Abstract B80: Tumor expression subtypes of high-grade serous ovarian cancer demonstrate associations with likelihood of complete resection: a single-center study.
Authors: Wang Chen , Bakkum-Gamez Jamie , Mariani Andrea , Cliby William , Goode Ellen 
Published: May 2016

Purpose: Ovarian cancer (OC) patients received maximum benefits when complete dissection with no macroscopic disease is achieved. It has been suggested that surgical outcome is associated with tumor biology and therefore can be predicted from tumor molecular characteristics such as gene expression levels. Noticeably, several debulking-associated genes have been independently reported based on meta-data analysis and further validations in individual center's cohorts. Furthermore, a recent OC study of the cancer genome atlas (TCGA) project revealed the presence of four expression subtypes in high-grade serous ovarian cancer (HGSOC). We have independently confirmed this association with prognosis in our OC cohort. With the awareness that surgical practices and rates of complete resection vary among institutions, we sought to evaluate whether expression changes of previously reported debulking-associated genes are associated with complete dissection in a HGSOC cohort in a center with an aggressive surgical approach. Further, we also tested if the HGSOC four expression subtypes are associated with complete dissection.

Experimental Design: We constructed a cohort of 262 stage III/IV HGSOC patient cases diagnosed in Mayo Clinic between 1993 and 2011. Cases were categorized into two groups based upon debulking outcome: 84 complete resection cases with no gross visible residual disease (RD0), 178 cases with residual disease greater than 0 cm (RD1). Tumor mRNA expression was previously measured using Agilent 4x44k platforms. Eight previously published debulking-associated genes were evaluated for their expression differences between RD0 and RD1 patient groups using t-test: FABP4, ADH1B, POSTN, CXCL14, FAP, NUAK1, PTCH1 and TGFBR2. For testing subtype-debulking associations, we first quantified molecular subtype activation scores of individual tumors using single-sample gene set enrichment analysis (ssGSEA), and computed standardized scores after permutation-based scaling adjustments to account for gene set size difference. Then, standardized subtype scores are associated with complete dissection (RD0) vs. other surgical outcome (RD1) using logistic regression. The independent subtype-associations were further evaluated by adjusting known debulking outcome factors, including age, ascites, tumor grade and stage.

Results: For eight previously reported debulking-associated genes, only one demonstrated a significant expression difference between RD0 and RD1 groups: CXCL14, t-test p-value = 9.2x10-3. When comparing debulking vs. HGSOC subtypes, we observed a significantly reduced probability of complete resection for the mesenchymal subtype (p-value = 1.1x10-2, OR = 0.56, 95% CI [0.35, 0.87]). Consistent with this observation, we have previously described the mesenchymal subtype as a poor prognosis group. On the other hand, the immunoreactive subtype was associated with a higher likelihood of complete resection (p-value = 9.4 x 10-3, OR=2.19, 95% CI = [1.22, 4.01]). The significant associations between these two subtype activities and complete resection in advanced stage disease remained after adjusting for age, ascites, tumor grade and sub-stage: mesenchymal (p-value = 1.5 x 10-2 ,OR = 0.48, 95% CI = [0.26, 0.85]); immunoreactive subtype (p-value = 4.8 x 10-2 , OR = 2.11, 95% CI = [1.04, 4.53]).

Conclusion: This single center HGSOC analysis demonstrates the important of validation of debulking signatures in centers with diverse rates of complete resection. We were only able to validate an association with complete resection for one of eight previously reported debulking-associated genes. We also showed that HGSOC subtypes have significant associations with likelihood of complete dissection. Further studies are warranted for confirming subtype associations in other institutional HGSOC cohorts.

Citation Format: Chen Wang, Jamie Bakkum-Gamez, Andrea Mariani, William Cliby, Ellen Goode. Tumor expression subtypes of high-grade serous ovarian cancer demonstrate associations with likelihood of complete resection: a single-center study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B80.