Abstract P6-03-12: High MELK expression levels correlate with shorter overall survival in breast cancer

Abstract

Abstract Background Triple-negative breast cancer (TNBC) is thought to relapse and metastasize because cancer stem cells (CSCs) resist conventional chemotherapy and radiotherapy and later give rise to secondary tumors. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to play a critical role in promoting cell proliferation, CSC maintenance, apoptosis, and transformation. MELK is frequently upregulated in basal-like breast cancers but is not expressed in normal vital organs (Lin et al, Breast Cancer Res 2007;9:R17; Wang et al, eLife 2014;10.7554/eLife.01763). We hypothesized that MELK is upregulated in TNBC and that high expression correlates with poor progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS) in breast cancer. Methods This retrospective study involved the World Inflammatory Breast Cancer Consortium dataset comprising 389 patients from 3 institutions (The University of Texas MD Anderson Cancer Center, General Hospital Sint-Augustinus, and Institut Paoli-Calmettes) with clinical and tumor data and gene expression (GE) profiles. We studied the 314 patients with stage I-III breast cancer (84 TNBC and 230 non-TNBC) within this dataset. Hormone receptor (HR) and HER2 status was defined using the GE data [ESR1 (probe set 205225_at), PGR (208305_at), ERBB2 (216836_s_at)]. We defined high MELK mRNA GE (probe set 204825_at) as ≥7.0 using a Martingale residual plot. Time-to-event endpoints were summarized using the Kaplan-Meier method and compared between or among groups using the log-rank test. Multicovariate Cox proportional hazard models were applied to assess the effect of covariates on survival endpoints. Results Median age of patients was 54 yrs (range, 24-89). Disease stage was III in 48.4% of patients, II in 30.9%, and I in 20.7%. Most tumors had ductal histology (82.5%) and almost half had nuclear grade III (49.7%). MELK expression was significantly higher in TNBC than in the HR+HER2-, HR+HER2+, and HR-HER2+ subtypes (p<0.0001, Kruskal-Wallis test). Median follow-up was 5.7 years. In univariate analysis, patients with MELK-overexpressing tumors had significantly shorter PFS, DMFS, and OS times than patients with low MELK expression (table). In multicovariate Cox regression model, high MELK expression did not have independent prognostic value for PFS (p=0.37) or DMFS (p=0.29); however, compared with low expression, was associated with a higher risk of death (hazard ratio=1.79; 95% CI=1.11-2.89; p=0.02), adjusted for tumor stage, IBC status and TNBC status and stratified by the study center. Conclusion High MELK expression was an independent prognostic factor of OS in breast cancer. Our preliminary results and those of others suggest that MELK may be an important therapeutic target for breast cancer, particularly TNBC, where the MELK expression level was significantly higher than in other subtypes; this warrants further investigation with a large dataset. This study justifies developing MELK inhibitors in TNBC. 5-year DFS, DMFS and OS ratesEndpointMELK GESurvival Probability95%CILog-rank test p valueRFS<773.364.7-80.10.0112 ≥751.843.2-59.8 DMFS<775.366.8-82.00.0081 ≥753.544.8-61.5 OS<784.376.3-89.70.0002 ≥762.753.9-70.4  Citation Format: Takahiro Kogawa, Diane D Liu, Gaurav B Chauhan, Juliana M Taliaferro, Hiroko Masuda, Steven J Van Laere, François Bertucci, Yu Shen, Naoto T Ueno, Kevin N Dalvy, Chandra Bartholomeusz. High MELK expression levels correlate with shorter overall survival in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-03-12.