Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer

Abstract

Background More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1 ), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. Methods We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. Results We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. Conclusions These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.

RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer

“…In this context, a broad sequencing-based assay, like RNA-sequencing, to generate generic transcriptome data, from which a multitude of different readouts can be derived, presents an attractive alternative. In addition to the current study suggesting that RNA-sequencing can provide benchmarked intrinsic subtype and ROR scores, RNA-sequencing has also been reported to be able to provide reliable models for current conventional BC biomarkers 29 , 32 , 33 and to identify expressed somatic mutations in for example ESR1 and PIK3CA 43 , 44 that may be important for future clinical management. Moreover, an upfront testing of all breast cancer cases would cut lead-times for molecular assay results and may also allow future implementation of prognostic or treatment predictive signatures in additional clinical subgroups, like TNBC and HER2 -amplified cases, for which there are none in clinical use today.…”

RNA Sequencing-Based Single Sample Predictors of Molecular Subtype and Risk of Recurrence for Clinical Assessment of Early-Stage Breast Cancer

“…In this context, a broad sequencing-based assay, like RNA-sequencing, to generate generic transcriptome data, from which a multitude of different readouts can be derived, presents an attractive alternative. In addition to the current study suggesting that RNA-sequencing can provide benchmarked intrinsic subtype and ROR scores, RNAsequencing has also been reported to be able to provide reliable models for current conventional BC biomarkers 23,48,49 and to identify expressed somatic mutations in for example ESR1 and PIK3CA 58,59 that may be important for future clinical management. Moreover, an upfront testing of breast cancer cases irrespective of subtype would cut lead-times for molecular assay results and may also allow future implementation of prognostic/treatment predictive signatures for clinical subgroups, like TNBC and HER2amplified cases, for which there are none in clinical use today.…”

Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors

“…From this cohort, we analyzed RNA-seq data from 3207 patients with longer follow-up (diagnosed between 1 September 2010 and 31 March 2015). The present cohort is a subset of the previously described cohort of 3217 patients 46 – 48 , which has been reduced to 3207 samples due to additional quality controls. The clinical characteristics are presented in Table 1 and are in concordance with the typical clinicopathological properties of breast cancer patients in Sweden.…”