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BRCA1/BRCA2 germline mutations and chemotherapy-related hematological toxicity in breast cancer patients

  • Alex Friedlaender
  • Aurélie Vuilleumier
  • Valeria Viassolo
  • Aurélie Ayme
  • Solène De Talhouet
  • Jean-Damien Combes
  • Julien Peron
  • Alexandre Bodmer
  • Sophie Giraud
  • Adrien Buisson
  • Valerie Bonadona
  • Isabelle Gauchat-Bouchardy
  • Olivier Tredan
  • Pierre O. Chappuis
  • S. Intidhar Labidi-GalyEmail author
Epidemiology
  • 102 Downloads

Abstract

Purpose

BRCA1 and BRCA2 proteins are central to DNA repair process through homologous recombination. We hypothesize that BRCA1/BRCA2 mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy.

Methods

We included women with primary breast cancers screened for BRCA1/BRCA2 germline mutations and treated with (neo)adjuvant chemotherapy in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3–4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort).

Results

Overall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the 3 groups.

Conclusions

BRCA1 germline mutations is associated with greater acute hematological toxicity in breast cancer patients. These observations could have implication for primary prophylaxis with G-CSF.

Keywords

Breast cancer BRCA mutation Toxicity Febrile neutropenia Haploinsufficiency Chemotherapy 

Notes

Acknowledgements

We thank all the patients who agreed to participate to this study. We thank Dr A. Hugli, Dr M. Forni, Dr B. Exquis, Dr C. De Pree, Dr C. Irle, Dr L. Waelchli and Prof. A.-P. Sappino for providing clinical data. We thank Mrs L. Zulianello for the iconographic support.

Funding

A. F. received a Grant from the Fondation Henriette Meyer.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study complies with the current laws in Switzerland and France.

Informed consent

Informed consent was obtained from all alive participants included in the study in Geneva. For this type of study, formal consent is not required.

Supplementary material

10549_2018_5127_MOESM1_ESM.pdf (432 kb)
Supplementary material 1 (PDF 431 KB)
10549_2018_5127_MOESM2_ESM.pdf (247 kb)
Supplementary material 2 (PDF 247 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alex Friedlaender
    • 1
  • Aurélie Vuilleumier
    • 1
  • Valeria Viassolo
    • 1
  • Aurélie Ayme
    • 2
  • Solène De Talhouet
    • 3
  • Jean-Damien Combes
    • 4
  • Julien Peron
    • 5
    • 6
  • Alexandre Bodmer
    • 1
  • Sophie Giraud
    • 7
  • Adrien Buisson
    • 7
  • Valerie Bonadona
    • 8
  • Isabelle Gauchat-Bouchardy
    • 2
  • Olivier Tredan
    • 3
  • Pierre O. Chappuis
    • 1
    • 2
  • S. Intidhar Labidi-Galy
    • 1
    • 9
    Email author return OK on get
  1. 1.Department of OncologyHôpitaux Universitaires de GenèveGenevaSwitzerland
  2. 2.Department of Genetic Medicine, Laboratory and Clinical PathologyHôpitaux Universitaires de GenèveGenevaSwitzerland
  3. 3.Department of Medical OncologyCentre Léon BérardLyonFrance
  4. 4.Infections and Cancer Epidemiology GroupInternational Agency for Research on CancerLyonFrance
  5. 5.Departement of Medical Oncology, Institut de Cancérologie des Hospices Civils de LyonCentre Hospitalier Lyon SudPierre-BéniteFrance
  6. 6.UMR CNRS 5558, Université Lyon 1LyonFrance
  7. 7.Division of Molecular Genetics, Hospices Civils de LyonGroupe Hospitalier Edouard HerriotLyonFrance
  8. 8.Unit of Prevention and Genetic EpidemiologyUMR CNRS 5558, Centre Léon BérardLyonFrance
  9. 9.Department of Internal Medecine Specialities, Faculty of MedecineUniversité de GenèveGenevaSwitzerland

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