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.

浸润性小叶癌（ILC）是乳腺癌的一种未被研究的亚型，在晚期环境中需要新颖的治疗方法。为了研究ILC对内分泌治疗的获得性耐药性，我们最近对长期缺乏雌激素的细胞株进行了RNA测序，并将FGFR4过表达确定为可治疗的首要靶标。在这里，我们显示FGFR4表达在经内分泌治疗的远处转移中也显着增加，相对于成对的原发性乳癌，ILC的平均倍数变化为4.8，而浸润性导管癌（IDC）的平均倍数变化为2.4倍。此外，我们现在报道，FGFR4热点突变在转移性乳腺癌中富集，另外对ILC的富集也提示了FGFR4激活的多模式选择。