Combined genomic and molecular analysis defines prognostic markers of relapse in stage IA-IC1 clear cell ovarian carcinoma

Objective

Clear cell ovarian carcinoma (CCOC) is generally associated with a favourable prognosis, but up to 30% of low-stage cases relapse within five years. The benefit of adjuvant chemotherapy for low-stage CCOC (FIGO stage IA-IC1) remains uncertain. This study aimed to identify molecular and immune markers associated with relapse in a well-characterized CCOC cohort.

Methods

Using the Edinburgh Ovarian Cancer Database, we identified 85 CCOC cases. Targeted DNA sequencing assessed genomic alterations and tumour immune infiltration was evaluated using CD3 and CD8 immunohistochemistry on tissue microarrays. Tumours were stratified by stage (IA-IC1, IC2-II, III-IV), and both univariate and multivariate analysis applied for progression-free survival (PFS) included stage, age, genomic features, and immune markers.

Results

Common genomic alterations included ARID1A (49%) and PIK3CA (42%) mutations, PIK3-AKT pathway perturbations (60%), and mismatch repair-related mutational signatures (25.9%). Genomic and molecular features were not significantly associated with tumour stage; however, low-stage tumours (IA-IC1) were enriched in CD3+ (40% cases) and CD8+ (29% cases) tumour-infiltrating lymphocytes (TILs) compared to higher-stage tumours (IC2-II: 13%/7%; III-IV: 9%/0% cases). In univariate analysis, low CD3+ TIL levels were significantly associated with reduced progression-free survival (HR = 4.4, P = 0.042, 95% CI 1.1-18). ARID1A wild-type status was linked to poorer PFS but only in low-stage tumours HR = 7.2, P = 0.088; 95% CI 0.74-72). Notably, the combination of ARID1A wild-type status and CD3+ depletion identified a high-risk subgroup among low-stage CCOC cases (HR = 11.7, P = 0.050; 95% CI 1-138), highlighting potential as a composite risk marker set.

Conclusions

Combined ARID1A mutation and low CD3+ve TIL levels are suggestive of higher recurrence risk in low-stage CCOC patients. These findings support further investigation of targeted therapies or immune checkpoint inhibitors in larger CCOC cohorts.

Highlights

• We report a well-characterized CCOC cohort with rich clinical, genomic and molecular data.

• Common mutations included ARID1A (49%) and PIK3CA (42%), with MSI in 9%, showing no significant enrichment across tumour stages.

• Low-stage CCOC has higher levels of CD3+ & CD8+ tumour infiltrating leukocytes than in advanced-stage disease.

• ARID1A wild-type tumours with CD3+ TIL depletion represent a high-risk subgroup of low-stage CCOC.

• Findings support further study and highlight potential markers for recurrence risk.