Abstract P3-05-08: Prevalence and prognosis of ER-loss in advanced invasive lobular carcinoma

Abstract Introduction: Estrogen receptor (ER) loss occurs in about 20% of recurrent breast cancers (BC) and is associated with unresponsiveness to endocrine therapy (ET) and poor prognosis. Prior studies evaluating ER-loss included predominately patients with invasive ductal carcinoma (IDC), and therefore the impact of ER-loss in invasive lobular carcinoma (ILC) is unknown. In this retrospective analysis, using real-world data, we aimed to determine the prevalence and clinical significance of ER-loss in ILC. Methods: Advanced BC were molecularly profiled at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene panel or whole-exome sequencing), RNA (whole transcriptome sequencing, WTS) and immunohistochemistry (IHC) of select markers. A large real-world evidence (RWE) database combining Caris’ molecular data with clinical information obtained from insurance claims data (CODEai) was interrogated and overall survival (OS) was calculated from time of tissue collection to last patient contact. A tumor was considered to have ER-loss if therapies approved only for ER-positive BC were prescribed prior to obtaining a negative ER IHC result. OS was compared using Kaplan-Meier estimates for defined patient cohorts; significance was determined as p values < 0.05. For molecular analyses, Fisher-Exact or Chi-Square tests were used to determine p values. Correction for multiple comparisons was performed using Benjamini-Hochberg to calculate q values. Results: The RWE database included 24,824 patients with advanced BC. At the time of tissue collection for molecular profiling, 6,786 advanced BC patients had been previously treated with ET (with or without mTOR or CDK4/6 inhibitors), of whom 1,338 had data available on histologic classification and ER IHC. The final analytical cohort included 263 patients with ILC and 1,075 with IDC. ER-loss was identified in 11.4% of ILC (n=30/263) and 19.6% (n=210/1075) of IDC (p=0.0017). In ILC, ER-loss was associated with significantly worse OS (HR: 1.75, 95%CI: 1.10-2.79, p=0.016) compared with no ER-loss. In the cohort of patients with ER-loss, patients with ILC had significantly worse OS compared with IDC (HR=2.03, 95% CI: 1.267-3.251, p=0.003). Further, when 1,016 tumors with ER-loss (regardless of histology) were stratified by the median OS (mOS=11mo), positive PD-L1 expression (34% vs. 22%, p=0.04, q=0.22), HER2 IHC positivity (16% vs. 7.8%, p=0.003, q=0.08) and HER2 amplification (16% vs. 4.7%, p=0.0006, q=0.04) were enriched in patients with longer mOS; while amplification of TEFB (0.38% vs. 2.6%, p=0.047, q=0.23) and MYB (0.38% vs. 2.6%, p=0.047, q=0.23) were enriched in patients with shorter mOS. WTS identified 197 differentially expressed genes, the majority of which were enriched in patients with longer mOS (q< 0.05). Conclusions: In this large real-word dataset, ER-loss likely occurred in 11.4% of ILC and was associated with worse OS compared to both patients with IDC and ER-loss and ILC without ER-loss. Our analysis had several limitations; notably, our definition of ER-loss was based on prior treatment, we could not distinguish between de novo or recurrent metastatic disease and time of tissue collection was not standardized during the course of treatment. Thus, additional studies are needed to confirm these findings. However, this study does suggest that ER-loss occurs in a subset of patients with ILC and has poor prognostic implications. Citation Format: Whitney L. Hensing, Joanne Xiu, W. Michael Korn, Stephanie L. Graff, Irene Kang, Evanthia T. Roussos Torres, Arielle L. Heeke, Andrew A. Davis, Nusayba A. Bagegni, Katherine K. Clifton, Ron Bose, Cynthia Ma, Foluso O. Ademuyiwa. Prevalence and prognosis of ER-loss in advanced invasive lobular carcinoma [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 P3-05-08.