Abstract P4-10-24: Cyclin E overexpression is associated with high risk 70 gene signature, and may indicate intrinsic resistance to CDK4/6 inhibitors
Authors: Mittempergher Lorenza , McKelley Joe , Bhaskaran Rajith , Uygun Sahra , Bernards René , van 't Veer Laura J , Glas Annuska M , Audeh William 
Published: March 2020

Background: The use of CDK4/6 inhibitors (CDK4/6i) is a promising therapeutic strategy for recurrent ER+, HER2- breast cancers that have escaped previous treatment targeting the endocrine pathway. A number of adjuvant and neoadjuvant trials with CDK4/6i in early breast cancer are also underway. However, no clear predictive biomarkers for resistance are available other than loss of the RB1 tumor suppressor gene. Cyclin E genes (CCNE1, CCNE2) play a critical role in cell cycle control with approximately 25% of breast cancer overexpressing CCNE2, and there is a significant correlation between CCNE2 and CCNE1 expression1,2,3. Furthermore, a positive correlation between expression of CCNE1 and resistance to CDK4/6i (i.e. palbociclib)4,5,6 has been reported in vitro and in a gene expression analysis from the PALOMA-3 trial. The 70-gene MammaPrint® (MP) signature is a prognostic assay that stratifies early-stage breast cancer (ESBC) patients into Low and High-risk of distant relapse. One of the 70 genes is CCNE2, shown to be associated with resistance to both endocrine therapy and CDK4 inhibition7. Considering the potential role of the Cyclin E genes as biomarker of resistance for CDK4/6i, we assessed the expression of CCNE2 in a large series of ESBCs with respect to their MP risk profile.

Methods: The mRNA expression of CCNE2 (and CCNE1) was measured in a series of 5022 breast cancer samples for which FFPE microarray full-transcriptome data were available for testing. Intensities were Lowess normalized and log2 transformed. The 80-gene BluePrint (BP) profile8 was used in combination with MP to stratify patient samples based on their molecular subtype: Luminal A- (MP Low Risk, BP Luminal), Luminal B- (MP High Risk, BP Luminal), HER2- and Basal-type. Wilcoxon rank sum test was used to examine expression differences.

Results: CCNE2 is significantly higher expressed in MP High risk compared to MP Low risk tumors when all samples are included (p &lt;0.0001). When looking at the clinically ER positive BP Luminal group, CCNE2 is significantly higher expressed in the Luminal B compared to the Luminal A tumors (p &lt;0.0001). However, we observe a broad distribution of CCNE2 expression within the Luminal group, indicating a biological diversity in both Luminal A and B tumors, which CCNE2 may help to further define. Specifically, Luminal B tumors have a range of CCNE2 expression with the highest levels being in the highest MP risk interval (Ultra High). Of importance, CCNE1 showed similar expression patterns as CCNE2.

Conclusions: Our preliminary results show that MP could help in stratifying BP Luminal-type B tumors in subgroups with differential CCNE2 expression. Since increased CCNE1 expression is correlated with CDK4/6i resistance, and CCNE2 is a functionally-related gene whose expression correlates to some extent with CCNE1, it is reasonable to speculate that high CCNE2 expression and MP High Risk Luminal B may also correlate with CDK4/6i resistance, a testable hypothesis.

This warrants additional analyses that integrate treatment response data to support and further investigate these observations. Our exploratory analysis also highlights the added value of a multi-gene signature profile versus single-gene testing as tool for patient stratification and treatment recommendation.

Refernces:

1. Asghar U et al Nat Rev Drug Discov. 2015

2. Caldon C et al Cell Div. 2010

3. Payton M et al Oncogene. 2002

4. Turner N et al. J Clin Oncol. 2019

5. Chandarlapaty S et al J Clin Oncol. 2019

6. Guarducci C et al NPJ Br Cancer. 2018

7. Caldon CE et al Mol Cancer Ther. 2012

8. Krijgsman O et al BRCT 2012

Citation Format: Lorenza Mittempergher, Joe McKelley, Rajith Bhaskaran, Sahra Uygun, René Bernards, Laura J van 't Veer, Annuska M Glas, William Audeh. Cyclin E overexpression is associated with high risk 70 gene signature, and may indicate intrinsic resistance to CDK4/6 inhibitors [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 P4-10-24.