Abstract B013: Folate receptor alpha (FRa) expression and correlation with other molecular alterations in high grade serous endometrial cancer (EC)
Authors: Porter Rebecca L. , Elias Sandy , Xiong Niya , Polak Madeline , Fahey Kayla , Tayob Nabihah , Qi Courtney , Feeney Carina , Narayan Swati , Curtis Jennifer , Campos Susana , Krasner Carolyn , Lee Elizabeth , Stover Elizabeth , Wright Alexi A. , Liu Joyce F. , Matulonis Ursula A. , Konstantinopoulos Panagiotis 
Published: March 2024

Abstract
Background: Advanced and recurrent EC remains a therapeutic challenge with rising mortality rates and few options beyond first line platinum-based chemotherapy and immunotherapy. Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and maytansinoid payload DM4, is FDA-approved for patients with FRa-high platinum resistant ovarian cancer (PROC). FRa is also expressed in EC and is associated with poor prognosis. Here, we evaluate FRa expression levels and associations with other molecular alterations, including in HER2, MYC and CCNE1, in patients with advanced/recurrent serous EC. Methods: Paraffin fixed tumor tissue from 110 patients who signed prescreening consent for a phase 2 study testing the combination of MIRV with pembrolizumab in recurrent/persistent serous EC (NCT03835819) were analyzed for FRα expression by IHC (Ventana, Inc). All patients had advanced or recurrent MSS serous EC and had received 1-3 prior lines of therapy. FRα positivity was defined as ≥50% of cells with ≥2+ membrane staining based on results from a phase 1b study of mirv and pembrolizumab in PROC (Matulonis U, SGO 2018 abstract 74). HER2/neu expression was assessed by independent pathology review at the treating institution. Tumor mutational burden (TMB), amplification of CCNE1, MYC and ERBB2 and other somatic mutations were determined in tumors with next generation sequencing (NGS). Results: 37 of 110 tumors were determined to be FRa positive (FRa+) with FRa ≥50% for an overall positivity rate of 33.63%. The median membrane positivity was 20.5% (IQR: 3-51.25). Within a cohort of 44 patients with available tumor NGS, the average TMB was 6.23 (SD: 3.34) and did not differ between FRα+ and -negative (FRα-) tumors at 5.74 and 6.45, respectively (p=0.73). Of 32 tumors with HER2 IHC performed, 5 (16%) were both FRα+ and HER2+ (2+ or 3+); 7 (22%) were FRα+ and HER2-, 5 (16%) were FRα- and HER2+, and 15 (47%) had negative expression for both. CCNE1, MYC and ERBB2 amplifications were present in 1 (9%), 0 and 3 (27%) of FRα+ tumors, and 6 (23%), (8) 31%, and 2 (8%) and of FRα- tumors, respectively. There was no association between expression of FRα and HER2 (Fisher exact test, p=0.44), nor with amplification of CCNE1 (p=0.65), MYC (p=0.08) and ERBB2 (p=0.14). The most common co-occurring somatic mutations were in PIK3CA, with similar frequency in FRα+ (55%) and FRα- (42%) tumors. Conclusions: An FRα positivity rate of 33.6% in this large cohort of serous EC tumors supports further clinical development of MIRV in this high-risk subtype of EC. Within a limited cohort subset, it does not appear that FRα expression correlates with TMB or HER2 expression, or with CCNE1, MYC or ERBB2 amplifications. This data highlights the importance of comprehensive testing of EC tumors for all relevant biomarkers that may guide selection of targeted therapies. Additional studies are needed to explore FRα expression in other molecular subsets of EC and to determine the longitudinal stability of ADC target expression.
Citation Format: Rebecca L. Porter, Sandy Elias, Niya Xiong, Madeline Polak, Kayla Fahey, Nabihah Tayob, Courtney Qi, Carina Feeney, Swati Narayan, Jennifer Curtis, Susana Campos, Carolyn Krasner, Elizabeth Lee, Elizabeth Stover, Alexi A. Wright, Joyce F. Liu, Ursula A. Matulonis, Panagiotis Konstantinopoulos. Folate receptor alpha (FRa) expression and correlation with other molecular alterations in high grade serous endometrial cancer (EC) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B013.