or total body irradiation. For chest radiotherapy, we also collected data on the specific field(s) that were treated. Each chest radiotherapy field was converted into one of the following field classifications based on the field description by the individual cohorts: whole lung, total body irradiation, mantle, mediastinum, axilla, spine or other chest without axilla (left/right/unknown laterality). Details on delivered chemotherapy drugs and on cumulative doses were also recorded, except for NWTSG, for which only information on the drug name, but not on cumulative dose was available. In addition, for cohort members affected by one or multiple subsequent malignancies, diagnosis date and, if available, respective treatment information was collected. Since treatment for subsequent cancers (eg, thyroid cancer, lung cancer or a thoracic sarcoma) may affect the baseline risk of breast cancer thereafter, owing to further exposure to chest radiation, anthracyclines or hormone therapy, such additional data allow for sensitivity analyses to evaluate the potential influence of these situations in clinical reality.

      View this table:
      Table 1

      Available items in the International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer database

      Outcome ascertainment

      The process of ascertainment of subsequent (invasive and in situ) breast cancer and other subsequent malignancies for each participating cohort is summarised in table 2. For all subsequent malignancies, information of morphology, topography, diagnosis year and month was collected. For subsequent breast cancer, laterality, hormone receptor status (ie, oestrogen receptor, human epidermal growth factor receptor 2 and progesterone receptor) was additionally collected, when available.

      View this table:
      Table 2

      Subsequent breast cancer ascertainment/validation process for each participating study

      Potential confounding and effect modifying variables

      Information on age at menarche, menopausal status and age at menopause, pregnancies (age at first birth and number of children), oral contraceptives and hormone replacement therapy (including duration of use) was collected from self-reported questionnaires and/or abstracted from medical records (table 1). To date, this information is available for more than half of the cohort members, with varying completeness across variables. In addition, some other information was provided as optional variables if this data was available, for example: race/ethnicity, family history of breast cancer, treatment protocol name, ovarian transposition (oophoropexy) before pelvic field irradiation and cancer predisposition syndromes.

      Depending on the specific research questions and the corresponding outcomes, we intend to apply multiple imputation methods to the relevant confounding and effect modifying variables, whenever necessary and feasible.

      Patient and public involvement

      Survivor representatives are invited and included in the process of guideline development for breast cancer surveillance among childhood cancer survivors in the IGHG, in which knowledge gaps and research priorities were identified and formulated. This work serves as a prelude to the initiation of this consortium. Survivors were represented in the grant development process and are involved throughout the project to provide survivors’ research perspectives when needed and increase public awareness and understanding. When the studies are complete, survivors and their families through survivorship organisations (eg, VOX in the Netherlands) will be involved in and also provide independent dissemination of research progress and findings to the survivor network and the public to motivate community engagement in and beyond the study.

      Findings to date

      Currently, the consortium cohort includes 21 892 female five-year childhood/adolescent cancer survivors who accrued 444 023 person-years of follow-up attained from the date of five-year survival. The range of calendar years of childhood cancer diagnosis was from 1946 to 2012, and the latest follow-up ended in 2021. The median age at primary cancer diagnosis was 5.4 (IQR 2.5–11.9) years. The median duration from five-year survival to the end of follow-up was 19.3 (IQR 13.0–27.8) years; 18.9% (n=4145) of females were followed for ≥30 years since 5-year survival. The median attained age at last follow-up was 32.2 (IQR 24.0–40.4) years, and the consortium cohort included 1592 (7.3%) survivors who reached age 50 years, and 211 (1.0%) survivors who reached age 60 years. In all, 4240 (19.4%) childhood/adolescent cancer survivors were treated with radiotherapy to the chest, and 9308 (42.5%) were treated with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinoma in situ and 12 lobular carcinomas in situ) and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively. Table 3 describes the demographic and clinical characteristics of the pool of survivors eligible for our study. The consortium cohort includes relatively more renal tumour survivors (24.5% of all survivors) than the general childhood cancer survivor population, because of the inclusion of the NTWSG cohort, which exclusively includes renal tumour survivors. Tables 4 and 5 present the specific information on radiotherapy treatment and anthracycline and alkylating agent chemotherapy treatment. For more detailed information on survivors included in our study, please see the online supplemental table 2.

      View this table:
      Table 3

      Demographic and clinical characteristics of female childhood/adolescent cancer survivors included in the International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer by each participating study

      View this table:
      Table 4

      Childhood cancer radiotherapy treatment characteristics of female childhood/adolescent cancer survivors included in the International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer by each participating study

      View this table:
      Table 5

      Childhood cancer anthracycline and alkylating agent chemotherapy treatment characteristics of female childhood/adolescent cancer survivors included in the International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer by each participating study

      The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer represents a newly established pooled study. Several analyses on clinically relevant questions regarding subsequent breast cancer are currently ongoing. Individual study groups included in this consortium have published on subsequent breast cancer risks before. An overview of cohort-specific published findings relevant to the first tier of three clinical questions that led to the establishment of the consortium is summarised in online supplemental table 3. In addition, selected other cohort-specific findings relating to subsequent breast cancer risk are highlighted.

