Abstract
Invasive lobular carcinoma (ILC) is an understudied subtype of breast cancer that requires novel therapies in the advanced setting. To study acquired resistance to endocrine therapy in ILC, we have recently performed RNA-Sequencing on long-term estrogen deprived cell lines and identified FGFR4 overexpression as a top druggable target. Here, we show that FGFR4 expression also increases dramatically in endocrine-treated distant metastases, with an average fold change of 4.8 relative to the paired primary breast tumor for ILC, and 2.4-fold for invasive ductal carcinoma (IDC). In addition, we now report that FGFR4 hotspot mutations are enriched in metastatic breast cancer, with an additional enrichment for ILC, suggesting a multimodal selection of FGFR4 activation. These data collectively support the notion that FGFR4 is an important mediator of endocrine resistance in ILC, warranting future mechanistic studies on downstream signaling of overexpressed wild-type and mutant FGFR4.
Highlights
Invasive lobular carcinoma (ILC) is a common histological subtype, accounting for 10–15% of all breast cancer diagnoses
FGFR4 is overexpressed in 8/8 ILC cell line models and 4/4 invasive ductal carcinoma (IDC) cell line models at the RNA level relative to parental cells subjected to short-term estrogen deprivation (Fig. 1a, top panel)
The FGFR4 overexpression in our ILC long-term estrogen deprived (LTED) cells was observed relative to parental cells in full serum, at the RNA and protein level (Fig. 1a, bottom panel)
Summary
Invasive lobular carcinoma (ILC) is a common histological subtype, accounting for 10–15% of all breast cancer diagnoses. Since most of these tumors are estrogen receptor positive (ER+), patients with ILC are often treated with endocrine therapy. These treatments are highly efficacious for most patients initially, longterm recurrences remain a major clinical problem for ILC.[1,2] We have recently performed RNA-Sequencing on paired, metachronous primary, and metastatic tumors to the brain and bone.[3,4] Here, we perform a subset analysis on the previously published clinical data, focusing only on ER+ patients treated with endocrine therapy prior to their recurrence, as well as report additional FGFR4 expression data from paired gastrointestinal (GI) and ovarian metastases.[5]
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