Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor Positive Breast Cancer [Research Articles]

We sought to uncover novel genetic drivers of hormone-receptor positive (HR+) breast cancer, employing a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes including PIK3CA, AKT3, RAF1 and ESR1 in 14% (24/173) of unselected patients with advanced HR+ breast cancer. Fluorescence in situ hybridization (FISH) confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in non-transformed cells deregulates phosphoprotein signaling, cell proliferation and survival in 3-dimensional culture, while expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus -negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.

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