Mutational profiles of ovarian cancer in Chinese patients revealed potential therapeutic targets and prognostic markers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17525-e17525
Author(s):  
Weiwei Feng ◽  
Tianjiao Lyu ◽  
Hua Liu ◽  
Yahui Jiang ◽  
Lifei Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Prognostic Markers ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Chinese Patients ◽  
Disease Stage ◽  
Platinum Sensitivity ◽  
Platinum Resistant

e17525 Background: Ovarian cancer (OC) is a common and lethal gynecologic malignancy. The prognosis of OC is variable among different patients treated with standard of care therapies. Herein, we described mutational profiles of OC to identify underlying therapeutic targets and prognostic markers. Methods: The study was performed in 38 Chinese patients with high-grade serous ovarian cancer (HGSC), the most common subtype of OC. Most patients (86.8%) had advanced disease (stage III-IV). Tissue samples were subjected to capture-based targeted sequencing using a panel consisting of 520 cancer related genes. Mutational profiles including gene mutations and copy number variations (CNVs) were evaluated in each patient. Homologous recombination deficiency (HRD) status was also assessed. Analysis of mutational profile with platinum-sensitivity, progression-free survival (PFS) and platinum-free interval (PFI) were performed. Results: Genetic alterations were mainly identified in TP53 (97%), BRCA1 (24%), RB1 (21%), FGF23 (21%), CCND2 (18%), RECQL4 (18%) and NF1 (16%). CNVs were comprehensively distributed in 242 genes with 76% (29/38) of patients harboring at least one CNV. In addition to BRCA1, genetic alterations were also presented in other homologous recombination repair (HRR) genes including CDK12 (5%), BRCA2 (3%), ATM (3%), BRIP1 (3%), CHEK1 (3%) and FANCI (3%). There were 22 of 38 (58%) patients with genetic alterations of the HRR pathway. In the study, 28 patients were platinum-sensitive (74%) and 10 were platinum-resistant (26%). Platinum-sensitivity was significantly associated with BRCA1/2 mutations (p < 0.01). In platinum-resistant patients, 7 of 10 patients harbored genetic alterations of actionable therapeutic targets such as PIK3CA, TSC1 and HER2 alterations. The prognosis analysis indicated that BRCA1/2 mutations were significantly associated with improved PFI (p < 0.05) and marginally associated with improved PFS (p = 0.05). Although no association was observed between HRD status and patient prognosis, subgroup analysis in patients with R0 resection found positive HRD showing significant association with better PFI (p < 0.05) and marginal association with better PFS (p = 0.06). Further analysis of HRD classified by NF1 revealed different PFS and PFI among patients harboring positive HRD, negative HRD with NF1 mutations and negative HRD with wild type NF1 (p < 0.05). The study also observed association of LRP1B mutations and RAD52 amplification with worse PFS (p < 0.05). Conclusions: In OC patients, genetic mutations were frequently occurred in both HRR and non HRR genes. CNVs were widely presented in many genes and patients. The mutational profiling also identified a number of potential therapeutic targets and prognostic markers at molecular level which could contribute to personalized treatment and management of OC.

scholarly journals Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer

2020 ◽  
Author(s):  
Yan Rong ◽  
Li Li
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Data ◽  
First Line ◽  
Clinical Value ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Line Chemotherapy ◽  
Sensitive Group

Abstract Objectives: To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.Method: HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.Results: 16 patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p<0.0001, p<0.0001) as well as CA125 after 1st cycle chemotherapy (p<0.0001, p<0.0001).Conclusions: Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.

scholarly journals Homologous Recombination Deficiency Associated With Response to Poly (ADP-Ribose) Polymerase Inhibitors in Ovarian Cancer Patients: The First Real-Word Evidence From China

2022 ◽  
Vol 11 ◽  
Author(s):  
Jing Ni ◽  
Wenwen Guo ◽  
Qian Zhao ◽  
Xianzhong Cheng ◽  
Xia Xu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Multiple Regression ◽  
Real World ◽  
Cox Regression ◽  
Predictive Biomarker ◽  
Homologous Recombination Deficiency ◽  
Platinum Sensitivity ◽  
Polymerase Inhibitors

