Abstract PD8-07: Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic breast cancer
Authors: Fowler AM , Rassman S , DeGrave M , Ong I , Powers GL , Salem K , Kumar M , Woo K , Mahajan AM 
Published: February 2018

Abstract
Background: Resistance to endocrine therapy remains a challenge for patients with metastatic hormone receptor positive breast cancer. Mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in patients with endocrine resistance and correlates with reduced survival. The occurrence of mutations in the gene for progesterone receptor (PGR), another important biomarker in breast cancer, has not been reported.
Objective: Determine the frequency of mutations in ESR1 and PGR in patients with newly diagnosed metastatic ER+ breast cancer treated with adjuvant endocrine therapy at our institution, and identify whether these mutations are associated with worse patient survival.
Methods: This is an IRB-approved, HIPAA-compliant retrospective study of patients with ER+ metastatic breast cancer identified from our comprehensive cancer center registry. Eligible patients must have received at least 6 months of adjuvant endocrine therapy with biopsy-proven diagnosis of metastatic or locally recurrent disease. Next-generation sequencing of the coding regions of ESR1 and PGR was performed on extracted tumor genomic DNA. Analysis was limited to protein coding mutations. Clinicopathologic data was collected and correlated with the genomic information for each patient. Associations between mutation status and clinicopathologic factors were analyzed using Fisher's exact test. Kaplan-Meier method with log-rank test was used to analyze overall survival (OS) from time of metastatic diagnosis.
Results: The study included 35 women (35-88 yr old). Metastatic sites included bone (N=13), brain (N=6), chest wall (N=2), liver (N=4), lung/pleura (N=4), and lymph nodes (N=6). PGR mutations were identified in 66% of patients (23/35; 95%CI 48-81%), and were more common than ESR1 mutations (10/35; 29%; 95%CI 15-46%). Mutations in both PGR and ESR1 were identified in 26% (9/35), and neither mutation was identified in 31% (11/35). Neither mutation was associated with prior adjuvant aromatase inhibitor or tamoxifen therapy. There was no significant association between ESR1 or PGR mutations and metastatic site, although 75% (3/4) of patients with liver metastases had an ESR1 mutation compared to 23% (7/31) without liver metastases (p=0.061). The differences in median OS between ESR1 wildtype vs mutant (1.6 mo vs 1.0 mo, p=0.14) and PGR wildtype vs mutant (2.6 mo vs 1.3 mo, p=0.56) were not significant. However, patients with both mutations may have worse median OS compared patients with neither or only one mutation (1.0 mo vs 1.6 mo vs 4.0 mo, p = 0.073).
Conclusions: The overall survival of metastatic ER+ breast cancer patients with ESR1 or PGR mutations were not statistically significant compared with those without mutations. Despite the small sample size, there is a trend that patients with mutations in both genes may have worse survival. To the best of our knowledge, the PGR mutation rate in metastatic breast cancer has not previously been reported. Interestingly in our data set, PGR mutations were identified more commonly than mutations in ESR1. The significance of PGR mutations is not known, nor whether this could be a future indicator of treatment resistance or a target for therapy.
Citation Format: Fowler AM, Rassman S, DeGrave M, Ong I, Powers GL, Salem K, Kumar M, Woo K, Mahajan AM. Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-07.