E A Reijm1, A M Timmermans1, M P Look1, M E Meijer-van Gelder1, C K Stobbe2, C H M van Deurzen3, J W M Martens1, S Sleijfer1, J A Foekens1, P M J J Berns4, M P H M Jansen1. 1. Department of Medical Oncology, Cancer Genomics Netherlands. 2. Department of PATHAN BV, Laboratory Pathology, Sint Franciscus Hospital, Rotterdam, The Netherlands. 3. Department of Medical Oncology, Cancer Genomics Netherlands Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam. 4. Department of Medical Oncology, Cancer Genomics Netherlands p.berns@erasmusmc.nl.
Abstract
BACKGROUND: Metastatic breast cancer (MBC) is a highly heterogeneous disease with great differences in outcome to both chemo- and endocrine therapy. Better insight into the mechanisms underlying resistance is essential to better predict outcome to therapy and to obtain a more tailored treatment approach. We have previously described that increased mRNA expression levels of Enhancer of Zeste homolog (EZH2) are associated with worse outcome to tamoxifen therapy in MBC. Here, we explored whether this is also the case for EZH2 protein expression. PATIENTS AND METHODS: A tissue microarray (TMA) was created using formalin-fixed, paraffin-embedded estrogen receptor (ER)-positive primary breast tumor tissues of 250 MBC patients treated with first-line tamoxifen. Quantity and intensity of EZH2 expression were determined by immunohistochemistry (IHC) and both were used to generate and group scores according to a previously described method for scoring EZH2. RESULTS: In total, 116 tumors (46%) were considered to be EZH2 positive. The presence of EZH2 protein expression was significantly associated with progression-free survival (PFS) in both univariate [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.17-1.97, P = 0.002] and multivariate analysis including traditional factors associated with tamoxifen outcome (HR 1.41, 95% CI 1.06-1.88, P = 0.017). Considering quantity irrespective of intensity, tumors with >50% EZH2-positive cells had the worst PFS (HR 2.15, 95% CI 1.42-3.27, P < 0.001), whereas intensity alone did not show a significant association with PFS. Application of other methods of scoring EZH2 positivity resulted in a similar significant association between the amount of EZH2 positive cells and PFS. CONCLUSION: In addition to EZH2 mRNA levels, these results suggest that protein expression of EZH2 can be used as a marker to predict outcome to tamoxifen therapy. This provides new rationale to explore EZH2 inhibition in the clinical setting and increases the possibilities for a more personalized treatment approach in MBC patients.
BACKGROUND:Metastatic breast cancer (MBC) is a highly heterogeneous disease with great differences in outcome to both chemo- and endocrine therapy. Better insight into the mechanisms underlying resistance is essential to better predict outcome to therapy and to obtain a more tailored treatment approach. We have previously described that increased mRNA expression levels of Enhancer of Zeste homolog (EZH2) are associated with worse outcome to tamoxifen therapy in MBC. Here, we explored whether this is also the case for EZH2 protein expression. PATIENTS AND METHODS: A tissue microarray (TMA) was created using formalin-fixed, paraffin-embedded estrogen receptor (ER)-positive primary breast tumor tissues of 250 MBCpatients treated with first-line tamoxifen. Quantity and intensity of EZH2 expression were determined by immunohistochemistry (IHC) and both were used to generate and group scores according to a previously described method for scoring EZH2. RESULTS: In total, 116 tumors (46%) were considered to be EZH2 positive. The presence of EZH2 protein expression was significantly associated with progression-free survival (PFS) in both univariate [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.17-1.97, P = 0.002] and multivariate analysis including traditional factors associated with tamoxifen outcome (HR 1.41, 95% CI 1.06-1.88, P = 0.017). Considering quantity irrespective of intensity, tumors with >50% EZH2-positive cells had the worst PFS (HR 2.15, 95% CI 1.42-3.27, P < 0.001), whereas intensity alone did not show a significant association with PFS. Application of other methods of scoring EZH2 positivity resulted in a similar significant association between the amount of EZH2 positive cells and PFS. CONCLUSION: In addition to EZH2 mRNA levels, these results suggest that protein expression of EZH2 can be used as a marker to predict outcome to tamoxifen therapy. This provides new rationale to explore EZH2 inhibition in the clinical setting and increases the possibilities for a more personalized treatment approach in MBCpatients.
Authors: Yinghui Zhang; Lynn Wester; Jichao He; Tamar Geiger; Marja Moerkens; Ram Siddappa; Jean A Helmijr; Mieke M Timmermans; Maxime P Look; Caroline H M van Deurzen; John W M Martens; Chantal Pont; Marjo de Graauw; Erik H J Danen; Els M J J Berns; John H N Meerman; Maurice P H M Jansen; Bob van de Water Journal: Oncogene Date: 2018-01-22 Impact factor: 9.867
Authors: Maurice P H M Jansen; Leen Sas; Anieta M Sieuwerts; Caroline Van Cauwenberghe; Diana Ramirez-Ardila; Maxime Look; Kirsten Ruigrok-Ritstier; Pascal Finetti; François Bertucci; Mieke M Timmermans; Carolien H M van Deurzen; John W M Martens; Iris Simon; Paul Roepman; Sabine C Linn; Peter van Dam; Marleen Kok; Filip Lardon; Peter B Vermeulen; John A Foekens; Luc Dirix; Els M J J Berns; Steven Van Laere Journal: Mol Oncol Date: 2015-03-04 Impact factor: 6.603
Authors: Kimberly D van der Willik; Mieke M Timmermans; Carolien Hm van Deurzen; Maxime P Look; Esther A Reijm; Wendy Jhp van Zundert; Renée Foekens; Anita Mac Trapman-Jansen; Michael A den Bakker; Pieter J Westenend; John Wm Martens; Els Mjj Berns; Maurice Phm Jansen Journal: Am J Cancer Res Date: 2016-01-15 Impact factor: 6.166