Homologous recombination deficiency (HRD) is an approved predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of positive HRD in the real world and the relationship between HRD status and PARPi in Chinese ovarian cancer patients remain unknown. A total of 67 ovarian cancer patients who underwent PARPi, either olaparib or niraparib, were enrolled and passed inclusion criteria from August 2018 to January 2021 in the Affiliated Cancer Hospital of Nanjing Medical University. HRD status correlation with Progression-free survival (PFS) was analyzed and summarized with a log-rank test. Univariate and multiple cox-regression analyses were conducted to investigate all correlated clinical factors. Approximately 68.7% (46/67) patients were HRD positive and the rest 31.3% (21/67) were HRD negative. The PFS among HRD-positive patients was significantly longer than those HRD-negative patients (medium PFS 9.4 m vs 4.1 m, hazard ratio [HR]: 0.52, 95% CI: [0.38–0.71], p &lt;0.001). Univariate cox-regression found that HRD status, Eastern Cooperative Oncology Group (ECOG) status, BRCA status, previous treatment lines, secondary cytoreductive surgery and R0 resection were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status and ECOG were the independent factors to predict PFS (HR: 0.67, 95% CI: [0.49–0.92], p = 0.01; HR: 2.20, 95% CI: [1.14–4.23], p = 0.02, respectively). In platinum sensitivity evaluable subgroup (N = 49), HRD status and platinum sensitivity status remain significant to predict PFS after multiple regression correction (HR: 0.71, 95% CI: [0.51–0.98], p = 0.04; HR: 0.49, 95% CI: [0.24–1.0], p = 0.05, respectively). This is the first real-world study of HRD status in ovarian cancer patients in China, and we demonstrate that HRD is an independent predictive biomarker for PARP inhibitors treatment in Chinese ovarian cancer patients.

scholarly journals 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

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 &lt; 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 &lt; 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.

scholarly journals Early clearance of serum HE4 and CA125 in predicting platinum sensitive and prognosis in epithelial ovarian cancer

2020 ◽  
Author(s):  
Yan Rong ◽  
Li Li
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Data ◽  
First Line ◽  
Clinical Value ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Line Chemotherapy ◽  
Sensitive Group

Abstract Objectives: To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitive and prognosis in patients with ovarian cancerMethod: HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.Results: 16 patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p < 0.0001, p < 0.0001) as well as CA125 after 1st cycle chemotherapy (p < 0.0001, p < 0.0001).Conclusions: Our data suggest that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitive and risk to progress and relapse.

Homologous recombination deficiency and platinum rechallenge in platinum-resistant ovarian cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5576-5576 ◽  
Author(s):  
Alexandre Andre B. A. Da Costa ◽  
Marcela Marinelli Salvadori ◽  
Camila Vieira Valadares ◽  
Carlos Stecca ◽  
Louise Brot ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Response Rate ◽  
Homologous Recombination Deficiency ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
The Impact

5576 Background: Ovarian carcinomas show homologous recombination deficiency (HRD) in up to 50% of cases and in 15 to 20% of cases occur due to germline BRCA1 or BRCA2 mutations. BRCA mutated tumors are more sensitive to PARP inhibitors and platinum based chemotherapy. The objective of this study was to characterize a cohort of ovarian cancer patients regarding HRD and to evaluate the impact of these scores in prolonged platinum sensitivity. Methods: Thirty one ovarian cancer patients with platinum resistant recurrence reexposed to platinum based chemotherapy were selected. Paraffin embedded tumor samples from 14 patients were analyzed using ONCOSCAN assay (Affymetrix) to evaluate HRD scores. The association of the scores with response rate to platinum rechallenge, overall survival and clinical pathologic factors was evaluated. Results: From the cohort of 31 patients, 15 samples from 14 patients were analyzed for genomic alterations. Median scores were 19.5 for TAI, 12.5 for cnLOH+L, 26.0 for LST and 6.3 for HRD. High scores were found in 10 out of 14 (for cnLOH+L score) and 9 out of 14 (for LST score) patients. Seven of the 14 patients analyzed analyzed for genomic alterations had response, which suggested homologous recombination deficiency. No significant differences were observed between response rates for high versus low scores. Numerically, cnLOH+L, LST and HDR scores were higher in patients with response to treatment compared to those without response. Median overall survival was 13.4 months from the beginning of platinum rechallenge and no difference in survival according to scores was observed. Among the clinical pathologic factors, family history of breast or ovarian cancer or personal history of breast cancer was associated to higher response rate to platinum rechallenge. Conclusions: In conclusion,HRD scores showed to be potential markers of response to platinum rechallenge in the platinum resistant setting. Further studies are necessary to clarify the best cutoffs for each score, the impact of tumor heterogeneity and the analysis of tumor samples in the moment of treatment. Positive family history of cancer is a clinical factor predictvie of platinum rechallenge response.

scholarly journals Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yan Rong ◽  
Li Li
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Data ◽  
First Line ◽  
Clinical Value ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Line Chemotherapy ◽  
Sensitive Group

Abstract Objectives To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer. Method HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS. Results Sixteen patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p< 0.0001, p< 0.0001) as well as CA125 after 1st cycle chemotherapy (p< 0.0001, p< 0.0001). Conclusions Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.

