Genomic alterations, molecularly targeted therapy and race: Real world data from the Endometrial Cancer Molecularly Targeted Therapy Consortium (LBA 8)

Abstract

<b>Objectives:</b> There has been considerable adoption of next-generation sequencing (NGS) and tumor testing to direct therapy in patients with advanced/recurrent endometrial cancer (EC), but the impact of this approach to date is unclear. We sought to confirm the proportion of patients with at least one actionable genomic alteration; assess associations between molecular alterations and race; and whether the use of molecularly targeted therapy improves response, progression-free survival (PFS) and overall survival (OS) in patients with metastatic EC. <b>Methods:</b> We formed a national multidisciplinary consortium of translational and clinical investigators to study patients with advanced/recurrent EC with tumor testing treated with systemic therapies. Tumor testing and treatment decisions were based on the treating physician's recommendation. Data were abstracted regarding age; stage; grade; histology; race; ethnicity, treatment; genomic alterations (mutations, amplifications); protein expression for Her2, p53, mismatch repair (MMR) proteins, ER and PR; Her2 FISH; microsatellite instability (MSI); treatment response; and survival. Survival outcomes and response rates will be compared to historical controls. Statistical analysis performed using SAS v9.4. <b>Results:</b> 994 patients across 12 centers were enrolled in the database. The median age was 64 years (range: 22–93). 67.2% were White; 22.7% Black; 2.4% Asian and 3.0% Hispanic. The histologic subtypes were 49.7% (n=495) endometrioid, 20.2% (n=201) serous, 10.9% (n=108) carcinosarcoma, 7.9% (n=79) mixed, and 3.7% (n=37) clear cell. 414 (41.6%) received paclitaxel/carboplatin based frontline chemotherapy, 672 (67.6%) had recurrent/persistent disease and were treated with a median of 2 (range: 0-9) therapies. 764 (76.9%) patients had tumor testing. Over 54% of patients had at least one actionable genomic alteration. NGS testing revealed the following alterations: <i>PI3K</i> (31.5%), <i>TP53</i>(30.5%), <i>PTEN</i> (25.4%), <i>CTNNB1</i> (7.2%), <i>AKT</i> (2.3%), <i>ESR</i> (1.4%), <i>mTOR</i> (1.1%), <i>TSC2</i> (0.8%), <i>POLE</i> (0.6%), and (6.1%) had high tumor mutational burden (TMB-H). Black patients were more likely to have tumors with <i>TP53</i> genomic alterations (41.6 vs 26.6%, p<0.001), and less likely to have alterations in the <i>PI3K (22.6% vs 34.1%, p<0.001) and PTEN (11.9% vs 29.9%, p<0.001) pathways</i> compared to White patients. Moreover, Black patients were less likely to have tumors with high TMB (3.1 vs 7%, p=0.001). 461 (46.4%) had additional molecular testing. IHC demonstrated 65 (6.5%) had 2-3+ Her2 overexpression, 155 (15.6%) p53 overexpression, 141 (14.2%) MMR deficiency, 336 (33.8%) ER positivity, and 261 (26.3%) PR positivity; 28 (2.8%) Her2 amplification via FISH; and 115 (11.6%) had MSI based on PCR (Table). A subset analysis of those who developed persistent or recurrent disease and received matched molecularly targeted therapy is ongoing to assess response and survival outcomes. <b>Conclusions:</b> This new multicenter consortium is facilitating the development of real-world data on patterns of genomic testing and use of molecularly targeted therapies in patients with metastatic EC, and includes a racially and geographically diverse patient population. This effort has the potential to better define the role of targeted therapies in evolving EC treatment landscape.