Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

Mark van Barele; Delal Akdeniz; Bernadette A M Heemskerk-Gerritsen; Genepso; Nadine Andrieu; Catherine Noguès; Christi J van Asperen; Marijke Wevers; Margreet G E M Ausems; Geertruida H de Bock; Charlotte J Dommering; Encarnacion B Gómez-García; Flora E van Leeuwen; Thea M Mooij; Douglas F Easton; Antonis C Antoniou; D Gareth Evans; Louise Izatt; Marc Tischkowitz; Debra Frost; Carole Brewer; Edit Olah; Jacques Simard; Christian F Singer; Mads Thomassen; Karin Kast; Kerstin Rhiem; Christoph Engel; Miguel de la Hoya; Lenka Foretová; Anna Jakubowska; Agnes Jager; Margriet G A Sattler; Marjanka K Schmidt; Maartje J Hooning

doi:10.1093/jnci/djad116

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

Mark van Barele
, Delal Akdeniz
, Bernadette A M Heemskerk-Gerritsen
, Genepso
, Nadine Andrieu
, Catherine Noguès
, Christi J van Asperen
, Marijke Wevers
, Margreet G E M Ausems
, Geertruida H de Bock
, Charlotte J Dommering
, Encarnacion B Gómez-García
, Flora E van Leeuwen
, Thea M Mooij
, Douglas F Easton
, Antonis C Antoniou
, D Gareth Evans
, Louise Izatt
, Marc Tischkowitz
, Debra Frost

Carole Brewer, Edit Olah, Jacques Simard, Christian F Singer, Mads Thomassen, Karin Kast, Kerstin Rhiem, Christoph Engel, Miguel de la Hoya, Lenka Foretová, Anna Jakubowska, Agnes Jager, Margriet G A Sattler, Marjanka K Schmidt, Maartje J Hooning^*

^*Corresponding author for this work

Erasmus University Medical Center Rotterdam
French National Institute of Health
PSL Research University, Paris
Mines ParisTech, Fontainebleau, France.
Département d'Anticipation et de Suivi des Cancers
Leiden University Medical Centre
Radboud University Medical Center
University Medical Center Utrecht
University of Groningen
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Maastricht University Medical Center+
The Netherlands Cancer Institute
Cambridge University Hospitals NHS Foundation Trust
Department of Genetic Medicine, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
Royal Devon & Exeter NHS Foundation Trust
National Institute of Oncology, Budapest
Genomics Center
Medical University of Vienna
University Hospital Cologne
Leipzig University
San Carlos Clinical Hospital
Masaryk Memorial Cancer Institute
Pomeranian Medical University

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC.

METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided.

RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively).

CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

Original language	English
Journal	Journal of the National Cancer Institute
Volume	115
Issue number	11
Pages (from-to)	1318-1328
ISSN	0027-8874
DOIs	https://doi.org/10.1093/jnci/djad116
Publication status	Published - 8. Nov 2023

Funding

The Masaryk Memorial Cancer Institute study is supported by MH CZ-DRO (Masaryk Memorial Cancer Institute 00209805). EMBRACE is supported by the Cancer Research UK grants C1287/A23382, C1287/A26886 and PRCPJT-Nov21\100004). D. Gareth Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). Antonis C. Antoniou is funded by Cancer Research UK grants PPRPGM-Nov20\100002 and C12292/A20861. M. Tischkowitz was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). We thank all study participants for contributing to the registry of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), which is supported by the German Cancer Aid (grant No. 110837) and the Federal Ministry of Education and Research (grant No. 01GY1901). The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following collaborating centers in the Netherlands: Netherlands Cancer Institute (coordinating center), Amsterdam; Erasmus Medical Center, Rotterdam; Leiden University Medical Center; Radboud University Medical Center Nijmegen; University Medical Center Utrecht; Amsterdam Universiy Medical Center, University of Amsterdam; Amsterdam University Medical Center, Vrije Universiteit Amsterdam; Maastricht University Medical Center; University of Groningen; The Netherlands Comprehensive Cancer Organisation (IKNL); the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA). HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. The HEBON study is supported by Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, and NKI 12535; the Netherlands Organisation of Scientific Research grant NWO 91109024; Pink Ribbon grants 110005 and 2014-187.WO76; BBMRI grant NWO 184.021.007/CP46; the Transcan grant JTC 2012 Cancer 12-054. The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France, the Ligue Nationale Contre le Cancer, by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, No. 2014-008) and is being supported by Institut National du Cancer-DGOS, grant PRT-K22-076 and by the “Programmes labellisés (PGA) 2022” of the Fondation ARC (N°ARCPGA2022010004414_4863). This work was partially supported by Spanish Association Against Cancer grant AECC08, RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation grant SAF2010-20493 and the Spanish Ministry of Economy and Competitiveness grant SAF2014-57680-R. INHERIT was supported by the Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program—grant No. CRN-87521—and the Ministry of Economic Development, Innovation and Export Trade—grant No. PSR-SIIRI-701. Jacques Simard is a chairholder of the Canada Research Chair in Oncogenetics. Hospital Clinico San Carlos: This work was supported by grant RD06/0020/0021 from ISCIII, Spanish Ministry of Science and Innovation.

