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Abstract
Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. Our previous study on ovarian clear-cell carcinoma found histone deacetylase 6 (HDAC6) overexpression led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and a therapeutic target for ovarian HGSC. The clinical significance of HDAC6 as a predictor of prognosis and chemoresistance in HGSC was immunohistochemically evaluated. In addition, expression of programmed cell death ligand-1 (PD-L1), and hypoxia-inducible factor-1α (HIF1α) were analyzed using clinical samples from 88 patients with ovarian HGSC, and their clinicopathological characteristics were reviewed. Twenty-three patients had high HDAC6 expression, 10 positive PD-L1 expression, and 33 high HIF-1α expression. HDAC6 up-regulation was correlated with not undergoing interval debulking surgery (p<0.001), incomplete surgical resection (p=0.002), and frequent occurrence of stable disease/progressive disease according to the Response Evaluation Criteria in Solid Tumors (p=0.005) criteria. On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with reduced progression-free (p=0.001) and overall (p=0.008) survival. On multivariate analysis, high HDAC6 expression (hazard ratio=1.65, 95% confidence interval 1.03-2.66; p=0.039) and surgery status were independent prognostic factors of progression-free survival. PD-L1 and HIF1α expression positively correlated with that of HDAC6. HDAC6 may become a potential therapeutic target in patients with ovarian HGSC since its up-regulation is considered to be associated with a poor prognosis in patients with this cancer.
Highlights
Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence
histone deacetylase 6 (HDAC6) up-regulation was correlated with not undergoing interval debulking surgery (p < 0.001), incomplete surgical resection (p = 0.002), and frequent occurrence of stable disease/progressive disease according to the response evaluation criteria in solid tumors (RECIST) (p = 0.005) criteria
On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with decreased progression-free survival (p = 0.001) and overall survival (p = 0.008)
Summary
Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. In our previous study on ovarian clear cell carcinoma, histone deacetylase 6 (HDAC6) led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and therapeutic target for ovarian HGSC. Ovarian cancer is the leading cause of death owing to cancers of the female genital tract, with high-grade serous carcinoma (HGSC) being the most frequent histological type [1]. HGSC shows a good response to a combination of platinum and taxane agents, which is a standard chemotherapy regimen for epithelial ovarian cancers. HGSCs recur frequently and gradually acquire resistance to these standard chemotherapy regimens [2]. New strategies have been devised for patients with ovarian cancer with BRCA mutations [5] or platinum-sensitive recurrence [6]. Treatments for patients with TP53 mutations or those with platinum-resistant recurrence have yet to be developed
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