Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Surgical Margins After Neoadjuvant Radiation for Locally Advanced Vulvar Carcinoma: What is an Adequate Margin?

OBJECTIVE: We aim to explore whether the surgical tumor free margin is important for overall survival (OS) and local control in patients who undergo neoadjuvant radiation (RT) for vulvar cancer. METHODS: A retrospective review from 2004 to 2021 of patients who underwent RT followed by surgical resection was performed. Patients were categorized into groups based on margin status (no residual disease, >8 mm, close margins defined as 1 to 7 mm, or positive). Local control and OS were analyzed using the Kaplan-Meier with log rank test. Multivariate analysis was performed with cox hazards model. RESULTS: Eighty-three patients were included. A complete pathologic response (pCR) was found in 56% (n=46) of patients. The median follow-up time was 35 months (range: 4 to 216). The median OS for the entire cohort was 46 months (95% CI: 32.3-59.7). Having a pCR improved both OS and disease-free survival (DFS) compared with residual disease by 81 and 91 months, respectively ( P <0.001). In the 2 patients with a margin >8 mm, there was no statistical difference in survival between those with close margins (46 vs. 25 mo, P =0.485). Factors that significantly impacted both OS and DFS were depth of invasion (DOI) and LVSI. On multivariate analysis of those with residual disease, there was no difference in OS or DFS by margin status but having a DOI >9 mm showed decreased OS (HR: 3.654; 95% CI: 1.317-10.135). CONCLUSIONS: In this cohort, response to RT, not margin status drives survival and recurrence. Given residual disease, the optimal margin is not clear, as there were only 2 patients with >8 mm margins. A close or positive margin had no impact on OS or local recurrence. A DOI >9 mm significantly impacts both OS and local recurrence even when accounting for other factors.

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.