IHC-based prognostic sub-stratification of ovarian endometrioid carcinoma

Ovarian endometrioid carcinoma (OEC) is the second most common histotype associated with the most favorable prognosis among ovarian carcinomas. Similar to endometrial carcinoma, OEC exhibit significant molecular diversity. We aimed to develop a practical immunohistochemical (IHC) prognosticator by integrating IHC biomarkers with clinical substage, and surgical outcomes. This multi-institutional study included participants with primary invasive OEC from the Alberta Cancer Registry (AOVT), Mayo Clinic, and Disease of the Ovary and their Evaluation Study (DOVE). Pathology review excluded misclassified high-grade serous and mesonephric carcinomas leaving 422 OEC cases (AOVT N=158; DOVE N=143; Mayo N=121) with available tumor biospecimens who did not receive neoadjuvant treatment. Clinical characteristics included age, stage, grade, residual disease and 5-year survival. Clinical risk group was defined by combining stage and residual disease: Low (FIGO stage IA/IB & no macroscopic disease), Intermediate (stage IC-II& no macroscopic disease), High (stage III/IV or macroscopic disease). Tissue microarrays were stained for TP53, PMS2, MSH6, PGR, and CTNNB1 using IHC and were scored by a single pathologist. Tumors were hierarchically categorized as TP53-abnormal (TP53abn)/PGR-loss, mismatch-repair deficient (MMRd, via PMS2 and MSH6), nuclear-CTNNB1 (nCTNNB1), or no-specific-immunohistochemical-profile (NSIP). Overall survival (OS) at 5 years was compared across clinical risk and biomarker groups using Cox regression, adjusted for age and site to generate hazard ratios (HR), and 5-year survival rates (5-YSR). High clinical risk group was associated with worse 5-year OS compared to low & intermediate risk (p<0.0001). Hierarchical IHC biomarker groups were also associated with 5-year OS, adjusted for age and study site (p<0.0001), with consistently worse survival for combined TP53abn/PGR-loss (n=17, HR=6.07, 95% CI 2.78-13.26), PGR-loss only (n=55, HR=4.17, 95% CI 2.19-7.94), TP53abn only (n=29, HR=2.04, 95% CI 0.85-4.90), and better survival for nuclear-CTNNB1 (n=146, HR=0.22, 95% CI 0.07-0.65) compared to NSIP (n=132). Within the low-risk group, MMRd, nCTNNB1, or NSIP had greater than 97% 5-YSR, while OEC with TP53abn/PGR-loss or PR-loss only had less than 75% 5-YSR. Within the intermediate group, only nCTNNB1 exceeded a 5-YSR of greater than 97%. Within the high-risk group, 5YSR for nCTNNB1 OEC was 90.9%, compared to only 16.7% for TP53abn/PGR-loss. This IHC-based algorithm refines prognosis beyond clinical substage. It identifies low-risk patients with unfavorable prognosis (TP53abn/PGRloss, PGR loss only) who may benefit from adjuvant therapy, and also patients with favorable prognosis within the intermediate group for whom adjuvant therapy could be de-escalated. Further patient selection for chemo vs. hormone therapy in the high-risk group may be improved by biomarkers.