Abstract 3349: Loss of GATA2 promotes invasion and predicts cancer recurrence and survival in FIGO stage I uterine serous carcinoma

Background: Uterine cancer is the 4th most common cancer in women. Its incidence is increasing and its mortality rate also is rising. Uterine serous carcinoma (USC) is an aggressive uterine cancer subtype that is responsible for 40% of uterine cancer deaths. Although 50% of USC patients present with cancer localized to the uterine body (FIGO stage I) and should be cured by staging hysterectomy, 30% of these patients later recur in the absence of adjuvant combination paclitaxel-carboplatin chemotherapy. There is no reliable method to identify which USC patients are at risk of USC recurrence, so most patients receive risk-reducing adjuvant chemotherapy associated with significant morbidity. A priori knowledge of recurrence risk would enable a risk-stratified approach to adjuvant therapy to reduce morbidity and optimize survival. GATA Binding Protein 2 (GATA2) is a transcription factor that supports progesterone receptor signaling in the uterus. We recently generated anti-GATA2 monoclonal antibodies that can routinely detect GATA2 by standard immunohistochemistry (IHC). Methods: We assembled a retrospective multi-institutional cohort of 81 patients with primary FIGO stage I USCs. Associations between GATA2 levels and clinicopathologic metrics were evaluated using Student’s t-test, Fisher’s exact test, Kaplan-Meier method, and Cox proportional hazards ratio. Gene targets including GATA2 were depleted from Ark1 and Ark2 patient-derived USC cell lines using siRNA or shRNA, and cell invasion evaluated using Matrigel-coated membranes and organoid-based natural hydrogel. RNA-seq, anti-GATA2 ChIP-seq, and western blotting enabled identification of GATA2 gene targets. Results: GATA2 expression in USC tumors ranged from 0-100% GATA2+ tumor nuclei. USCs with >15% GATA2+ nuclei were defined as GATA2-high based on an initial inflection point in the data that optimally delineated patients by outcome. The 39% of patients with GATA2-high USCs had 100% recurrence-free, 100% disease-specific, and 87% overall survival. These outcomes were significantly better than patients with GATA2-low USCs. Depletion of GATA2 in USC cell lines increased invasion in vitro. In patients who received no adjuvant chemotherapy (n=18), those with GATA2-high USCs had 100% recurrence-free survival compared to 50% recurrence-free survival in GATA2-low USC patients. A multi-omic approach identified SIN3 Transcription Regulator Family Member B as a GATA2 target gene that suppressed USC invasion in vitro. Conclusions: GATA2 IHC identifies FIGO stage I USC patients with a greatly reduced risk of USC recurrence. A GATA2 guided personalized medicine approach using standard IHC methods could be rapidly implemented in most hospital settings, would reduce treatment-related morbidity, and may optimize survival for USC patients. Citation Format: Usha S. Polaki, Trey E. Gilpin, Apoorva T. Patil, Emily Chiu, Paula M. Manan Mejias, Pei Hui, Maria Virumbrales-Muñoz, Lisa Barroilhet, Stephanie M. McGregor, Emery H. Bresnick, Daniel R. Matson. Loss of GATA2 promotes invasion and predicts cancer recurrence and survival in FIGO stage I uterine serous carcinoma [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 3349.