title: BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial.
abstract: BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide.
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: West German Study Group, Germany.|Breast Centre Niederrhein, Moenchengladbach, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Gluz
authors.affiliation: West German Study Group, Germany.|Brustzentrum, Ludwig-Maximillian University Munich, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: Universitäts-Frauenklinik Duesseldorf, Germany.
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Mohrmann
authors.affiliation: Universitäts-Frauenklinik Duesseldorf, Germany.
authors.forename: Raihana
authors.initials: R
authors.lastname: Diallo-Danebrock
authors.affiliation: Breast Centre Niederrhein, Moenchengladbach, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Pelz
authors.affiliation: Genomics Core Facility, NKI-AVL, Amsterdam, The Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Kruizinga
authors.affiliation: Genomics Core Facility, NKI-AVL, Amsterdam, The Netherlands.
authors.forename: Arno
authors.initials: A
authors.lastname: Velds
authors.affiliation: Genomics Core Facility, NKI-AVL, Amsterdam, The Netherlands.
authors.forename: Marja
authors.initials: M
authors.lastname: Nieuwland
authors.affiliation: Genomics Core Facility, NKI-AVL, Amsterdam, The Netherlands.
authors.forename: Ron M
authors.initials: RM
authors.lastname: Kerkhoven
authors.affiliation: West German Study Group, Germany.|Universitäts-Frauenklinik Lübeck, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: West German Study Group, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Frick
authors.affiliation: West German Study Group, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kates
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: West German Study Group, Germany.|Breast Centre Niederrhein, Moenchengladbach, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitz
authors.affiliation: Universitäts-Frauenklinik, University of Heidelberg, Germany.|National Center for Tumour Diseases, University of Heidelberg, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Marme
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D016019:Survival Analysis; D013852:Thiotepa / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D015251:Epirubicin; D003520:Cyclophosphamide; D013852:Thiotepa
keywords: BRCA1; alkylating chemotherapy; copy number profiling; predictive biomarker