      Strengths and limitations

      This study, to our knowledge, represents the largest cohort of childhood/adolescent cancer survivors with detailed information on treatment and subsequent breast cancer occurrences. Pooling individual patient observations from eligible cohorts worldwide will improve statistical power for the identification of risks of subsequent breast cancer associated with specific treatments, for which power was insufficient in the individual cohorts. Combining data will also increase the sample of childhood/adolescent cancer survivors who have attained 60 years of age, which will enable more precise estimation of the risk for subsequent breast cancers in this ageing population. The differences between studies (eg, primary cancer types, cancer treatment and reproductive factors) will also be considered analytically. Moreover, there may be more heterogeneity in treatment exposures in our study than in the single cohorts, given that childhood/adolescent cancer treatment protocols differ among the various countries contributing to this consortium.45 In childhood/adolescent cancer, specific treatment combinations tend to cluster by type of cancer (and, associated with that, treatment age), treatment era (and, thus, also attained age and follow-up) and country. The heterogeneity of treatment exposure, in particular regarding variation in treatment combinations across countries, creates a better possibility to disentangle single treatment exposures in the pooling effort, because better adjustments can be done for other treatments.

      Of note, the participants in our study were recruited exclusively from North American and European cohorts, predominantly consisting of individuals of European ancestry. The homogeneity of our sample, in this respect, may limit the generalisability of the results to other populations. Moreover, while initial full-consortium analyses focus on three a priori defined clinical research questions, the infrastructure of this individual pooled data project will facilitate analyses of additional effects of lifestyle, specific reproductive and genetic factors, which are available for varying subgroups of the combined individual pooled data cohort, and which will be considered in future efforts. In addition, the consortium collaboration and structure can provide a robust source of information for identifying other knowledge gaps, including other subsequent malignancies. The established pipeline can be readily expanded to a larger cohort of childhood/adolescent cancer survivors, including both female and male survivors.

      Data availability statement

      Data are available on reasonable request. 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 pseudonymised data is 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 JCT (J.C.Teepen@prinsesmaximacentrum.nl), which will be considered by the consortium.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants. The contributing cohort-study teams obtained IRB and/or Ethics Committee approval or exemption in their respective contributing institute. The pooling effort is exempt from review in compliance with Dutch law and regulations for health research involving human beings. Data sharing agreements between the Princess Máxima Center for Pediatric Oncology and all data providers are in place.

      Acknowledgments

      We thank Giulio J. D’Angio and Norman E. Breslow for their contribution to the set up of the NWTSG. We also thank Susan Smith for critical review of the manuscript.

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      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • Collaborators The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer includes the listed co-authors and the following collaborators: K. Scott Baker, Fred Hutchinson Cancer Research Center, Seattle, WA, USA and University of Washington, Seattle, WA, USA; Amy Berrington de González, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Miriam R. Conces, Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA and Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Louis S. Constine, University of Rochester Medical Center, Rochester, NY, USA; Daniel M. Green, St. Jude Children’s Research Hospital, Memphis, TN, USA; Mike Hawkins, Centre for Childhood Cancer Survivor Studies, University of Birmingham, Birmingham, UK; Tara O. Henderson, University of Chicago Medicine Comer Children’s Hospital, Chicago, IL, USA; Geert O. Janssens, University Medical Centre Utrecht, Utrecht, The Netherlands and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Lene Mellemkjaer, Danish Cancer Society Research Center, Copenhagen, Denmark; Kevin C. Oeffinger, Duke University Medical Center, Durham, NC, USA; Raoul Reulen, Centre for Childhood Cancer Survivor Studies, University of Birmingham, Birmingham, UK; Jeanette F. Winther, Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark and Department of Clinical Medicine, Faculty of Health, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.

      • Contributors YW and JCT performed the analyses. YW, JCT and CMR drafted the manuscript. YW, JCT, CMR, LCMK, FEvL, GTA, WL, FdV, MMH, CEK, MAA, NH, CD-G, ID, RMH, MJE, CSM, JPN, HJHvdP, LLR, MS, LMT and NW contributed to the conception or design of the work, critically revised the manuscript, and approved the final version. JCT is the guarantor for this study. CMR and JCT are joint last authors.

      • Funding This work was supported by the Children Cancer Free Foundation (KiKa, Grant No. 325 title: Risk factors for female breast cancer after treatment for childhood and adolescent cancer: individual patient data analyses of an internationally pooled cohort; CMR, FEvL, LCMK, principal investigators). The CCSS and SJLIFE cohorts are supported by the National Cancer Institute (CA55727, GTA, principal investigator; CA195547, MMH and LLR, principal investigators) as well as support to St. Jude Children’s Research Hospital also provided by the Cancer Center Support (CORE) grant (CA21765, C. Roberts, principal investigator) and the American Lebanese Syrian Associated Charities (ALSAC). The NWTSG was supported by the National Cancer Institute (CA054498, N.E. Breslow and WL, principal investigator). The DCCSS LATER is supported by the Dutch Cancer Society (DCOG2011-5027, CMR, FEvL, Wim Tissing, principal investigators and UVA2012-5517, CMR, LCMK, principal investigators). The FCCSS is funded by the Fondation ARC (PopHARC Grant) and the Agence Nationale pour la Recherche Médicale (ANR, Hope-Epi Grant). 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; KLS-5432-08-2021), Kinderkrebs Schweiz (www.kinderkrebs-schweiz.ch)) and Kinderkrebshilfe Schweiz (www.kinderkrebshilfe.ch). The DHL has been supported by Dutch Cancer Society (NKI 2010-4720).

      • Competing interests None declared.

      • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.