Highly Expressed Progesterone Receptor B Isoform Increases Platinum Sensitivity and Survival of Ovarian High-Grade Serous Carcinoma

Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms’ expression, platinum sensitivity, and survival in ovarian HGSC. Material and methods: This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Results: Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson’s correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. Conclusions: When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated.

Download Full-text

The Impact of Progesterone Receptor Expression on Platinum Sensitivity and Survival Outcomes in Patients With Ovarian Clear Cell Carcinoma

10.21203/rs.3.rs-683804/v1 ◽

2021 ◽

Author(s):

Chen-Hsuan Wu ◽

Hung-Chun Fu ◽

Yu-Che Ou ◽

Jui Lan ◽

Hao Lin

Keyword(s):

Progesterone Receptor ◽

Cell Carcinoma ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Receptor Expression ◽

Survival Outcomes ◽

Platinum Sensitivity ◽

Platinum Sensitive ◽

Platinum Resistant ◽

The Impact

Abstract BackgroundOvarian clear cell carcinoma (OCCC) is considered to be a relatively platinum-resistant malignancy. In the present study, we investigated the impact of progesterone receptor (PR) expression on platinum sensitivity and survival outcomes in patients with OCCC.MethodsWe retrospectively reviewed 80 patients with OCCC who underwent surgery followed by adjuvant chemotherapy, and analyzed PR expression by immunohistochemical staining. The PR expression was quantified using the H-score. The platinum sensitivity and survival outcomes were compared between those with a weak and strong PR expression. Cisplatin viability experiments were performed in OCCC cell lines (TOV-21G) with different PR expressions.ResultsAmong the 80 patients, 66 and 14 were considered to have platinum-sensitive and platinum-resistant disease, respectively. The mean PR H-score of the platinum-sensitive tumors was significant higher than that of the platinum-resistant tumors (p=0.002). Although there were no significant differences in progression-free and overall survival between the patients with high and low PR expressions, the patients with a high PR expression had a trend towards better survival. In cell models, PR protein was weakly detectable in TOV-21G cells. Through transfection of PR gene, TOV-21G cells were shown to have a strong PR expression by Western blot analysis. After treating the TOV-21G cells with cisplatin, we found that the overexpression of PR enhanced cisplatin cytotoxicity. ConclusionsThe patients in this study with a strong PR expression were associated with better platinum sensitivity and survival, and this was compatible with our experimental findings. The value of PR as a tumor sensitizer to cisplatin in OCCC should be further investigated.

Download Full-text

Prognostic value of progesterone receptor expression in tubo-ovarian high-grade serous carcinoma of the COEUR cohort

Histopathology ◽

10.1111/his.13784 ◽

2019 ◽

Vol 74 (4) ◽

pp. 663-666 ◽

Cited By ~ 1

Author(s):

Cécile Le Page ◽

Kurosh Rahimi ◽

Anne-Marie Mes-Masson ◽

Martin Köbel

Keyword(s):

Progesterone Receptor ◽

Prognostic Value ◽

Receptor Expression ◽

Serous Carcinoma ◽

High Grade ◽

Progesterone Receptor Expression

Download Full-text

Comparison of survival outcomes in optimally and maximally cytoreduced stage IIIC ovarian high‐grade serous carcinoma: Women with only peritoneal tumor burden versus women with both peritoneal and lymphogenous dissemination

Journal of Obstetrics and Gynaecology Research ◽

10.1111/jog.14075 ◽

2019 ◽

Vol 45 (10) ◽

pp. 2074-2081

Author(s):

Ilker Selcuk ◽

Mehmet M. Meydanli ◽

Ibrahim Yalcin ◽

Kemal Gungorduk ◽

Sedat Akgol ◽

...

Keyword(s):

Tumor Burden ◽

Serous Carcinoma ◽

Survival Outcomes ◽

High Grade ◽

Stage Iiic ◽

Peritoneal Tumor

Download Full-text

Prognostic value of PD-1 and PD-L1 expression in patients with high-grade urothelial carcinoma of the upper urinary tract.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.358 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 358-358

Author(s):

Laura-Maria Krabbe ◽

Barbara Heitplatz ◽

Ryan C Hutchinson ◽

Solomon L Woldu ◽

Sina Preuss ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Prognostic Value ◽

