Antibody drug conjugate targets are highly differentially expressed across the major types of ovarian cancer

Abstract

Background: Antibody-drug conjugates (ADCs) are emerging anti-cancer agents. The folate receptor alpha (FOLRα)-directed ADC mirvetuximab soravtansine recently demonstrated clinical activity in platinum-resistant ovarian cancer, with other ADCs currently in development. The relative expression of FOLRα and other ADC targets is largely unknown across ovarian cancer histotypes.

Methods: Expression levels of the ADC targets FOLRα, TROP2 and B7-H4 were assessed by immunohistochemistry in patient cohorts using tumour tissue microarrays of the major ovarian cancer histotypes: high grade serous (HGSOC, n = 331); endometrioid (EnOC, n = 101) and clear cell ovarian carcinoma (CCOC, n = 60). Degree of expression was quantified by membrane histoscore.

Results: We observed differences in ADC target expression patterns across ovarian cancer histotypes. FOLRα expression was highest in HGSOC, with few EnOC or CCOC demonstrating positivity (HGSOC: 70.9 % FOLRα histoscore ≥50 vs 21.1 % and 29.3 % in EnOC and CCOC). B7-H4 was expressed in HGSOC, EnOC and CCOC (99.7 %, 89.8 % and 80.7 % with histoscore ≥50). CCOC were mostly TROP2 negative (89.3 % with histoscore <50); a subset of HGSOC and EnOC expressed TROP2 (54.8 % and 57.7 % with histoscore ≥50, respectively). There was no significant association between ADC target expression and molecular subtypes of HGSOC (BRCA1/2-mutant, CCNE1-gained, other) or EnOC (TP53-mutant, CTNNB1-mutant, POLE-mutant, MMR deficient, no specific molecular profile). In CCOC, ARID1A/B mutation was associated with lower B7-H4 expression (P-adj=0.024).

Conclusion: EnOC and CCOC are usually FOLRα negative, while HGSOC, EnOC and CCOC frequently express B7-H4. TROP2 positivity is limited to HGSOC and EnOC. Careful consideration of histotype and ADC target expression levels is warranted when designing and analysing clinical studies of ADCs.

Keywords: Antibody drug conjugate; B7-H4; Folate receptor alpha; Ovarian cancer; TROP2.