Abstract P1-09-04: Proliferation and p21 refine risk of relapse in residual disease after HER2-directed therapies
Authors: Bianchini G , Pienkowski T , Im Y-H , Bianchi GV , Tseng L-M , Liu M-C , Lluch A , de la Haba-Rodríguez J , Semiglazov V , Oh D-Y , Poirier B , Pedrini JL , Valagussa P , Gianni L 
Published: March 2017

Abstract
Background: Patients (pts) with residual disease (RD) after neoadjuvant therapy are at higher risk of relapse. We investigated whether biomarkers assessed at surgery in patients pts with RD in the NeoSphere study were informative for risk of distant event free survival (DEFS)
Methods: In NeoSphere 417 HER2+ pts were randomized to neoadjuvant TD, TPD, TP or PD (T=trastuzumab, P=pertuzumab, D=docetaxel), and received FAC/FEC and trastuzumab after surgery. 296 pts had RD. Affymetrix derived gene expression profiles (GEPs) were available at surgery for 201 pts (67.9%). 176 pts (60.1%) had paired samples before and after treatment with available GEPs. We investigated the prognostic value of proliferation evaluated by Mitosis Kinase Score (MKS) (Bianchini G Cancer Res 2010), and performed a gene discovery for association between gene expression at surgery and DEFS.
Results: MKS as continuous marker was associated with significantly higher risk of relapse when assessed at surgery (HR 1.80 [1.23-2.65]; p=0.002), but not before treatment (HR 1.50 [0.80-2.78]; p=0.20). In paired samples, there was an average decrease (p=9.2E-11) of MKS after treatment, which was prominent in ER+ and chemotherapy-containing arms. In ER- and TP arm there were cases of increase and of decrease of MKS. In ER+ the 5 years DEFS was 94.3% in the Low/Int MKS tertiles group (pooled) vs 70.5% in the High MKS tertile group (HR 5.41 [1.87-15.6]; p=0.002). In ER-, the 5 years DEFS was 85.0% in the Low/Int vs 64.1% in the High group (HR 2.89 [1.08-7.76]; p=0.035). Notably, MKS at surgery after the two monoclonal alone was also prognostic.
In the gene discovery approach only the expression of CDKN1A (p21)at surgery was associated with DEFS after correction for false discovery rate (FDR=0.01). Pre-treatment p21 was not associated with DEFS. Paired comparison showed significant upregulation of p21 in all patients, treatment arms and ER groups. The Int/High p21 tertiles group (pooled) had lower risk of recurrence than the low tertile in ER+ (HR 4.31 [1.60-11.6]; p=0.004) and in ER- (HR 5.81 [1.87-18.1]; p=0.002) groups. p21 in TP arm was also prognostic. MKS and p21 expression provided independent prognostic information and remained significant after correction for clinico-pathological variables (nodes and T stage) and tumor-infiltrating lymphocytes. Combining the two markers, there was a group at very low risk (Low/Int MKS and Int/High p21) and one at high risk (High MKS and Low p21). The other tertiles combinations had intermediate risk. In ER+, the 5 yrs DEFS was 94.9% in the low risk group and 52.9% in the high risk (p=1.9E-05). In ER-, the 5 yrs DEFS was 96.5% in the low and 45.5% in the high risk group (p=0.001).The markers' combination was also prognostic in the two monoclonal only arm.
Conclusions: Proliferation (MKS) and p21 expression are modulated by trastuzumab and/or pertuzumab regimens. Tumors with high MKS and low p21 in RD after neoadjuvant therapy defined a group at very high risk of relapse. Tumors with low/int proliferation and int/high p21 had low risk of recurrence similar to that of patients achieving pCR. Whether the pharmacodynamic modulation of p21 could be used as surrogate marker of long term benefit in patients with RD deserves additional investigation.
Citation Format: Bianchini G, Pienkowski T, Im Y-H, Bianchi GV, Tseng L-M, Liu M-C, Lluch A, de la Haba-Rodríguez J, Semiglazov V, Oh D-Y, Poirier B, Pedrini JL, Valagussa P, Gianni L. Proliferation and p21 refine risk of relapse in residual disease after HER2-directed therapies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-04.