Jorgensen, Brooke D.

Abstract Background: Ovarian endometrioid carcinoma (OEC) is an uncommon, understudied histotype that is distinguished from other histotypes by unique genomic features and high hormone receptor expression. There is growing interest in the biological relevance of subtyping using immunohistochemistry (IHC). Methods: Women with primary invasive OEC diagnosed from 1989 to 2010 were retrospectively identified from the population-based Alberta Cancer Registry, Canada. Pathology slide review and IHC staining for Napsin A, TP53, and WT1 were used to reduce histologic misclassification, resulting in N=166 participants (low-stage N=138, high-stage N=28), excluding those who received neo-adjuvant chemotherapy. The following markers were stained and scored on tissue microarrays: TP53 (normal/abnormal), PMS2/MSH6 (mismatch repair proficient [MMRp]/deficient [MMRd]), PGR (loss/retained), and CTNNB1 (nuclear/cytoplasmic). Using a hierarchical decision tree by stage group (low/high), we categorized tumors as TP53 abnormal, MMRd, PGR loss, nuclear CTNNB1, and no specific immunohistochemical profile (NSIP). Distributions and five-year disease specific survival (DSS) was estimated for each group; hazard ratios (HRs) adjusted for age were estimated using Cox regression with NSIP as referent group. Results: Among low-stage cases, five-year survival was as follows: 80% for TP53 abnormal (N=10, 7%), 87% for MMRd (N=15, 11%), 80% for PGR loss (N=10, 7%), 98% for nuclear CTNNB1 (N=63, 46%), and 95% for NSIP group (N=40, 29%). Overall, IHC group was associated with DSS among low stage cases (LRT p-value=0.006), and the group with nuclear CTNNB1 had a small but statistically significant DSS advantage (HR=0.089, 95% CI 0.011-0.742, p=0.025). TP53 and PGR loss suggested shorter DSS than the referent NSIP group, but not statistically significantly so (HR=1.26 and 3.08, respectively). Among high-stage cases, five-year DSS was as follows: 57% for TP53 abnormal (N=7, 25%), 75% for MMRd (N=8, 29%), 33% for nuclear CTNNB1 (N=3, 11%), and 17% for NSIP (N=10, 36%). There were no high-stage cases in the PGR-loss group. Nuclear CTNNB1 group had a shorter DSS among high-stage cases, but this was not statistically significantly so (HR=1.16, p=0.85). Conclusion: Pending replication in additional datasets, results suggest that OEC cases in nuclear CTNNB1 or NSIP IHC groups may have a favorable prognosis in which de-escalation of therapy can be considered. In addition, abnormal TP53 and loss of PGR may identify a high-risk subset of low-stage OEC. Citation Format: Brooke Jorgensen, Stacey Winham, Julie Cunningham, Sebastian Armasu, Chen Wang, Hunter Atkinson, Bryan McCauley, Linda Kelemen, Martin Koebel, Ellen Goode. Towards a combined immunohistochemistry-based subtyping of ovarian endometrioid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6499.

Abstract Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17–3.81; P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66–2.95; P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.