Abstract P2-03-22: Assessment of the relationship between duration of treatment with hormonal therapy and the detection of ESR1 mutations in hormone-receptor positive, HER2 negative, breast cancer
Authors: Ayettey-Anie Hannah , Ahmed Kamran A. , Washington Iman , Yamoah Kosj , Knepper Todd 
Published: March 2023

Abstract
Background Hormonal therapeutic agents such as the selective estrogen receptor modulator, tamoxifen, as well as the aromatase inhibitors (AIs), anastrozole, exemestane, and letrozole, are a mainstay in the treatment of patients with hormone-receptor positive (HR+) breast cancer. Despite the effectiveness of hormonal therapy in the treatment of patients with HR+ breast cancer, acquired resistance to both AIs and tamoxifen does occur, often associated with mutations of the estrogen receptor 1 (ESR1). Although the acquisition of ESR1 mutations in patients with HR+ breast cancer treated with hormonal therapy has been established as a mechanism of resistance, there is a paucity of data on the relationship between the duration of treatment with hormonal therapies and the development of ESR1 mutations. Using a cohort of patients with HR+ breast cancer who underwent next generation sequencing (NGS) as part of routine clinical care, we aim to assess the relationship between the duration of exposure to aromatase inhibitors and the detection of ESR1 mutations. The results of this study will further our understanding of ESR1-mutations and provide insight into strategies to optimize therapy for patients with HR+ breast cancers. Methods This is a retrospective analysis of patients 18 years of age or older treated at a single academic cancer center in the USA, diagnosed with HR+, HER2-negative breast cancer and who have received somatic NGS as part of clinical care over a six-year period through July 2019. Demographic, disease-related, and treatment related variables were collected along with genomic testing variables (ie. ESR1-mutation status) for each patient who met the inclusion criteria. Two patient groups were formed on the basis of ESR1-mutation status (present vs. absent) and compared on the basis of duration of treatment with AI, and other clinical and demographic categories. Results A total of 247 patients who were diagnosed with HR-positive, HER2-negative breast cancer and received NGS were identified and are included in this analysis. A total of 138 (56%) patients were assessed via tissue based NGS and 109 (44%) by liquid biopsy. The median age at time of sequencing was 58 years [57 years (ESR1-absent) vs. 60 years (ESR1-present); p =0.009]. The majority of patients were white (83%) and post-menopausal (57%). Invasive ductal carcinoma was the most common histological type (82%). Nearly all (96%) patients had stage IV disease at time of sequencing and ESR1 mutations were found exclusively in those with stage IV disease. ESR1 mutations were identified in 62 patients (25%). The median duration of treatment with aromatase inhibitors prior to testing was 19.3 months in both groups (ESR1 mutations absent vs. detected). There was no difference in prior tamoxifen use between groups (absent 43%, present 48%; p=0.48). In patients tested by tissue based NGS, ESR1 mutations were more frequently detected in metastatic sites (28% vs. 13%; p=0.03). Twenty-two patients for whom NGS did not identify an ESR1 mutation prior to July 2019 received subsequent NGS testing. Of these 22 patients, six (27%) had ESR1 mutations detected by subsequent NGS. In these six patients, ESR1-mutations were detected by NGS a median of 2.2 years (range 1.7 years to 2.6 years) after prior NGS. Conclusion There was no difference in duration of treatment with aromatase inhibitor therapy in patients with ESR1 mutations vs. those without ESR1 mutations detected by NGS. Patients with ESR1 mutations tended to be older. Although the detection of ESR1 mutations is associated with acquired therapy resistance and progression on treatment, a longer duration of treatment may make the emergence of ESR1 mutations more likely. These counterbalancing factors may have contributed to the results reported here.
Citation Format: Hannah Ayettey-Anie, Kamran A. Ahmed, Iman Washington, Kosj Yamoah, Todd Knepper. Assessment of the relationship between duration of treatment with hormonal therapy and the detection of ESR1 mutations in hormone-receptor positive, HER2 negative, breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-22.