Abstract P2-11-06: HER2 positive breast cancer and subclinical cardiotoxicity by echocardiogram 2D Strain, Do chemotherapy sequence matter?

Endocrine-resistance remains a major challenge for treatment of breast cancer. Multiple mechanisms for endocrine resistance have been proposed, including altered expression of ER co-regulators such as Retinoic Acid Receptor Alpha (RARα). Furthermore, crosstalk between estradiol and RA signaling is known and upregulation of RARα has been observed in tamoxifen resistance. We propose a novel treatment paradigm for a newly-defined subset of HR+ patients based on our discovery of a super-enhancer (SE) associated with the RARA locus. SEs are large, highly active chromatin regions that pinpoint cancer vulnerabilities. The RARA SE-identified vulnerability can be targeted using the potent, selective, and metabolically stable RARα agonist SY-1425 (tamibarotene). SY-1425 is approved in Japan to treat Acute Promyelocytic Leukemia, has a well-established efficacy and safety profile, and may enhance response to hormonal therapy (HT) in this newly-defined subset of HR+ patients potentially delaying the need for alternate treatment.Tumor samples from 42 breast cancer patients were analyzed across a range of molecular subtypes. We identified an SE linked to the RARA gene in 54.5% of the hormone positive patient samples. RARA SEs predicted sensitivity to SY-1425 in 12 breast cancer cell lines confirming their functional role, and showed a correlation with RARA gene expression. A panel of 37 breast cancer cell lines was tested for SY-1425 anti-proliferative activity and gene expression level...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Poster Session Abstracts Source Type: research