Abstract 1319: Luminal reprogramming, druggable mitogenic pathway activation, and rare outgrowth of occult basal cancers define ER loss in HR+/HER2- MBC

Abstract BACKGROUND: Estrogen Receptor (ER) expression is often lost in treatment-refractory, hormone-receptor (HR) positive metastatic breast cancers (MBC). The biological mechanisms allowing tumors to maintain viability—without the key driver of HR+ disease—are relatively unknown. To better define this subclass of MBCs, we analyzed transcriptome and targeted DNA-sequencing data of HR+/HER2- cases that lost ER at the time of recurrence. METHODS: A cohort of patients with primary HR+/HER2- breast cancer and subsequent loss of ER in the metastatic setting was identified. Loss of ER was defined as ER<1% in at least one metastatic sample. Transcriptome-capture RNA-sequencing was performed along with differential pathway analysis, PAM50 assignments, and fusion discovery. A subset of cases was analyzed with DNA-sequencing. RESULTS: We identified 46 patients with ER loss and archival tissue. Of them, 21 patient-matched primary and metastatic pairs were interrogated with RNA-seq. The metastases were collected at a median time of 6 years [range 1-14] from the HR+/HER2- primary diagnosis. In contrast to prior studies of patient-matched tumors, metastases harboring ER loss were more often transcriptionally distinct from their primary tumor—with 15/21 metastases (71.4%) having a discordant PAM50 subtype. The most common discordances were tumors switching from LumA to HER2-Enriched or LumA to LumB (both in 5 of 21 cases, 23.8%). Notably, none of the HER2-E cases harbored ERBB2 amplification. Luminal to basal switching was observed in two patients, but case review suggested the metastases being from occult primaries. Differential pathway expression analysis showed upregulation in mTOR, G2M checkpoint, and E2F pathways, suggesting selection of bypass mitogenic signaling in the absence of ER. Druggable features driving this transcriptional remodeling were identified, including an acquired in-frame 3’ BRAF fusion and biallelic loss of NF1 in two LumA to LumB cases. Further integration with clinicopathological features and DNA-level alterations will be presented. CONCLUSIONS: Altogether, these results demonstrate significant transcriptomic shifts in HR+/HER2- cancers that lose ER in the metastatic setting. We find ER loss is associated with ER-independent transcriptional reprogramming and multimodal mechanisms of druggable mitogenic pathway activation. In rare cases, an apparent luminal to basal switch occurs—but these events likely stem from occult disease. Importantly, most ER loss cases do not become basal-like, but rather retain their luminal identity in the absence of ER and co-opt other mitogenic pathways to achieve a more proliferative, ER-independent state. We propose that triple-negative disease in the setting of ER loss is biologically unique from canonical basal-like tumors and could benefit from a distinct therapeutic approach. Citation Format: Nolan Priedigkeit, Stefania Morganti, Alinés Lebrón-Torres, Kalie Smith, Melissa E. Hughes, Busem Binoga Kurt, Yvonne Y. Li, Hersh Gupta, Heather A. Parsons, Daniel L. Abravanel, Rinath M. Jeselsohn, Elizabeth A. Mittendorf, Adrian V. Lee, Steffi Oesterreich, Sara M. Tolaney, Andrew D. Cherniack, Nancy U. Lin, Ana C. Garrido-Castro. Luminal reprogramming, druggable mitogenic pathway activation, and rare outgrowth of occult basal cancers define ER loss in HR+/HER2- MBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1319.