Retrospective analysis of WSG AM01 tandem high dose chemotherapy trial in high risk primary breast cancer: A hypothesis generating study

Abstract

665 Background: The WSG AM 01 trial is the first one to report superiority of HDC in terms of DFS and OS in patients with >9 positive axillary lymph nodes. Retrospectively we tried to identify patient subgroups with maximum benefit from HDC. Methods: 403 patients were randomized to tandem HDC or to dose-dense conventional chemotherapy (DD). 236 tumors were available for central pathologic review (117/119). A panel of 34 markers were determined by IHC in TMA. Kaplan-Meier, Log rank and Cox proportional hazard models were used for uni- and multivariate analysis. We choose K-means clustering with K=5 and using Manhattan distance as similarity measure. Results: Pts: n=236 (HDC/DD): mean age 47.3/47.4 yrs, mean tumor sizes 3.5/3.4cm, mean positive lymph nodes 17.2/17.0, HR+ 55%/53%, G3 44%/35%. HDC was superior to DD (p=0.02). Multivariate analysis demonstrated a significant correlation for grading, tumor size, PR+. HR > 2 were reported for the following markers: Her2neu+, p53+, bcl2−, Ck 5/6 and 17+, Ck8−, c-kit+, vimentin+, ETR 1/2, BCRP+. Triple negative tumors (TN) (31%) had a large benefit from HDC (HR DD vs. HD: 3.06, 95%CI:1.41–6.06). Groups identified by K-means clustering could be attributed to luminal-A-(31%), luminal-B-(27%), her2-(11%), basal like-(11%) type and a so far undefined proliferative group (20%) characterized mainly by the absence of specifying markers. Interestingly, the proportion of the above mentioned molecular subtypes within of high risk populations very similar to those reported for less selected populations. Her2, basal-like and the undefined proliferative group had significantly worse outcome when compared to luminal tumors (p<0.01). Very poor prognosis if treated by conventional CT was observed in basal like (HR DD vs HD=2.66 95%CI: 0.9–7.9) und the undefined group (HR=1,72, 95%CI:0.92–3.21), where most of the TN tumors were found. Conclusions: Tandem HDC is superior to DD conventional CT for treatment of HRBC. The largest benefit from high dose chemotherapy was reported for younger patients with TN poor differentiated tumors, >2cm. Negative hormone receptor status, p53+, bcl2−, MIB/p16+ and BCRP+ predicted benefit from dose intensification. Subgroups are small and may help to generate further hypothesises. No significant financial relationships to disclose.