EZH2 Is Overexpressed in -like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy.

PURPOSE

BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human -deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in -deficient murine mammary tumors.

EXPERIMENTAL DESIGN

EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. We classified 370 tumors by copy-number profiles as -like or non--like and examined its association with EZH2 expression. Additionally, we assessed loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinum-based chemotherapy compared with standard anthracycline-based chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a -deficient mouse model.

RESULTS

The highest EZH2 expression was found in BRCA1-associated tumors harboring a mutation, -promoter methylation or were classified as like. We observed a greater benefit from high-dose platinum-based chemotherapy in -like and non--like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in -deficient mice in comparison with single agents.

CONCLUSIONS

Our findings demonstrate that EZH2 is expressed at significantly higher levels in -deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of -like status. EZH2 inhibition improves the antitumor effect of platinum drugs in -deficient breast tumors .