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

Abstract

#45 Background: The role of HER2 and Topoisomerase IIα (TOPO2α) as predictors of anthracycline sensitivity remains controversial. To address this we conducted an analysis of HER2, Topoisomerase IIα amplification (TOPO2α-amp) and deletion (TOPO2α-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/TopoIIα 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 TOPO2α-amp, 9% were TOPO2α-del, 18% were polysomic for C17 and 62% had high Ki67 (>13.0%). HER2-amp and TOPO2α-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, TOPO2α, 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 TOPO2α status. Given the lack of consistency seen in previous studies with respect to HER2 and TOPO2α, 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). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 45.

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

“…This was recently confirmed in an analysis of BR9601, NEAT and MA.5 (Bartlett et al, 2009a(Bartlett et al, , 2009b(Bartlett et al, , 2010. Analysis of Chr17CEP duplication in BR9601, NEAT and MA.5 suggests chromosome 17 to be an independent predictive marker of anthracycline sensitivity.…”

“…However, larger studies, including the recent meta-analysis, also fail to show any consistent predictive value of HER2 amplification or overexpression with respect to anthracyclines (Di Leo et al, 2009;Bartlett et al, 2009a), in direct contrast to the early studies of dose escalation. It would seem that although HER2 and proliferation may select for patients more likely to respond to dose-dense therapy, there is now clear evidence that both HER2-positive and HER2-negative tumours can respond to anthracycline treatment (Di Leo et al, 2009;Bartlett et al, 2009aBartlett et al, , 2010. Therefore, on the basis of current evidence it would seem inappropriate to withhold anthracyclines from HER2-negative patients.…”

“…Similar to results from the Belgian trial, the analysis showed TOP2A amplifications, but not deletions, to be predictive of outcome on anthracycline-based therapy. However, subsequent studies, including that in the NEAT/BR9601 trial, failed to confirm this finding (Bartlett et al, 2009a). Taken together, studies analysing the interaction between HER2/TOP2A genetic aberrations or TOP2A genetic aberrations have failed to either confirm or refute their role as predictive markers of anthracycline response (Knoop et al, 2005;Di Leo et al, 2009;O'Malley et al, 2009;Bartlett et al, 2009a).…”

“…However, subsequent studies, including that in the NEAT/BR9601 trial, failed to confirm this finding (Bartlett et al, 2009a). Taken together, studies analysing the interaction between HER2/TOP2A genetic aberrations or TOP2A genetic aberrations have failed to either confirm or refute their role as predictive markers of anthracycline response (Knoop et al, 2005;Di Leo et al, 2009;O'Malley et al, 2009;Bartlett et al, 2009a). Similar to results for HER2, the recent meta-analysis of four phase III anthracycline trials suggests that TOP2A amplified, deleted and nonamplified cases may all gain greater benefit from anthracycline treatment than CMF (Di Leo et al, 2009;Bartlett et al, 2009a).…”

“…Data are emerging that suggest that the true marker of anthracycline sensitivity may have both a functional and a genetic link to HER2 and TOP2A. Recent evidence has suggested polysomy of chromosome 17 (more recently defined as duplication of the centromeric region (CEP)) as a predictive marker of anthracycline sensitivity (Bartlett et al, 2009a(Bartlett et al, , 2010. Chr17CEP duplication may imply a possible disruption of cell cycle dynamics, DNA repair mechanisms and proliferation, thereby providing a functional link to both HER2 and TOP2A.…”