Abstract PD6-5: Profiling of ESR1-mutated metastatic breast cancers by FoundationOne® allows a broad genomic understanding for potential clinical implications
Authors: Palma Norma A , Ali Siraj , Frampton Garrett , Wang Kai , Gilmore Hannah , Peguero Julio , Harris Lyndsay N , Cristofanilli Massimo , Chmielecki Juliann , Ross Jeffrey S , Morosini Deborah , Miller Vincent A , Stephens Phil J , Palmer Gary , O'Shaughnessy Joyce 
Published: May 2015

Abstract
Background: Estrogen receptor (ER) inhibition is an important treatment option for advanced breast cancer (BC) pts. Recent studies describe recurring somatic mutations in codons 537 and 538 within the ligand-binding domain (LBD) of ∼ 20% of ER+ metastatic disease, but not treatment-naïve ER+ cancer or ER-negative disease, that render the ER constitutively active and confer partial resistance to endocrine agents. Few studies have described the clinicopathologic and genomic covariates that accompany the ESR1 genomic alterations (GAs). Correlating genomic events as captured by FoundationOne in pts with ESR1-mutated BCs with clinical history may provide clinical insight into these alterations.
Methods: Hybridization capture of 3769 exons of 236 cancer-related genes and 47 introns from 19 genes that are frequently rearranged in cancer were fully sequenced to high, uniform coverage using FoundationOne (Foundation Medicine, Cambridge, MA).
Results: 176 of the 2,208 (7.9%) BC pt cases harbored ESR1 alterations. 1127 short variants (SV) were detected in 176 patient samples for an average of 6.4 GA/sample. 16.5% SV (186/1127) were ESR1 GAs with an average of 1.0 ESR1 GAs/sample. ESR1 GAs consisted of base substitutions (77%) and amplifications (20%, median copy number 9X, range 6-28). Base substitutions occurred at codons 538 (71/145) and 537 (70/145) and at two other novel sites, 341 (2/145) and 563 (1/145). A patient-derived xenograft study suggested that tumors refractory to ER inhibitors and harboring ESR1 amplification could be responsive to higher doses of estradiol. (Li et al, Cell Reports, 2013). The most frequently co-occurring GAs were PIK3CA (37.5%), GATA3 (22.7%), TP53 (24.4%), MAP3K1 (10.2%) and CDH1 (7.9). Collection of data on tissue sites sequenced, treatments and outcomes on these pts with ESR1 GAs are ongoing. Of note, one pt had recurrent disease following adjuvant tamoxifen and letrozole. FoundationOne testing of her recurrent bony disease revealed an ESR1 Y537 alteration along with mutations in PIK3CA, APC, and RAD51. She has been on fulvestrant monotherapy with stable metastatic disease 13 + months.
Conclusions: We found through FoundationOne testing that ESR1 GAs are reasonably common in advanced BCs, with base substitutions accounting for 77% of ESR1 GAs and amplifications for 20%. Identification and characterization of ESR1-mutated advanced BC pts by comprehensive genomic profiling capable of detecting both base substitutions and copy number changes may identify clinically relevant GAs. Clinical correlation is pending.
Citation Format: Norma A Palma, Siraj Ali, Garrett Frampton, Kai Wang, Hannah Gilmore, Julio Peguero, Lyndsay N Harris, Massimo Cristofanilli, Juliann Chmielecki, Jeffrey S Ross, Deborah Morosini, Vincent A Miller, Phil J Stephens, Gary Palmer, Joyce O'Shaughnessy. Profiling of ESR1-mutated metastatic breast cancers by FoundationOne® allows a broad genomic understanding for potential clinical implications [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD6-5.