Background Invasive Lobular Carcinoma (ILC) is an understudied subtype of breast cancer. Distinctive properties of ILC include growth patterns, metastatic behavior, receptor status (almost universally estrogen receptor (ER) positive), and survival outcomes (Long-term survival is lower in patients with ER+ ILC compared to the other main histological subtype, invasive ductal carcinoma). Our lab recently generated six long-term estrogen deprivation (LTED) models of ILC cells. We performed RNA-Sequencing on these six LTED cell lines and identified differentially expressed genes compared to their parental cells cultured with estrogen. We overlapped these results with a previously published analysis of a tamoxifen-resistant ILC cell line and found that FGFR4 is the most consistently overexpressed gene in the setting of acquired resistance to endocrine therapy in ILC cells.
Hypothesis FGFR4 is an important mediator of resistance to endocrine therapy in ILC.
Methods To study the role of FGFR4 in acquired resistance to endocrine therapy, we used siRNA, multiple shRNAs, and specific small molecule inhibition for growth assays of ILC cells. To study the role of FGFR4 in de novo resistance to endocrine therapy, we collected 129 well curated ER+ ILC tumor specimens. We performed gene expression analysis on the pre-treatment samples using a custom NanoString panel.
Results FGFR4 inhibition decreases parental and LTED ILC cell growth in classic 2D growth conditions, in the setting of ultra-low attachment, and in colony formation assays. Mechanistically, FGFR4 and estrogen signaling are antagonistic in parental ILC cells. In our clinical samples, increased expression of FGFR4 is predictive of shorter time to distant recurrence.
Conclusion FGFR4 may play an important role in both acquired and de novo resistance to endocrine therapy in ILC. Future studies will assess the efficacy of combining FGFR4 inhibitors with ER-targeted therapy for patients with ILC.
Citation Format: Kevin Levine, Jian Chen, Matthew Sikora, Nilgun Tasdemir, George Tseng, Shannon Puhalla, Rachel Jankowitz, David Dabbs, Priscilla McAuliffe, Adrian Lee, Steffi Oesterreich. Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2017-3612