Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer.

Karina J Matissek,A John Iafrate,Leif W Ellisen,Andrew Schultz,Gustavo Werutsky,Nora Horick,Sheng Sun,Zongli Zheng,Kristofer Patel,Jessica St Louis,Paul E Goss,Arlene Chan,Srinivas Vinod Saladi,Aditya Bardia,Dianne M Finkelstein,Maristela L Onozato,Allison Macleay,Mehrad Tavallai,Nuran Beşe,Sahsuvar Gokgoz ,Henry L Gómez ,Elif Demirdöğen ,İsmet Taşdelen ,Ünal Egelí ,Yanin Chávarri‐Guerra ,Vivian Lee ,Márcio Debiasi ,Dennis Sgroi ,Carlos H Barrios ,Pedro Emanuel Rubini Liedke ,Şahsine Tolunay ,Long P Le ,Piiha Lotta Jerevall ,Tanja Badovinac-Črnjević

doi:10.1158/2159-8290.cd-17-0535

Abstract

We sought to uncover genetic drivers of hormone receptor-positive (HR+) breast cancer, using 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. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas 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 rearrangement-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.Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Liu et al., p. 354This article is highlighted in the In This Issue feature, p. 253.

Highlights

The majority of primary breast cancers express estrogen receptor (ER) and progesterone receptor (PR) and are responsive to therapies that target the estrogen response pathway
We applied anchored multiplex PCR (AMP) to tumor specimens from 110 sequential patients with advanced HR+ breast cancer who had presented to our clinic and had undergone clinical somatic tumor genotyping (Clinical Genotyping Cohort)
This otherwise unselected patient cohort is representative of patients presenting with advanced HR+ disease, as most (>80%) had initially presented as stage II and higher, and the majority who presented with primary disease received adjuvant hormonal therapy (>90%) and/or chemotherapy (57%)

Summary

Introduction

The majority of primary breast cancers express estrogen receptor (ER) and progesterone receptor (PR) and are responsive to therapies that target the estrogen response pathway. The pathways that confer hormonal therapy resistance have been studied extensively, yet our understanding of them remains relatively limited. Most notable among these are growth factor signaling networks that converge on the PI3K and MAPK pathways. Somatic mutations affecting these pathways are hallmarks of HR+ breast cancer but are found in only a subset of tumors, suggesting that additional, undetected genetic events contribute to this disease [3]

Methods

Results

Conclusion