scholarly journals Pembrolizumab in Combination with Bevacizumab and Oral Cyclophosphamide in Heavily Pretreated Platinum-Resistant Ovarian Cancer

2021 ◽  
Author(s):  
Angeliki Andrikopoulou ◽  
Michalis Liontos ◽  
Efthymia Skafida ◽  
Konstantinos Koutsoukos ◽  
Kleoniki Apostolidou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Disease Stage ◽  
Oral Cyclophosphamide ◽  
First Line ◽  
Platinum Resistant ◽  
Heavily Pretreated

Abstract Background: Immune checkpoint inhibitors (ICIs) have been widely implemented in the treatment of solid tumors. Although epithelial ovarian carcinoma is considered as scarcely immunogenic, the presence of tumor-infiltrating T lymphocytes (TILs) in the ovarian tumor microenvironment (TME) could increase sensitivity to immune checkpoint inhibitors (ICIs). Combinations of ICIs with chemotherapy, anti-VEGF compounds and PARP inhibitors are under evaluation in ovarian cancer. Recently, a Phase II study evaluated the efficacy of Pembrolizumab in Combination with bevacizumab and oral cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian cancer.Methods: Herein, we present a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pretreated ovarian cancer in the Oncology Unit of Alexandra University Hospital.Results: Median age at diagnosis was 54.5 years (SD; 8.9; range: 44–72). All patients were diagnosed with high-grade serous ovarian carcinoma (HGSC). Initial disease stage was FIGO IIIC (8/10; 80%), IIIB (1/10; 10%) and IIC (1/10; 10%)). Patients were heavily pretreated with a median of 6 (range: 4–9) prior lines of systemic therapy. All patients have experienced disease progression on first-line platinum-based chemotherapy and median PFS to first-line treatment was 20.1 months (95%CI; 11.4 – 28.7). Patients received a median of 4 cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 2-11). ORR was 20% (2/10) with two patients achieving partial response (PR) and two patients achieving stable disease (SD) while disease control rate (DCR) was 40% (4/10). Median PFS was 2.7 months (95%; 0.6 – 4.8) and 6-month PFS rate 20%. Conclusions: Though our data reflect a small population, we here demonstrate that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in platinum-resistant recurrent ovarian carcinoma. This novel combination provides a promising alternative in heavily pretreated patients that have otherwise limited treatment options.

scholarly journals Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Vera L. Silva ◽  
Jayeta Saxena ◽  
Francesco Nicolini ◽  
Joseph I. Hoare ◽  
Stephen Metcalf ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Damage Tolerance ◽  
Tumour Response ◽  
In Vivo Model ◽  
High Grade ◽  
Dna Damage Tolerance ◽  
Platinum Sensitivity ◽  
Platinum Resistant ◽  
Mechanistic Investigation

AbstractHigh-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine’s predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.

scholarly journals Inflammatory indexes as predictive factors for platinum sensitivity and as prognostic factors in recurrent epithelial ovarian cancer patients: a MITO24 retrospective study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alberto Farolfi ◽  
Emanuela Scarpi ◽  
Filippo Greco ◽  
Alice Bergamini ◽  
Lucia Longo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Prognostic Factors ◽  
Epithelial Ovarian Cancer ◽  
Predictive Factor ◽  
Second Line ◽  
Independent Predictive Factor ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Bevacizumab Treatment

Abstract Neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII) are prognostic factors in epithelial ovarian cancer (EOC). Their predictive value for platinum-sensitivity and their role in recurrent EOC are unknown. A total of 375 EOC patients were retrospectively analyzed. The correlation between baseline NLR and SII, and platinum-free interval (PFI) according to first line bevacizumab treatment were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Subsequently NLR and SII calculated before second line treatment initiation were evaluated to identify a potential correlation with progression-free survival (PFS) and overall survival (OS) in platinum-sensitive and in platinum-resistant population. In multivariate analysis, NLR ≥ 3 is an independent predictive factor for PFI at 6 months in the chemotherapy group (OR = 2.77, 95% CI 1.38–5.56, p = 0.004), not in bevacizumab treated patients. After having adjusted for ECOG performance status, histology, ascites, bevacizumab treatment at second line and BRCA status, NLR ≥ 3 and SII ≥ 730 are significantly associated with worse OS in platinum-sensitive (HR = 2.69, 95% CI 1.60–4.53, p = 0.002; HR = 2.11, 95% CI 1.29–3.43, p = 0.003, respectively), not in platinum-resistant EOC patients. Low NLR is an independent predictive factor for platinum-sensitivity in patients treated without bevacizumab. NLR and SII are prognostic factors in recurrent platinum-sensitive EOC patients.

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