FRα, TROP2, and B7-H4 Expression Varies Significantly Across Ovarian Cancer Histotypes, Influencing ADC Potential

Ovarian cancer histotypes, high-grade serous (HGSOC), endometrioid (EnOC), and clear cell carcinoma (CCOC), exhibit distinct molecular profiles, influencing therapeutic responses. With the FDA approval of the FRα-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (Elahere) for platinum-resistant ovarian cancer, understanding histotype-specific target expression is critical.¹ Investigators from the University of Edinburgh analyzed FRα, TROP2, and B7-H4 expression to identify actionable ADC targets across these histotypes.²

FRα expression showed significant variation across histotypes. This marker was expressed the highest in the HGSOC cohort (70.9%) with a median histoscore of 10, whereas CCOC and EnOC showed markedly lower expression at 29.3% and 21.1%, respectively. The median histoscores for these latter groups were 10 for CCOC and 3.33 for EnOC, with both showing statistically significant differences compared with HGSOC (P < 0.001).

TROP2 expression patterns revealed striking histotype-specific differences. CCOC tumors were predominantly TROP2-negative (89.3%), contrasting with the moderate expression seen in HGSOC (54.8%) and EnOC (57.7%). Statistical analysis confirmed significantly lower TROP2 expression in CCOC compared with both HGSOC and EnOC (P < 0.001 for both comparisons).

Notably, B7-H4 emerged as the most consistently expressed target across all histotypes. Expression rates were high in HGSOC (99.7%), followed by EnOC (89.8%) and CCOC (80.7%).

The overall study cohort was comprised of 492 patients who were categorized by ovarian cancer histotype: HGCOC (n =331), EnOC (n = 101), and CCOC (n = 60). The overall median age was 60.5 years (28-88). The median age by histotype was 61 years (range, 35-86), 58.5 years (range, 28-88), and 60 years (range, 30-79), respectively. Further, no patients received neoadjuvant chemotherapy.

Residual disease status (RDS) was determined to be either macroscopic (40.8%) or zero (48.8%) in the overall cohort. When evaluated by histotype, RDS was 52% and 35.6% in the HGSOC cohort, 19.8% and 73.3% in the EnOC cohort, and 14.8% and 80.3% in the CCOC cohort, respectively.

In the overall population and the HGSOC cohort, the majority of patients had International Federation of Gynaecology and Obstetrics (FIGO) stage III disease (49.2% and 66.5%, respectively), whereas for the EnOC and CCOC cohorts, the majority had FIGO stage I disease (41.6% and 42.6%, respectively).

Correlation With Other Molecular Features

Additional molecular analyses provided further insights. These molecular features were extracted for use in the study: CTNNB1 mutation status, TP53 mutation status, POLE mutation status, and MMR status.

Within the HGSOC cohort, ADC target expression levels were investigated for association with BRCA1/2 mutation status (germline or somatic) and CCNE1g status. For FRα, B7-H4 and TROP2, there was no significant difference in expression between these molecularly defined subgroups in the HGSOC cohort.

In the EnOC cohort, clinically-relevant molecular features included POLE-mutant, TP53-mutant, MMR-deficient, and CTNNB1-mutant. The investigators determined that FRα and B7-H4 expression were comparable across these molecular subtypes. Further, although TROP2 expression appeared low in the TP53-mutant group, this was not significantly different compared with the other molecular subtypes (P = 0.070).

In the CCOC cohort, ARID1A/B-mutant tumors showed significantly reduced B7-H4 expression compared with wild type cases (P < 0.001), suggesting potential clinical utility for this biomarker.

This study’s comprehensive evaluation of ADC target expression across ovarian cancer histotypes provides a valuable roadmap for future therapeutic development. The researchers emphasized the need for histotype-specific treatment strategies and recommend incorporating target expression analysis in clinical trials to identify patient populations most likely to benefit from ADC therapies. Particular attention should be given to B7-H4, which may offer promising candidates for therapeutic strategies, based upon the frequent expression of this marker across HGSOC, EnOC and CCOC cohorts.

REFERENCES:

1. FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. FDA news. Accessed July 23, 2025. https://tinyurl.com/52a9hyb2

2. Porter JM, Jin C, Churchman M, et al. Antibody drug conjugate targets are highly differentially expressed across the major types of ovarian cancer. Eur J Cancer. 2025;224:115522. doi:10.1016/j.ejca.2025.115522