title: High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer.
abstract: In previous studies, high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high-dose (HD) alkylating chemotherapy compared with a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD [4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses were available. High RNA expression of XIST (n = 5) and low protein expression of 53BP1 (n = 3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence-free survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer.
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Vollebergh
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Opdam
authors.affiliation: MRC Holland, Amsterdam, the Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Jonkers
authors.affiliation: MRC Holland, Amsterdam, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Loden
authors.affiliation: Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. s.linn@nki.nl.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; 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* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D051379:Mice; D011379:Prognosis; D016016:Proportional Hazards Models; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D062085:RNA, Long Noncoding; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C077885:XIST non-coding RNA