A four gene signature predicts benefit from anthracyclines: evidence from the BR9601 and MA.5 clinical trials
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Melanie Spears1, Fouad Yousif2, Nicola Lyttle1, Paul C. Boutros2,3,4, Alison F. Munro5, Chris Twelves6, Kathleen I. Pritchard7,8, Mark N. Levine9, Lois Shepherd10 and John MS. Bartlett1,5
1 Transformative Pathology, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada
2 Informatics and Bio-computing, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada
3 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
5 Edinburgh Cancer Research UK Centre, MRC IGMM, University of Edinburgh, Crewe Road South, Edinburgh, UK
6 Leeds Institute of Cancer and Pathology and Cancer Research UK Centre, St James’ University Hospital, Leeds, UK
7 Sunnybrook Odette Cancer Centre, Toronto, ON, Canada
8 University of Toronto, Toronto, ON, Canada
9 McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
10 NCIC Clinical Trials Group (NCIC CTG] and Queen’s University, Kingston, ON, Canada
Melanie Spears, email:
Keywords: breast cancer, anthracycline, chromosome instability, predictive biomarker
Received: July 20, 2015 Accepted: August 10, 2015 Published: September 10, 2015
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.
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