Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Nolan Priedigkeit,Anna Machleidt,Adrian V Lee,Peter C Lucas,Jay K Kolls,Kai Ding,Jens-Uwe Blohmer,Steffi Oesterreich,William Horne,Barbara Ingold-Heppner,Tian Du,Carsten Denkert

doi:10.1186/s13058-020-01379-3

Abstract

BackgroundEndocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. In this study, we aimed to determine acquired genomic changes in endocrine-resistant disease.MethodsWe performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen deprivation and identified acquired genomic changes versus each tumor’s matched primary.ResultsDespite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C, were found to have single nucleotide variant (SNV) enrichments in more than one recurrence. Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A, TP53, FOXO1, BRD1, NCOA1, and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common—including outlier gains in TP63 (n = 5 cases [42%]), NTRK3 (n = 5 [42%]), NTRK2 (n = 4 [33%]), PAX3 (n = 4 [33%]), FGFR4 (n = 3 [25%]), and TERT (n = 3 [25%]). Recurrent losses involved ESR1 (n = 5 [42%]), RELN (n = 5 [42%]), SFRP4 (n = 4 [33%]), and FOSB (n = 4 [33%]). ESR1-depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers.ConclusionsTaken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease; highlights the importance of longitudinal RNA profiling; and identifies a common ESR1-depleted endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.

Highlights

Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer
Expression and copy number changes in local recurrences Dual hybrid-capture DNA/RNA sequencing was performed for 1385 cancer genes on 12 paired primary tumors and local recurrences from patients with ER
Unlike a previous transcriptome-wide analysis of primary breast cancers and matched bone metastases [30], there was no significant correlation in pair transcriptional similarity and time to recurrence— a trend towards negative correlation was observed (Pearson R = − 0.37, p value = 0.236)

Summary

Introduction

Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. Hormone receptor-positive breast cancer has served as a prototype for targeted therapy due to the wellestablished efficacy of estrogen deprivation. Because of these approaches, breast cancers are somewhat unique in that recurrences can occur years, sometimes decades following the primary diagnosis [1,2,3,4]. Identifying the biological mediators that allow breast cancer cells to bypass their dependence on estrogen is a crucial step in understanding advanced breast cancer biology and defining novel therapeutic targets. Defining these molecular processes in patient samples, has been challenging because of the logistics in obtaining well-characterized, longitudinally collected biospecimens. More recently discovered mechanisms include ESR1 fusions and amplifications [13, 14]

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