Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy.


Journal

European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373

Informations de publication

Date de publication:
03 2021
Historique:
received: 01 10 2020
revised: 02 12 2020
accepted: 04 12 2020
pubmed: 11 1 2021
medline: 21 9 2021
entrez: 10 1 2021
Statut: ppublish

Résumé

BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Sections du résumé

BACKGROUND
BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities.
METHODS
Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored.
RESULTS
Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies.
CONCLUSIONS
gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Identifiants

pubmed: 33423006
pii: S0959-8049(20)31421-0
doi: 10.1016/j.ejca.2020.12.007
pii:
doi:

Substances chimiques

Anthracyclines 0
BRCA1 Protein 0
BRCA1 protein, human 0
BRCA2 Protein 0
BRCA2 protein, human 0
Taxoids 0
Cyclophosphamide 8N3DW7272P
Carboplatin BG3F62OND5

Types de publication

Comparative Study Journal Article Multicenter Study

Langues

eng

Sous-ensembles de citation

IM

Pagination

44-52

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest statement The authors declare the following conflicts of interest: A.S. reports receiving grants from Celgene, Roche, AbbVie; personal fees from Roche, AstraZeneca, Celgene, Roche, Pfizer, Novartis, MSD, Tesaro, Lilly, and others from Roche, outside the submitted work; C.H. reports receiving personal fees from Roche, Novartis, Lilliy, MSD, Astra Zeneca, and Pfizer; C.J. reports personal fees from Roche, AsraZeneca, Celgene, Pfizer, Novartis, and Amgen; F.J.C. reports receiving personal fees from AstraZeneca; receiving grants from GRAIL, others from Qiagen and Ambry Genetics, outside the submitted work; H.T. reports receiving personal fees from Novartis, Pfizer, AstraZeneca, Roche, Eisai, and Lilly, outside the submitted work; J.H. reports receiving grants and personal fees from Novartis, personal fees from Lilly, Astra Zeneca, Eisai, MSD, and Abbvie, personal fees and other from Pfizer and Roche, other from Daichii; receiving grants, personal fees and other from Celgene; receiving grants and personal fees from Hexal, outside the submitted work; J.U.B. reports receiving personal fees from AMGEN, ASTRA Zeneca, Novartis, Pfizer, Roche, SonoScape, and Sysmex, outside the submitted work; K.L. reports personal fees and non-financial support from Roche, Lilly, personal fees from Novartis and Genomic Health, outside the submitted work; K.R. reports personal fees from AstraZeneca, Tesaro and Pfizer, outside the submitted work; M.U. reports personal fees and non-financial support from Abbvie, Amgen GmbH, Eisai GmbH, Daiji Sankyo, Celgene GmbH, MSD Merck, Mundipharma, Roche Pharma AG, Odonate, TEVA Pharmaceuticals Ind Ltd., Sanofi Aventis Deutschland GmbH, Pfizer GmbH, Astra Zeneca and Lilly Int., Novartis, Clovis Oncology, and Myriad Genetics; personal fees from BMS, Lilly Deutschland, PUMA Biotechnology, Pierre Fabre, outside the submitted work; P.A.F. reports receiving personal fees from Novartis, Lilly, Pierre Fabre, and Seattle Genetics, Roche, Pfizer, Daiichi-Sankyo, Astra Zeneca, Eisai, Merck Sharp & Dohme; grants from Biontech, Cepheid. R.S. reports receiving grants from Cologne Furtune; S.L. reports receiving grants and other from AstraZeneca, Daiichi-Sankyo, Roche, Pfizer, Novartis, Abbvie, Amgen and Celgene during the conduct of the study; grants and non-financial support from Immunomedics; other from Seattle Genetics, PriME/Medscape, Lilly, Samsung, Eirgenix, BMS, Puma, MSD; personal fees from Chugai; grants from Teva and Vifor; outside the submitted work; In addition, S.L. has a patent EP14153692.0 pending. T.L. reports non-financial support from Pharma Mar, Celgene and Daiichi-Sankyo; personal fees and non-financial support from MSD, Pfizer, Roche, Clovis; personal fees from Amgen, Novartis, Teva, Tesaro, outside the submitted work; V.M. reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA, and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutic; No other potential conflict of interest relevant to this article was reported.

Auteurs

Jenny Furlanetto (J)

German Breast Group, Neu-Isenburg, Germany. Electronic address: Jenny.Furlanetto@gbg.de.

Volker Möbus (V)

Medical Clinic II, University Hospital Frankfurt, Germany.

Andreas Schneeweiss (A)

National Center for Tumour Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany.

Kerstin Rhiem (K)

Center for Familial Breast and Ovarian Cancer, University Clinic Köln, Germany.

Hans Tesch (H)

Center for Hematology and Oncology Bethanien Frankfurt, Germany.

Jens-Uwe Blohmer (JU)

Breast Center Charité-University Medicine Berlin, Germany.

Kristina Lübbe (K)

DIAKOVERE Henriettenstift, Clinic for Gynaecological Surgery, Senology and Oncology, Hannover, Germany.

Michael Untch (M)

HELIOS Clinic Berlin Buch, Germany.

Christoph Salat (C)

Hematological-oncological Practice Salat/Stötzer, München, Germany.

Jens Huober (J)

University Women's Hospital Ulm, Germany.

Peter Klare (P)

MediOnko-Institute GbR Berlin, Germany.

Rita Schmutzler (R)

Center for Familial Breast and Ovarian Cancer, University Clinic Köln, Germany.

Fergus J Couch (FJ)

Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Bianca Lederer (B)

German Breast Group, Neu-Isenburg, Germany.

Bernd Gerber (B)

University Women's Hospital at Clinic Südstadt, Rostock.

Dirk-Michael Zahm (DM)

SRH Wald-Clinic Gera, Germany.

Ingo Bauerfeind (I)

Clinic Landshut, Germany.

Valentina Nekljudova (V)

German Breast Group, Neu-Isenburg, Germany.

Claus Hanusch (C)

Red Cross Hospital München, Germany.

Christian Jackisch (C)

Sana-Clinic, Offenbach, Germany.

Theresa Link (T)

Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.

Eric Hahnen (E)

Center for Familial Breast and Ovarian Cancer, University Clinic Köln, Germany.

Sibylle Loibl (S)

German Breast Group, Neu-Isenburg, Germany.

Peter A Fasching (PA)

Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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