Abstract PS18-15: Real-world clinical-genomic data identifies the ESR1 clonal and subclonal circulating tumor DNA (ctDNA) landscape and provides insight into clinical outcomes
Authors: David Hanna, Jamie Hutchins, Junhua Yu, Enrique Marino, Naveen Kumar, Rajesh Kucharlapati, Rajesh Chavali, Gautam Nayak, Aaron Hardin, Stephen Fairclough, Victoria M Raymond, Kathryn Lang
Journal: Cancer Research (2021)

Abstract Introduction: ESR1 mutations are biological indicators of endocrine resistance observed in 20-30% of patients with metastatic breast cancer treated with aromatase inhibitor (AI) therapy. A number of ESR1 resistance mutations have been characterized, including single nucleotide variants in codons 380, 463, 536, 537, and 538. However, ESR1 resistance mutations have not been characterized using large-scale, real-world population studies. Here we describe the subclonal landscape of ESR1 resistance in a real-world dataset of patients with advanced breast cancer treated with anti-estrogen therapy. Methods: The GuardantINFORM™ clinical-genomic database links circulating tumor DNA (ctDNA) results (Guardant360®, Guardant Health) with de-identified aggregated clinical encounters including diagnosis, treatments, and real-world outcomes. GuardantINFORM was queried for adult patients, with a confirmed diagnosis of primary breast cancer, with at least one claim for endocrine therapy (tamoxifen and/or an AI), and at least one Guardant360 test completed following AI treatment. Data was reviewed retrospectively to determine the landscape of ESR1 alterations identified post AI-treatment. Results: 6,541 patients met inclusion criteria. The patient cohort was predominantly female (99%) with a median age at first anti-estrogen therapy of 59.7 years (range 25 - 91 years). 2,044 patients were positive for at least one ESR1 mutation (31%) on the post AI treatment Guardant360 test. 1,943 patients (95%) had an ESR1 mutation identified that is known to confer resistance to AI therapy while the remainder had ESR1 mutations of unknown clinical significance. The majority of patients (65.8%) had multiple ESR1 mutations one of which was always a canonical ESR1 resistance mutation (Table 1). Preliminary outcome analysis showed no difference in real-world overall survival in those with a canonical ESR1 mutation with or without an additional co-occurring subclonal ESR1 mutation. Additional analyses to understand the impact of co-occurring ESR1 alterations and time to therapy resistance is ongoing. Conclusions: Uniquely well-characterized clinical-genomic data in a proprietary dataset identified that approximately 30% of patients with advanced breast cancer had somatic ESR1 mutations following AI therapy, consistent with previously published data. The majority of patients had multiple subclonal ESR1 resistance mutations following AI treatment, always with a canonical resistance mutation, which did not impact real-world overall survival. Additional work is needed to explore the contribution of these ESR1 subclones to the time to clinical resistance. Table 1: Spectrum of ESR1 variants observed in eligible patients in GuardantINFORMESR1 mutationTotal prevalence in ESR1 positive patientsPrevalence as sole ESR1 variantPrevalence with additional ESR1 variant(s)D538G53.8%13.0%40.8%Y537S38.2%8.8%29.4%Y537N18.4%1.6%16.8%E380Q13.0%2.6%10.4%L536H5.0%0.4%4.6%S463P1.4%0.3%1.1%Other29.5%25.6%3.9% Citation Format: David Hanna, Jamie Hutchins, Junhua Yu, Enrique Marino, Naveen Kumar, Rajesh Kucharlapati, Rajesh Chavali, Gautam Nayak, Aaron Hardin, Stephen Fairclough, Victoria M Raymond, Kathryn Lang. Real-world clinical-genomic data identifies the ESR1 clonal and subclonal circulating tumor DNA (ctDNA) landscape and provides insight into clinical outcomes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-15.