Retrospective Data Highlight FRα and B7-H4 as Potential ADC Targets in Endometrial Cancer

Findings from a retrospective study demonstrated that either folate receptor alpha (FRα) or B7-H4 were expressed in more than 80% of endometrial cancers evaluated. Data were presented by Bobby May, MD, and colleagues at the 2025 Society of Gynecologic Oncology Winter Meeting.

Results indicated that among patients in the FRα cohort (n = 80), 82.5% of patient samples were positive for FRα expression, including 10% of patients who had high expression. In the B7-H4 cohort (n = 84), positive expression of B7-H4 was observed in 82.1% of samples, including a high expression in 28.6% of samples.

"Our study supports similar findings in literature with over 80% of endometrial cancer specimens exhibiting either FRα or B7-H4 expression to some degree,” explained May, a gynecologic oncology resident at Duke University’s School of Medicine in Durham, North Carolina.

Given the proportion of patients found to express one of these markers, May and colleagues pointed to FRα and B7-H4 as logical targets for the development of antibody-drug conjugates (ADCs) in endometrial cancer. Notably, no ADCs are currently approved by the FDA for the treatment of endometrial cancer.

Study Design

Investigators conducted a retrospective analysis of patients with advanced or recurrent endometrial cancer utilizing tumor specimens from the Endometrial Cancer Molecularly Targeted Therapy Consortium REDCap database and archival samples from the National Cancer Institute–funded Cooperative Human Tissue Network at Duke University. Samples needed to be from patients at least 18 years of age with advanced (stage III or IV) or recurrent endometrial carcinoma. Samples from patients with uterine sarcoma were not included. The study included 2 cohorts to evaluate FRα and B7-H4 expression.

"Our primary objective was to determine the frequency and degree of expression of FRα and B7-H4 through immunohistochemical [IHC] stains in advanced and recurrent individual cancer specimens based on molecular classifications as well as histologic subtypes,” May said.

Clinical and molecular characteristics, including mismatch repair (MMR) status, p53 status, and HER2 status, were evaluated.

Investigators also sought to evaluate the association between FRα and B7-H4 expression, clonal pathologic characteristics, and survival outcomes.

Statistical analyses included Kaplan-Meier estimates for overall survival (OS) and progression-free survival (PFS), as well as Cox proportional hazard models to determine hazard ratios.

Among both cohorts, histologic subtypes included low-grade endometrioid (FRα, 33.8%; B7-H4, 20.2%), high-grade endometroid (18.8%; 23.8%), serous (33.8%; 21.4%), clear cell (12.5%; 10.7%), and carcinosarcoma (1.3%; 23.8%).

Subgroup Analysis of FRα & B7-H4 Expression

High FRα expression was found to be more prevalent in patients with serous disease compared with other subtypes (P = .19). Conversely, high B7-H4 expression was more frequent in samples from patients with low-grade endometroid disease (P = .01).

A subgroup analysis of a combined cohort (n = 42) found that no tumor samples exhibited concurrent high expression of both FRα and B7-H4. However, 40.5% had high expression of one biomarker (FRα, 7.1%; B7-H4, 33.3%). Further, HER2-negative tumors were more likely to exhibit low or medium expression of both markers (69.2%) compared with tumors displaying high FRα (15.4%) or high B7-H4 (15.4%; P = .04).

Survival analyses indicated no significant association between FRα expression and clinical outcomes. The median PFS was 2.4 months (95% CI, 1.0-not evaluable [NE]) for patients with high FRα expression compared with 2.9 months (95% CI, 1.7-3.6) for those with low or medium expression (P = .8). Similarly, the median OS was 7.5 months (95% CI, 1.0-NE) in the high-expression group and 7.9 months (95% CI, 5.0-11.5) in the low-to-medium-expression group (P = .4).

“Further data [are] needed in larger studies using uniform antibodies and definitions of high expression to conclusively confirm expression patterns of B7-H4 and FRα in endometrial cancer. Overall, our findings support the evaluation of ADCs in endometrial cancer with prioritization and support to subgroups,” May concluded.

Reference

May B, Conway N, Truong T, Linhart S, et al. FRα, B7-H4, & HER2 Expression in Endometrial Cancer: Assessing the Promise of Antibody Drug Conjugate Therapies. Presented at: SGO 2025 Winter Meeting; January 30 - February 1, 2025; Whistler, British Columbia, Canada.