Abstract PO5-06-04: EMSY amplification co-occurs with FGF/FGFR axis amplification in Metastatic Breast Cancer

Abstract Background: Amplification of FGFR and its ligands play an important role in breast cancer onset and progression and mutations of this signaling axis are emerging as mechanisms of resistance to targeted treatments. Understanding the molecular landscape of tumors that harbor aberrations in the FGF/FGFR (FGF/R) axis may help define the biology of these tumors and lead to the development of novel personalized approaches for more effective treatments in this group of patients. Using publicly available datasets, this study aimed at identifying genomic alterations co-occurring with amplification (amp) of the FGF/R axis in Metastatic Breast Cancer (mBC) patients. Methods: We utilized data from three cohorts of mBC patients. The first cohort (c1) included 176 patients with mBC from an ongoing precision medicine program sponsored by the Side-Out Foundation where genomic testing was performed, using a targeted gene panel, in real-world settings by commercial labs based predominantly on tumor specimens collected between 2019 and 2023. Whole exome sequencing data was obtained from AACR Genomics Evidence Neoplasia Information Exchange (GENIE) to establish a second cohort (c2) of 301 patients and a third cohort (c3) of 216 patients with mBC. Lastly, we included a fourth cohort (c4, n=122) of patients with early breast cancer (eBC). Chi2 test and Fisher’s Exact test were used to find significant co-occurring events. Python, pandas, and shell scripting were used for data manipulation, analysis and performing statistical tests. Results: Alterations of the FGF/R axis occurred in 26% (n=46) of patients in c1 of which 76% (n=35) were HR+ tumors and 24% (n=11) were Triple Negative Breast Cancers. Specifically, we detected amp of FGF3 (n=24, 52%), FGF4 (n=23, 50%), FGF19 (n=17, 37%), FGFR1 (n=18, 39%). In patients with alteration of the FGF/R axis, the most frequent aberrations were CCND1 (n=22, 48%), ZNF703 (n=12, 26%), MYC (n=9, 20%), and EMSY (n=8, 17%) amp, along with mutations of PIK3CA (n=17, 37%) and TP53 (n=18, 39%). EMSY amp was found in none of the patients without alterations of the FGF/R axis and co-amplified with the FGF/R axis in 8 patients(100%) (p< 0.0001). Similar results were also detected in the two independent cohorts of patients retrieved from the GENIE database. In c2, co-amp of EMSY and FGF/R axis was found in 53 of the 56 patients (95%) harboring EMSY amp (p< 0.0001). In c3, 17 patients (89%) had co-amp of EMSY and FGF/R axis of the 19 patients with EMSY amp (p< 0.0001). However, when we looked at patients with eBC in c4, of the 10 patients with EMSY amp, 7 patients (70%) had co-amp of EMSY and FGF/R axis and this association was not significant (p = 0.09). Conclusion: Amplification of EMSY has been mostly reported in ovarian (~17%) and sporadic breast cancers (~13%). EMSY has been reported to behave as an oncogene and a transcriptional repressor. It is well known that it can interact with the BRCA2 protein and potentially contributes to the “BRCAness” of tumors harboring its amp. Studies have also suggested that EMSY may act as a transcriptional repressor that modulates the expression of antimetastatic microRNAs in breast cancer. In the three mBC cohorts included in this analysis, EMSY amp was detected in 8, 56, and 19 cases, respectively. However, when the analysis was restricted to tumors harboring amps of both EMSY and FGF/R axis, EMSY was amplified in 100%, 95%, and 89% of those cases. While co-amplification of the EMSY gene with members of the FGF/R axis may be explained by its close proximity to the FGF3/4/19, and CCND1 genes on chromosome 11, in our analysis these co-amplifications were significant only in patients with metastatic disease. As dissecting the complex molecular landscape of mBC continues to be an essential step for advancing personalized treatment and better patient care, understanding the phenotypic effects of these co-amplifications may provide unique opportunities for devising combinatorial treatments for these patients. Citation Format: Deepika Prasad, Edik Blais, Rick Dunetz, Emanuel Petricoin, Mariaelena Pierobon. EMSY amplification co-occurs with FGF/FGFR axis amplification in Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-04.