Abstract P6-07-07: ESR1 amplification and 5'-3' exon imbalance in metastatic breast cancer

Abstract

Abstract BACKGROUND: Growing evidence indicates that base pair mutations in ESR1 are relatively uncommon in newly diagnosed, treatment-naive breast cancer, but frequently acquired in hormone-resistant metastatic breast cancer (MBC). We and others have recently identified ESR1 gene fusion and amplification in MBC, with the ESR1 fusions generally encompassing AF1 and the DNA binding domain. The genomic break required for gene fusions often results in an imbalance in the DNA copy number of exons around the break. We examined ESR1 amplification and 5' and 3' exon copy number imbalance in MBC. MATERIALS and METHODS: We designed NanoString DNA hybridization probes against coding and non-coding exons (n=9) in ESR1 and 15 reference probes. We analyzed 128 samples consisting of 61 ER-positive and 44 ER-negative metastases, and 23 primary breast cancers. DNA copy number (CN) was determined using nSolver, with >2.7CN as copy number gain, and >10 as CN amplification. ESR1 CN was calculated by averaging the DNA copy number obtained from all coding exons. The 5'-3' copy number ratio was the average copy number of the 5' exons (3-6) divided by the 3' exons (7-10). RESULTS: 8 (13%) ER positive metastatic breast cancers showed ESR1 amplification with 5 (8%) having >2.7CN, and 3 (5%) with >10CN. In contrast, in ER-negative metastases, we did not detect any samples with amplification >10CN, and a gain (>2.7 CN) in one case. Similarly, in ER+ primary cancers we did not detect any samples with >10 CN amplifications and 2 samples with CN gain (>2.7 CN). ESR1 showed 5'-3' CN imbalance in 1 primary (5%) and in 5 metastatic (5%) breast cancers. We are currently confirming and expanding these data in a larger dataset. CONCLUSIONS: In addition to ESR1 mutations, ESR1 CN amplifications and 5'-3' imbalance are represent frequent occurrences in endocrine resistant breast cancer. Future studies are aimed at understanding whether the observed exon imbalances are associated with generation of fusion proteins, and whether and how ESR1 amplifications cause changes in endocrine treatment response. Citation Format: Oesterreich S, Basudan A, Preideigkeit N, Hartmaier RJ, Bahreini A, Gyanchandani R, Leone JP, Lucas PC, Hamilton RL, Brufsky AM, Lee AV. ESR1 amplification and 5'-3' exon imbalance in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-07.