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.
Highlights
Meta-analyses performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) confirm a significant increase in disease free and overall survival (OS) following the addition of anthracyclines to polychemotherapy [1]
Tumours with high CIN25 scores were associated with reduced distant relapse free survival (DRFS) (HR: 1.43, 95%CI 1.111.67, p = 0.004, Figure 2A) and OS (HR: 1.45, 95%CI 1.14-1.85, p = 0.003, Figure 2B)
The original chromosome instability (CIN) signature produced by Carter and colleagues used aneuploidy as a surrogate marker for CIN and both this and mRNA CIN signatures were associated with poor prognosis in multiple cancers [11,12]
Summary
Meta-analyses performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) confirm a significant increase in disease free and overall survival (OS) following the addition of anthracyclines to polychemotherapy [1]. Selecting the subset of patients who will benefit from adjuvant anthracycline whilst sparing other patients unnecessary toxicities remains a clinically highly relevant approach for early www.impactjournals.com/oncotarget breast cancer. Significant resources have been devoted to developing markers that may predict anthracycline benefit (HER2, TOP2A, Ch17CEP and TIMP1) with limited success [5,6,7,8,9]. Research from our group has linked the predictive effect of CEP17 in vivo to chromosome instability (CIN), which itself is predictive of anthracycline benefit in the BR9601 trial [10] and in preclinical models
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