Abstract 4950: The emergence of ESR1 mutations is associated with aromatase inhibitor and fulvestrant therapy

Abstract

Abstract Introduction: In recent studies, constitutively active recurrent ESR1 ligand binding mutations (LBD) were found in about 20% of metastatic (met) HR+ breast cancers ( BRCAs) and rarely in primary HR+ cancers. In our previous work, we analyzed clinical tissue samples and detected an association between the number of prior endocrine treatments and the prevalence of these mutations, suggesting the emergence of the ESR1 mutations under the selective pressure of endocrine treatment. More recently, the LBD ESR1 mutations were successfully detected in plasma cell free (cf)DNA in patients with met HR+ disease. The presence of mutant ESR1 cfDNA was found to be prognostic. Here we sought to study the association between endocrine treatments in the adjuvant (adj) and met settings and the prevalence of cfDNA ESR1 and PIK3CA mutations in patients with met HR+ BRCA. Methods: Plasma samples and detailed clinical data were collected from patients with met BRCA through the Collection of Specimens and Clinical Data program of the Breast Oncology Center at the Dana Farber Cancer Institute. Droplet Digital PCR was used for the detection of the most common ESR1 LBD mutations (E380Q, Y537C, Y537N, Y537S and D538G) and the 3 most common PIK3CA mutations (E542K, E545K and H1047R) in cfDNA. Fisher’s Exact Test was used for statistical analysis. Results: Plasma samples were collected from 155 patients with met BRCA. ESR1 mutations were found in 30.1% of the patients with HR+/HER2- negative disease (34/113). PIK3CA mutations were detected in 31.8% of patients with HR+/HER2- disease. The majority of the patients had either newly diagnosed met disease or progressive met disease at the time of the blood draw. 14 patients had stable met disease and among these patients, only 1 of these patients was found to have an ESR1 mutation and no PIK3CA mutations were detected. The majority of patients with ESR1 mutations (88%) and PIK3CA mutations (75%) had progressive disease. Patients that received an aromatase inhibitor (AI) either in the adj or met setting had a higher prevalence of ESR1 mutations compared to patients that had no AI treatment, regardless of whether or not they received tamoxifen (TAM) (prevalence was 32% for adj AI only, 40.4% AI in met only, No AI and no TAM 7.1% and TAM but no AI 6.7%). In addition fulvestrant treatment in the met setting was significantly associated with ESR1 mutations (odds ratio 3.38, p-value<0.01). Conversely, we did not detect any significant associations between endocrine treatments in the adj or met settings and PIK3CA mutations. Conclusions: Analysis of cfDNA can successfully detect ESR1 and PIK3CA mutations in newly diagnosed or progressive met BRCA patients and the emergence of the ESR1 mutations is associated with AI and fulvestrant treatment. These results support the serial monitoring of ESR1 mutations in cfDNA in met disease and highlight the need to study new agents to target these mutations. Citation Format: Yanan Kuang, Bilal Siddiqui, Jiani Hu, William T. Barry, Nancy U. Lin, Nikhil Wagle, Paul Kirschmeier, Pasi A. Jänne, Cloud Paweletz, Ian Krop, Eric P. Winer, Myles Brown, Rinath Jeselsohn. The emergence of ESR1 mutations is associated with aromatase inhibitor and fulvestrant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4950. doi:10.1158/1538-7445.AM2017-4950