Data from EZH2 Is Overexpressed in &lt;i&gt;BRCA1&lt;/i&gt;-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy

Jelle Wesseling,Gaurav Kumar Pandey,Kerstin Rhiem,Eric Hahnen,Marieke Van De Ven,Katarzyna Jóźwiak,Peter Bouwman,Peter Mallmann,Jos Jonkers,René Bernards,Luka Ozretić,Fabinshy Thangarajah,Carlos Caldas,Birgid Schömig-Markiefka,Julian Puppe,Maarten Van Lohuizen,Olaf Van Tellingen,Wolfram Malter,Tesa Severson,Mark Opdam,Philip C Schouten,Christian Eichler,Reinhard Büttner,Michael Hauptmann,Hans Christian Reinhardt ,Sabine C Linn ,Chiara Svetlana Brambillasca ,Rita K Schmutzler ,Esther H Lips

doi:10.1158/1078-0432.c.6528062

Data from EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy

Jelle Wesseling, Gaurav Kumar Pandey + Show 27 more

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https://doi.org/10.1158/1078-0432.c.6528062

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Publication Date: Mar 31, 2023

License type: CC BY 4.0

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<div>AbstractPurpose:BRCA1-deficient breast cancers carry a specific DNA copy-number signature (“BRCA1-like”) and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-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 BRCA1-like or non-BRCA1–like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 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 Brca1-deficient mouse model.Results:The highest EZH2 expression was found in BRCA1-associated tumors harboring a BRCA1 mutation, BRCA1-promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1-like and non-BRCA1–like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1-deficient mice in comparison with single agents.Conclusions:Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo.</div>

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