[45] Chromosome 17 polysomy (Ch17) as a predictor of anthracycline response: emerging evidence from the UK NEAT adjuvant breast cancer trial.

Bartlett JMS, Munro A, Dunn JA, Hiller L, Jordan S, Twelves CJ, Cameron DA, Thomas J, Campbell F, Rea DW, Provenzano E, Pharoah P, Caldas C, Earl H, Poole CJ Edinburgh University, Edinburgh, United Kingdom; University of Warwick, Coventry, United Kingdom; University of Bradford, United Kingdom; University of Leeds, Leeds, United Kingdom; University of Cambridge, United Kingdom; Addenbrookes Hospital, Cambridge, United Kingdom; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom; University of Birmingham, United Kingdom

Background: The role of HER2 and Topoisomerase II (TOPO2) as predictors of anthracycline sensitivity remains controversial. To address this we conducted an analysis of HER2, Topoisomerase II amplification (TOPO2-amp) and deletion (TOPO2-del), chromosome 17 polysomy (C17) and Ki67 as prognostic and predictive markers in the UK National Epirubicin Adjuvant Trial (NEAT) which compared classical CMF with Epirubicin followed by CMF (NEJM 2006;355:1851-62).
Methods: TMAs constructed with 1638/2021 tumors from patients in the NEAT study were analysed for HER2/TopoII gene alterations, C17 polysomy, and Ki67. Log-rank analyses explored the prognostic value of markers on relapse-free survival (RFS) and overall survival (OS). Cox-regression models tested independent prognostic value on RFS and OS in the presence of treatment, age, type of surgery, tumor size, nodal status, ER status and grade, and marker x treatment interactions for RFS and OS.
Results: Of 1625 NEAT samples analysed, 806(50%) received anthracycline-containing treatment; 985(61%) were 50 years old; 1114(69%) had nodal involvement; 791 (49%) were ER+ve; 961(59%) had G3 tumours; and 893 (56%) had tumour size >2cm. 19% were HER2-amp, 9% were TOPO2-amp, 9% were TOPO2-del, 18% were polysomic for C17 and 62% had high Ki67 (>13.0%). HER2-amp and TOPO2-del were significant poor prognostic factors (P<0.001) for RFS and OS, and were independent variables in multivariate analyses. Other factors did not reach significance at the 1% level. No significant treatment interaction with anthracyclines was seen for HER2-amp (OS p=0.25, RFS p=0.51). Polysomy C17 was not prognostic but exhibited a significant treatment interaction with anthracyclines (RFS p=0.02, HRs 0.96 95%CI 0.73-1.26 vs 0.56 95%CI 0.33-0.97, OS p=0.06, HRs 0.97 95%CI 0.72-1.30 vs 0.60 95%CI 0.33-1.08). Patients with C17 polysomic tumours had significantly greater benefit from anthracyclines.
Conclusions: Analysis of samples from the NEAT trial, which for the first time included HER2, TOPO2, Ki67 and C17, strongly suggest that the most powerful predictor of benefit from adjuvant anthracyclines is chromosome 17 polysomy, perhaps as a marker of chromosomal instability, with a weak effect for HER2-amp. No effect was observed for differing TOPO2 status. Given the lack of consistency seen in previous studies with respect to HER2 and TOPO2, we suggest that polysomy C17 could be the unifying predictive marker of anthracycline sensitivity, particularly as these data are confirmed by data from a separate meta-analysis of MA5 and BR9601 trials (SABCS2008).

Friday, December 12, 2008 4:30 PM

General Session 4 (3:30PM-5:00PM)