title: A four gene signature predicts benefit from anthracyclines: evidence from the BR9601 and MA.5 clinical trials.
abstract: Chromosome instability (CIN) in solid tumours results in multiple numerical and structural chromosomal aberrations and is associated with poor prognosis in multiple tumour types. Recent evidence demonstrated CEP17 duplication, a CIN marker, is a predictive marker of anthracycline benefit. An analysis of the BR9601 and MA.5 clinical trials was performed to test the role of existing CIN gene expression signatures as predictive markers of anthracycline sensitivity in breast cancer. Univariate analysis demonstrated, high CIN25 expression score was associated with improved distant relapse free survival (DRFS) (HR: 0.74, 95% CI 0.54-0.99, p = 0.046). High tumour CIN70 and CIN25 scores were associated with aggressive clinicopathological phenotype and increased sensitivity to anthracycline therapy compared to low CIN scores. However, in a prospectively planned multivariate analysis only pathological grade, nodal status and tumour size were significant predictors of outcome for CIN25/CIN70. A limited gene signature was generated, patients with low tumour CIN4 scores benefited from anthracycline treatment significantly more than those with high CIN4 scores (HR 0.37, 95% CI 0.20-0.56, p = 0.001). In multivariate analyses the treatment by marker interaction for CIN4/anthracyclines demonstrated hazard ratio of 0.35 (95% CI 0.15-0.80, p = 0.012) for DRFS. This data shows CIN4 is independent predictor of anthracycline benefit for DRFS in breast cancer.
authors.affiliation: Transformative Pathology, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Spears
authors.affiliation: Informatics and Bio-Computing, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.
authors.forename: Fouad
authors.initials: F
authors.lastname: Yousif
authors.affiliation: Transformative Pathology, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.
authors.forename: Nicola
authors.initials: N
authors.lastname: Lyttle
authors.affiliation: Informatics and Bio-Computing, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Edinburgh Cancer Research UK Centre, MRC IGMM, University of Edinburgh, Crewe Road South, Edinburgh, UK.
authors.forename: Alison F
authors.initials: AF
authors.lastname: Munro
authors.affiliation: Leeds Institute of Cancer and Pathology and Cancer Research UK Centre, St James' University Hospital, Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.affiliation: Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.|University of Toronto, Toronto, ON, Canada.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Levine
authors.affiliation: NCIC Clinical Trials Group (NCIC CTG] and Queen's University, Kingston, ON, Canada.
authors.forename: Lois
authors.initials: L
authors.lastname: Shepherd
authors.affiliation: Transformative Pathology, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.|Edinburgh Cancer Research UK Centre, MRC IGMM, University of Edinburgh, Crewe Road South, Edinburgh, UK.
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D043171:Chromosomal Instability; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D015996:Survival Rate
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: anthracycline; breast cancer; chromosome instability; predictive biomarker