Abstract PD5-09: Prognostic and predictive impact of genes and signatures measured with the BC360 panel (Nanostring) in node positive (≥pN2a) high risk patients (pts) receiving dose dense (dd) versus standard dosed chemotherapy in an adjuvant randomized trial with a long term follow-up (FU)
Authors: Reinisch Mattea , Gluz Oleg , Ataseven Beyhan , Schmid Peter , Blohmer Jens-Uwe , Dittmer-Grabwoski Christine , Rueland Anna , Bruzas Simona , Seiberling Christine , Harrach Hakima , Gebauer Daniel , Traut Alexander , Kuemmel Sherko 
Published: March 2020

Abstract
Background: Breast cancer (BC) patients with ≥ 4 positive lymph nodes have a particularly poor prognosis with shorter disease free survival (DFS) and overall survival (OS) than pts with pN1a. However this is a highly heterogeneous group. The implementation of genomic signatures and/or Ki-67 status for hormone receptor positive BC pts with node negative or positive (≤ pN1a) disease enables identification of a subgroup of pts with favourable outcome and no survival benefit from chemotherapy (CTX). However, here is lack of information regarding pts with ≥ 4 positive lymph nodes, and so far all patients receive a recommendation for CTX. In addition, there are no predictive factors for use of dd CTX in this group so far.
Methods: Between 1996–2000, 231 BC pts ≥ pN2a (median positive lymph nodes n= 6) with no evidence of distant metastases, were randomized to either adjuvant dd treatment with dd 3 × epirubicin (E, 90 mg/m2) + paclitaxel (P, 175 mg/m2) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m2, q2w), or standard (st) treatment : 4 × E + C (C, 600 mg/m2) q3w followed by 3 × CMF q3w. Pts in the dd arm had a significantly better DFS (adjusted p = 0.027) with a non-significant trend to better OS (adjusted p = 0.058). Due to the recruitment period, there is no information on the HER2 status of the included pts (Reinisch et al, 2018).
The BC360 panel analysis was performed on 147 tumor specimens (dd arm n= 75; st arm n= 72). Samples were run on the 770 gene BC360 panel with additional 6 spike-in genes. Genes related to adhesion and migration, immune activation, ER signaling, DNA damage and repair, apoptosis, and proliferation were analyzed. The survival analysis was used to create the forest plot incorporating a Cox proportional hazards model with the survival outcome as a dependent variable, the observed normalized gene expression or signature score data as a continuous covariate, and any grouping variable included as a strata variable in the model.
Results: After quality control, 144/147 tumor specimens were available for the analysis (dd arm: 72; st arm; 72). The intrinsic subtype was equivalently distributed between the arms. The expression of PD-L1 (p = 0.025), PD-L2 (p = 0.007) and the presence of macrophages (p = 0.019) were positively correlated with an improved DFS in pts receiving dd but not st CTX. An improved OS was also associated with the presence of macrophages (p = 0.018) and the expression of TGF-β (p = 0.035) only in pts receiving dd CTX.
Pts with a HER2 enriched subtype benefited from the use of dd CTX. Dd CTX does not influence the outcome in BRCAness and HRD positive pts regardless the applied CTX. Further prognostic and predictive factors correlated to a median FU of 20 years will be presented at the meeting.
Conclusions: To our best knowledge, this is the first time the BC360 panel was run on samples of a cohort of high risk pts with ≥ pN2a with a median long term FU of 20 years. Our data may indicate that markers associated with immune activation are predictive factors for the use of dd therapies. High risk pts with different benefit from CTX may be identified. In pts with a HER2 enriched subtype not having received anti-HER2 therapy, the application of dd therapy may correlate with a better outcome. This analysis highlights the prognostic and predictive value of gene signatures to provide treatment guidance.
Citation Format: Mattea Reinisch, Oleg Gluz, Beyhan Ataseven, Peter Schmid, Jens-Uwe Blohmer, Christine Dittmer-Grabwoski, Anna Rueland, Simona Bruzas, Christine Seiberling, Hakima Harrach, Daniel Gebauer, Alexander Traut, Sherko Kuemmel. Prognostic and predictive impact of genes and signatures measured with the BC360 panel (Nanostring) in node positive (≥pN2a) high risk patients (pts) receiving dose dense (dd) versus standard dosed chemotherapy in an adjuvant randomized trial with a long term follow-up (FU) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-09.