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.