P1-06-03: Predictive Value of HER2, Topoisomerase-II (Topo-II) and Tissue Inhibitor of Metalloproteinases (TIMP-1) for Efficacy of Taxane-Based Chemotherapy in Intermediate Risk Breast Cancer – Results from the EC-Doc Trial.
Authors: Gluz O , Erber R , Kates R , Kreipe H , Bartels A , Liedtke C , Pelz E , Huober J , Kuhn W , Nitz U , Hartmann A , Harbeck N , Brünner N 
Published: June 2012

Background: Despite extensive research, there is still no consensus on optimal predictors for use of taxane-based chemotherapy (cht) in early breast cancer. Some studies have revealed HER2 as a significant predictive marker for efficacy of taxanes and anthracyclines. TIMP-1 and Topo-II are reported to be predictive for anthracycline efficacy. In our previous reports, both Ki-67≥20% and central G3 status emerged as significant predictors for taxane benefit. We have now compared HER2 and Topo-II (as protein expression and gene amplification) and TIMP-1 immunoreactivity as well as factor combinations (HT (HER2/TIMP-1) and 2T (Topo-II/TIMP-1) regarding their predictive value for benefit from taxane-based cht.

Methods: The EC-Doc trial randomized 1950 patients with 1–3 positive LN to 6x CEF/CMF vs. 4xEC-4xDoc. Significantly better DFS and OS favoring EC-Doc have been previously reported (Nitz et al., SABCS 2008). Protein expression and gene amplification data as well central histology/grade were available for 772 patients. Survival analysis was performed using Cox proportional hazards and Kaplan-Meier statistics. Analysis of HER2 survival impact status was prospectively planned.

Results: The entire and the investigated study populations did not differ regarding baseline characteristics. After median follow up of 64 months, both DFS (5y 90% vs. 80%, p=0.006) and OS (5y 95% vs. 92%, p=0.022) rates significantly favored EC-Doc vs. CEF in this cohort as well. HER2 over-expression (3+ and/or FISH≥2.0) was reported in 158 tumors (20%), Topo-II aberration (deletion or amplification) was reported in 78 (49.4%) HER2+ and in 83 (13.6%) HER2−negative tumors; 496 tumors were classified as TIMP-1 immunoreactive (65.2%). None of these factors were significantly prognostic for EFS in this collective. Regarding DFS, EC-Doc was strongly superior to FEC in HER2+ tumors (HR=0.29, 95%CI: 0.12−0.7, p=0.006) but not in HER2− tumors (p=0.18). In Topo-II aberrated tumors, the benefit of EC-Doc was remarkably strong (HR=0.28, 95% CI: 0.11−0.69, p=0.006), whereas the benefit was not significant in Topo-II normal tumors (p=0.16), which comprise more than ¾ of the total. In contrast, Topo-II protein overexpression (&gt;10%) was not associated with a stronger benefit in either subgroup. The superiority of EC-Doc to FEC was significant in the larger group of TIMP-1 immunoreactive tumors (HR=0.57, p=0.025) but not in TIMP-1 negative tumors (p=0.14), similar behavior was seen in “HT” and “2T” subgroups (significance with HR about 0.5 in the “+” subgroups). In a multivariate model for DFS including age, tumor size, Ki-67, central grade, HR, HER2, TOPO_II aberration, TIMP-1 status, therapy and interactions of all these factors with therapy arm, the only significant therapy interaction was that of (high) Ki-67 (HR=0.76, 95% CI: 0.59−0.98, p=0.03); significant main effects in this model were age, central grade, and Ki-67.

Conclusions: These data suggest predictive significance for Topo-II aberration, TIMP immunoreactivity and HER2 over-expression as well as a multivariate predictive significance of high Ki-67 for enhanced benefit of taxane-based cht.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-03.