Cox Regression ◽

Tumor Infiltrating Lymphocytes ◽

Tissue Microarrays ◽

Tumor Stage ◽

Survival Outcomes ◽

High Grade ◽

Cancer Specific Survival ◽

Infiltrating Lymphocytes

358 Background: To investigate the prognostic value of PD-1 and PD-L1 expression in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: Tissue microarrays were created using 448 patients from the International UTUC collaboration who underwent extirpative surgery for high-grade UTUC and stained for PD-1 (antibody (AB): NAT105, diluted 1:250 from Ventana) and PD-L1 (AB: E1L3N prediluted from Cell Signaling). PD-1 and PD-L1 expression was assessed in a semi-quantitative fashion and any percentage of staining of the tumor cells (PD-L1) and tumor-infiltrating lymphocytes (PD-1) was considered positive. Univariate (UVA) and multivariate analyses (MVA) were performed to assess independent prognosticators of oncological outcomes. No funding was received. Results: Median age of the cohort was 69.2 years and 56.5% of patients were male. PD-L1 and PD-1 were positive in 24.1% and 37.5% of patients. PD-L1 positivity was associated with favorable pathological stage, where as PD-1 positivity was significantly associated with pelvicalyceal location, lymph node metastases, non-organ confined disease, presence of lymphovascular invasion, sessile architecture, necrosis, concomitant CIS, and history of non-muscle invasive bladder cancer. PD-L1 positivity was not significantly associated with survival outcomes. In Cox regression UVA, PD-1 positivity was associated with worse recurrence-free survival (RFS) (HR 1.5 (95%CI 1.08-2.14, p=0.016)), cancer-specific survival (CSS) (HR 1.5 (95%CI 1.07-2.19, p=0.021)), and overall survival (OS) (HR 1.5 (95%CI 1.10-1.97, p=0.009)). However in MVA, PD-1 positivity was not found to be an independent predictor of RFS, CSS or OS. Conclusions: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and was a significant prognosticator for RFS, CSS and OS on UVA in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort. In MVA, the independent prognostic value of PD-1 was not confirmed. PD-L1 positivity was associated with lower tumor stage, but not with other pathological characteristics or survival outcomes.

Download Full-text

High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis

Frontiers in Oncology ◽

10.3389/fonc.2021.761960 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wenwen Guo ◽

Xue He ◽

Jing Ni ◽

Liya Ma ◽

Xianzhong Cheng ◽

...

Keyword(s):

Ovarian Cancer ◽

Gene Set Enrichment Analysis ◽

Differentially Expressed ◽

High Grade ◽

Serous Ovarian Cancer ◽

Gene Set ◽

Platinum Sensitivity ◽

Platinum Sensitive ◽

Platinum Resistant ◽

Sensitive Group

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q < 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p < 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

Download Full-text

CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity

Scientific Reports ◽

10.1038/s41598-017-17119-1 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 19

Author(s):

Josephine B. Walton ◽

Malcolm Farquharson ◽

Susan Mason ◽

Jennifer Port ◽

Bjorn Kruspig ◽

...

Keyword(s):

Serous Carcinoma ◽

High Grade ◽

Platinum Sensitivity

Download Full-text

Surgical debulking improves survival in high-grade serous carcinoma regardless of platinum sensitivity

Gynecologic Oncology ◽

10.1016/s0090-8258(21)00747-2 ◽

2021 ◽

Vol 162 ◽

pp. S54-S55

Author(s):

Nicholas Cardillo ◽

Rei Christian Calma ◽

Yasmin Lyons ◽

Michael Goodheart ◽

Jesus Gonzalez Bosquet

Keyword(s):

Serous Carcinoma ◽

High Grade ◽

Platinum Sensitivity ◽

Surgical Debulking

Download Full-text

Estrogen receptor and progesterone receptor status and their prognostic implications in pelvic high-grade serous carcinomas: A retrospective study

10.21203/rs.2.17522/v1 ◽

2019 ◽

Author(s):

Ting Zhao ◽

Weiyong Gu ◽

Chenyun Zhang ◽

Hongyuan Jiang ◽

Yuan Lu

Keyword(s):

Estrogen Receptor ◽

Prognostic Factors ◽

Prognostic Factor ◽

Progesterone Receptor ◽

Survival Rates ◽

Progression Free Survival ◽

P53 Mutation ◽

Serous Carcinoma ◽

High Grade ◽

Stage Disease

Abstract Background: There is mounting evidence that ovarian, tubal and peritoneal high-grade serous carcinoma (HGSC) share common origin. It was also suggested that extrauterine HGSCs may originate from endometrium. The aim of this study is to compare the estrogen receptor (ER) and progesterone receptor (PR) status among pelvic HGSCs, and to analyze the prognostic role of ER and PR in pelvic HGSCs patients, and the prognostic factors in patients with different ER or PR status Methods: In total, 283 patients diagnosed with ovarian, tubal, peritoneal, and uterine HGSC were retrospectively analyzed. All patients’ diagnosis were reviewed by a panel of gynecologists and pathologists strictly according to criteria based on lesion distribution. Results: Patients in endometrial group were older than ovarian (60.1±8.0 vs. 54.1±8.3, p=0.000) and tubal (60.1±8.0 vs. 55.8±9.5, p=0.008) group. A higher proportion of ovarian group presented with advanced stage disease than fallopian and endometrial group (73.7% vs. 47.2%, p=0.000 and 73.7% vs. 47.4%, p=0.002, respectively). PR positivity rate was much lower in peritoneal compared to ovarian group (25.0% vs. 65.6%, p=0.000). There was no difference in survival rates among four groups. Although ER and PR were not prognostic factors for 5-year overall survival (OS) and progression-free survival (PFS), the prognostic factors were different in patients of distinct ER/PR status. More chemotherapy cycles was a protective prognostic factor in ER(+) or PR(+) patients but not in ER(-) or PR(-) patients. P53 mutation was adverse prognostic factor for OS in PR(-) patients but in PR(+) patients. Conclusions: PR positivity rate were much lower in peritoneal compared to ovarian HGSC. Although ER and PR were not prognostic factors in pelvic HGSCs, prognostic factors for survival were different in patients of different ER/PR status.

Download Full-text