Chromosome 17 polysomy: a unifying hypothesis underlying benefit from adjuvant anthracyclines?.

Abstract Abstract #6059 Background: Two retrospective studies reported conflicting evidence for HER2 as a predictor of benefit from adjuvant A. In the MA.5 study (NEJM 354:2103-11 2006) patients (pts) with HER2 +ve tumors benefited: whereas in the BR9601 study (JCO in press) those with HER2/HER1-3 -ve tumors gained from A. As HER2 is on chromosome 17, and polysomy is a potential marker of chromosomal instability, we hypothesised that chromosome 17 polysomy (C17) could be the underlying mechanism of the link between HER2 and sensitivity to A .
 Methods:. Triple color FISH was performed in 2 central labs (BR9601 Bartlett & MA5 O'Malley for HER2/TOP2α/centromere 17, Abbott, IL, USA). Local laboratory ER and PgR receptor and grade (G) were noted. BR9601 tumours were scored with a minimum of one C17 signals/cell: in MA.5 a minimum of 2 C17 signals were required for cells to be scored. These methodological differences did not affect HER2/17 ratios (confirmed by central validation - Isola) but necessitated different definitions for C17 polysomy defined as >1.86 observed copies/cell for BR9601 (Watters BCRT 2003 77:109-14) and >2.25 for MA.5 ( Goetz 2004).
 Results: FISH was successful in 97.9% (925/944) of available cases. C17 polysomy was detected in 40.1% of tumors (MA5 - 41.3% & BR9601 - 37.6%). C17 polysomy was associated with poorer OS & DFS (p=0.039 & 0.007, respectively). However C17 polysomy was associated with increased DFS in cases treated with A compared to CMF in both MA.5 (HR 0.62 p=0.004 vs 1.01 NS) and BR9601 (HR 0.48, p=0.016 vs 0.7 NS) and in a combined analysis (HR 0.57, C.I. 0.43-0.77, p = 0.005 vs 0.94 C.I. 0.73-1.21, NS respectively). C17 polysomy was also associated with increased OS in pts treated with A in BR9601 (HR: 0.49, 95% C.I. 0.25-0.96; p=0.034). Multivariate Cox regression analysis (including grade, size, ER status, nodes, polysomy & HER2) showed a highly significant effect of treatment and C17 polysomy (p<0.001), with a significant treatment by marker interaction between C17 polysomy and use of A for OS & DFS (HR 1.61, C.I. 1.01-2.57, p=0.047 and 1.75 C.I. 1.15-2.64, p=0.008 respectively). No treatment by marker effect was observed for HER2 in this multivariate analysis.
 Conclusions: Combined analysis of 2 adjuvant trials with differing effects of HER2 as a predictive marker of benefit from A show that in both trials C17 polysomy predicted for enhanced benefit from A. This is confirmed by Multivariate regression analysis showing a significant interaction of C17 as a marker with treatment. Polysomy 17 may reflect either chromosomal instability or polyploidy & further analysis is warranted to test this unifying hypothesis for prediction of benefit from adjuvant A.
 Acknowledgments: Abbott Laboratories, Scottish Cancer Therapy Network & Institute for Statistics in Disease, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Pfizer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6059.