Keywords

BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
Cohort Studies
Female
Humans
Prospective Studies

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van Barele, M., Akdeniz, D., Heemskerk-Gerritsen, B. A. M., Genepso, Andrieu, N., Noguès, C., van Asperen, C. J., Wevers, M., Ausems, M. G. E. M., de Bock, G. H., Dommering, C. J., Gómez-García, E. B., van Leeuwen, F. E., Mooij, T. M., Easton, D. F., Antoniou, A. C., Evans, D. G., Izatt, L., Tischkowitz, M., ... Hooning, M. J. (2023). Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation. Journal of the National Cancer Institute, 115(11), 1318-1328. https://doi.org/10.1093/jnci/djad116

@article{fb69319018724ed28066713dcc7afd3e,

title = "Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation",

abstract = "BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC.METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided.RESULTS: Of 3602 eligible patients, 2297 (64\%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15\% vs 3\%, P < .001), received chemotherapy more often (81\% vs 70\%, P < .001), and received endocrine therapy more often (50\% vs 35\%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95\% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95\% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95\% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95\% CI = 0.93 to 2.04 and HR = 1.56; 95\% CI = 1.11 to 2.19, respectively).CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.",

keywords = "BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Cohort Studies, Female, Humans, Prospective Studies",

author = "\{van Barele\}, Mark and Delal Akdeniz and Heemskerk-Gerritsen, \{Bernadette A M\} and Genepso and Nadine Andrieu and Catherine Nogu{\`e}s and \{van Asperen\}, \{Christi J\} and Marijke Wevers and Ausems, \{Margreet G E M\} and \{de Bock\}, \{Geertruida H\} and Dommering, \{Charlotte J\} and G{\'o}mez-Garc{\'i}a, \{Encarnacion B\} and \{van Leeuwen\}, \{Flora E\} and Mooij, \{Thea M\} and Easton, \{Douglas F\} and Antoniou, \{Antonis C\} and Evans, \{D Gareth\} and Louise Izatt and Marc Tischkowitz and Debra Frost and Carole Brewer and Edit Olah and Jacques Simard and Singer, \{Christian F\} and Mads Thomassen and Karin Kast and Kerstin Rhiem and Christoph Engel and \{de la Hoya\}, Miguel and Lenka Foretov{\'a} and Anna Jakubowska and Agnes Jager and Sattler, \{Margriet G A\} and Schmidt, \{Marjanka K\} and Hooning, \{Maartje J\}",

year = "2023",

month = nov,

day = "8",

doi = "10.1093/jnci/djad116",

language = "English",

volume = "115",

pages = "1318--1328",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "11",

}

van Barele, M, Akdeniz, D, Heemskerk-Gerritsen, BAM, Genepso, Andrieu, N, Noguès, C, van Asperen, CJ, Wevers, M, Ausems, MGEM, de Bock, GH, Dommering, CJ, Gómez-García, EB, van Leeuwen, FE, Mooij, TM, Easton, DF, Antoniou, AC, Evans, DG, Izatt, L, Tischkowitz, M, Frost, D, Brewer, C, Olah, E, Simard, J, Singer, CF, Thomassen, M, Kast, K, Rhiem, K, Engel, C, de la Hoya, M, Foretová, L, Jakubowska, A, Jager, A, Sattler, MGA, Schmidt, MK & Hooning, MJ 2023, 'Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation', Journal of the National Cancer Institute, vol. 115, no. 11, pp. 1318-1328. https://doi.org/10.1093/jnci/djad116

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation. / van Barele, Mark; Akdeniz, Delal; Heemskerk-Gerritsen, Bernadette A M et al.
In: Journal of the National Cancer Institute, Vol. 115, No. 11, 08.11.2023, p. 1318-1328.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

AU - van Barele, Mark

AU - Akdeniz, Delal

AU - Heemskerk-Gerritsen, Bernadette A M

AU - Genepso

AU - Andrieu, Nadine

AU - Noguès, Catherine

AU - van Asperen, Christi J

AU - Wevers, Marijke

AU - Ausems, Margreet G E M

AU - de Bock, Geertruida H

AU - Dommering, Charlotte J

AU - Gómez-García, Encarnacion B

AU - van Leeuwen, Flora E

AU - Mooij, Thea M

AU - Easton, Douglas F

AU - Antoniou, Antonis C

AU - Evans, D Gareth

AU - Izatt, Louise

AU - Tischkowitz, Marc

AU - Frost, Debra

AU - Brewer, Carole

AU - Olah, Edit

AU - Simard, Jacques

AU - Singer, Christian F

AU - Thomassen, Mads

AU - Kast, Karin

AU - Rhiem, Kerstin

AU - Engel, Christoph

AU - de la Hoya, Miguel

AU - Foretová, Lenka

AU - Jakubowska, Anna

AU - Jager, Agnes

AU - Sattler, Margriet G A

AU - Schmidt, Marjanka K

AU - Hooning, Maartje J

PY - 2023/11/8

Y1 - 2023/11/8

N2 - BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC.METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided.RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively).CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

AB - BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC.METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided.RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively).CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Cohort Studies

KW - Female

KW - Humans

KW - Prospective Studies

U2 - 10.1093/jnci/djad116

DO - 10.1093/jnci/djad116

M3 - Journal article

C2 - 37369040

SN - 0027-8874

VL - 115

SP - 1318

EP - 1328

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 11

ER -

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

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