Abstract P2-05-05: A four gene signature predicts anthracycline benefit: Evidence from the BR9601 and MA5 breast cancer trials
Authors: Spears Melanie , Lyttle Nicola S , Yousif Fouad , Munro Alison F , Twelves Christopher , Pritchard Kathleen I , Levine Mark N , Shepherd Lois , Bartlett John MS 
Published: May 2015

Background: Chromosome instability (CIN) in solid tumours is associated with poor prognosis and results in numerical and structural chromosomal aberrations. Recent evidence from both the BR9601 and MA.5 trials has demonstrated CEP17 duplication as a predictive marker of anthracycline benefit. CIN25 and CIN70 gene expression profiles have previously been published and predict survival response. An analysis of the BR9601 and MA5 clinical trials was performed to test the role of CIN gene expression signatures as a marker of anthracycline sensitivity.

Methods: RNA was extracted from patients in both the BR9601 and MA5 studies and analysed through Nanostring technology. Log-rank analyses explored the prognostic values of the signatures on distant relapse-free survival (DRFS). Cox-regression models tested independent prognostic value on DRFS in the presence of treatment, age, tumour size, nodal status, ER status and grade, and treatment by marker interactions.

Results: Of the 761 samples available from the BR9601 and MA5 cohorts we successfully analysed 703 (92.4%). High CIN25 and CIN70 scores were associated with age (p&lt;0.0001), grade (p0.0001), PgR negativity (p&lt;0.0001) and ER negativity (p&lt;0.0001). In univariate analysis, high CIN25 score was associated with decreased DRFS (HR: 0.74, 95% CI 0.54-0.99, p=0.046). In a multivariate analysis with adjustment for size, nodal status, ER, pathological grade, HER2, CIN25, treatment and treatment by marker only pathological grade, nodal status and tumour size were significant predictors of outcome.

A more limited set of genes that reflected CIN was established by examining the expression profile of the genes and clustering them. The combined cohort was split into a 60% training and 40% validation set. The area under the curve (AUC) was calculated and the gene signature with the greatest AUC was selected and termed CIN4. Patients with low CIN4 score benefited from anthracycline treatment compared to those that had high CIN4 score (HR 2.72, 95% CI 1.48-5.02, p=0.001). No significant benefit with CMF treatment was observed in (HR: 1.02, 95% CI 0.58-1.82, p=0.92). After multivariate analysis the treatment by marker interaction for CIN4 had a hazard ratio of 2.10 (95% CI 2.18-30.38, p= 0.001).

Conclusion: High CIN70 and CIN25 scores were associated with an aggressive phenotype and showed a potential increased sensitivity to anthracycline therapy compared to those with low CIN scores. CIN4 was an independent predictor of anthracycline benefit for DRFS. However, further work in larger patient cohorts such as NEAT is warranted.

Citation Format: Melanie Spears, Nicola S Lyttle, Fouad Yousif, Alison F Munro, Christopher Twelves, Kathleen I Pritchard, Mark N Levine, Lois Shepherd, John MS Bartlett. A four gene signature predicts anthracycline benefit: Evidence from the BR9601 and MA5 breast cancer trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-05.