Abstract P2-10-03: Genomic markers but not molecular subtypes provide prognostic impact and predict anthracycline efficacy in early triple-negative breast cancer: Results from the prospective WSG PlanB trial
Authors: Gluz O , Liedtke C , Prat A , Christgen M , Gebauer D , Kates R , Pelz E , Clemens M , Warm M , Aktas B , Kuemmel S , Pare L , Krabisch P , Kreipe HH , Wuerstlein R , Nitz U , Harbeck N 
Published: February 2018

Abstract
Background: Optimal treatment, particularly use of anthracyclines in aggressive triple-negative breast cancer (TNBC), is still a controversial issue in early BC management. However, TNBC exhibits substantial molecular heterogeneity: for example, the immune phenotype seems to be associated with better outcome. An important clinical issue in early TNBC is to quantify the impact of subtypes as well as individual genes on survival and especially on anthracycline benefit.
Methods: In PlanB, patients with ER and PR&lt;1% (local or central lab), HER2- EBC were treated by TC (6 cycles Docetaxel/Cyclophosphamide) or EC-Doc (4xEpirubicin/Cyclophosphamideà4xDocetaxel) (overall n=2449, HER2-). RNA isolation was successfully performed in n=402/449 patients with available follow-up. Gene (n=119) expression data by Nanostring® platform were entered into univariate and multivariate Cox models for disease-free survival (DFS) to identify genes (and combinations) with potential prognostic and/or predictive impact. Median follow-up was 60 months.
Results: RNA expression results were available in n=394 (203 TC vs. 191 EC-Doc): PAM-50 subtype: basal-like 82%; HER2-enriched 7%; luminal (A or B) 3.5%; normal-like 7.4%. Median age was 54; 78% were node-negative. In patients with “discordant” tumors (HR positive by local or central assessment), 76% were still basal-like, compared to 86% in “concordant” TNBC. Of 27 patients with HER2-enriched subtype, HER2 status was positive by central assessment in only five cases (18%).
Within this TN cohort, 5y DFS was similar in TC (83%) and EC-Doc (79%) arms; positive nodal status and tumor size &gt;2 cm were (unfavorable) clinical-pathological prognostic markers. Prognostic or predictive impacts of molecular subtype, risk of recurrence subgroups, or proliferation indices were not seen.
Twelve genes (incl. CD8, EGFR, GPR160, SPINT2) showed potential multivariate prognostic impact by entering the “forwards stepwise” multivariate Cox model for DFS. The upper half of patients according to the resulting “twelve-gene signature” had well over 90% 5y-DFS, whereas the lowest quartile had under 60% 5-y DFS. Several genes (incl. ERBB2, FOXC1) showed potential for a predictive impact regarding TC vs. EC-Doc by interaction analysis. Further details and perspectives for testing the robustness of these potential impacts will be presented at the meeting.
Conclusions
To our knowledge, these are the first results from a prospective, adjuvant taxane-based trial regarding molecular predictors of anthracycline efficacy and PAM-50-based prognostic factors in early TNBC. ERBB2 expression, but not HER2-enriched subtype, was predictive for A-benefit in HER2-negative BC. Molecular heterogeneity of TNBC beyond basal-like vs. non-basal-like subtype is clinically relevant and should be considered for patient stratification in ongoing trials with combination therapy. The identified prognostic gene signature should be validated in the WSG-ADAPT-TN and other TNBC trials.
Citation Format: Gluz O, Liedtke C, Prat A, Christgen M, Gebauer D, Kates R, Pelz E, Clemens M, Warm M, Aktas B, Kuemmel S, Pare L, Krabisch P, Kreipe HH, Wuerstlein R, Nitz U, Harbeck N. Genomic markers but not molecular subtypes provide prognostic impact and predict anthracycline efficacy in early triple-negative breast cancer: Results from the prospective WSG PlanB trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-03.