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.

Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17543-e17543
Author(s):  
Xiaoxiang Chen ◽  
Jing Ni ◽  
Xia Xu ◽  
Wenwen Guo ◽  
Xianzhong Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Regression Analysis ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Real World ◽  
Cox Regression ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Homologous Recombination Deficiency ◽  
Polymerase Inhibitors

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.

Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease.

1996 ◽  
Vol 14 (9) ◽  
pp. 2546-2551 ◽  
Author(s):  
E Bajetta ◽  
A Di Leo ◽  
L Biganzoli ◽  
L Mariani ◽  
F Cappuzzo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Confidence Interval ◽  
Cancer Patients ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Ca 125 ◽  
Resistant Disease ◽  
Platinum Resistant ◽  
Exact Confidence Interval

PURPOSE The aim of the study was to evaluate the activity of vinorelbine (VNLB) in a population of advanced ovarian cancer patients, with particular attention to defining its role in platinum-resistant disease. PATIENTS AND METHODS Thirty-three patients were recruited and treated with VNLB 25 mg/m2 intravenously (IV) weekly. the median age was 53 years, performance status 0 to 2, and number of previous chemotherapy regimens two (range, one to five). Twenty-four patients were platinum-resistant; the remaining nine either were platinum-sensitive (four cases) or had undetermined sensitivity (five cases). RESULTS The mean delivered dose-intensity of VNLB was 67% of the planned level, because 60% of the cycles were delayed due to neutropenia or anemia. Four partial responses (PRs) and one complete response (CR) were observed, for an overall response rate of 15% (95% exact confidence interval, 5.1% to 31.9%). All the responses occurred in the subgroup of 24 platinum-resistant cases, in whom the response rate was 21% (95% exact confidence interval, 7.1% to 42.1%). Seven patients became stabilized on VNLB, and 27% of the cases showed a reduction in serum cancer antigen 125 (CA 125) levels. G3/G4 side effects consisted of neutropenia, anemia, and worsening of preexisting peripheral neuropathy. No treatment-related deaths occurred. CONCLUSION VNLB led to a 21% response rate in the population of heavily pretreated and platinum-resistant ovarian cancer patients. Further studies of VNLB alone or in combination with taxanes are warranted in patients with less pretreatment.

Inhibition of Wnt signaling as therapeutic option in platinum-resistant ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17050-e17050 ◽  
Author(s):  
Fabian Trillsch ◽  
Valentina Preinfalk ◽  
Martina Rahmeh ◽  
Marianne Vogel ◽  
Bastian Czogalla ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Membrane ◽  
Wnt Signaling ◽  
Cancer Patients ◽  
Metabolic Activity ◽  
Therapeutic Option ◽  
Ovarian Cancer Cell Line ◽  
Ovarian Cancer Cells ◽  
Platinum Resistant ◽  
Platinum Based Chemotherapy

e17050 Background: New therapeutic approaches for platinum-resistant ovarian cancer patients are urgently needed. In this context, Wnt signaling appears to be a promising target so that inhibition of this pathway in platinum-resistant cell lines was aim of the present study. Methods: The ovarian cancer cell line A2780 and its platinum-resistant clone A2780cis were treated with different concentrations of Wnt singaling inhibitors SB216761, XAV939, and triptolides. Metabolic activity and cell viability was estimated by MTT cell proliferation assays. Immunohistochemistry for ß-Catenin visualized activity of the Wnt pathway. Results: MTT proliferation tests revealed an impaired proliferation following treatment with all three agents. While triptolides already led to significantly reduced metabolic activity after 48h, this effect was seen for SB216761 and XAV939 not before 72h. Immunohistochemistry for ß-Catenin confirmed inhibition of Wnt signaling. Following XAV939 treatment of A2780cis, ß-Catenin signals shifted from the nucleus towards the cell membrane. Conclusions: Re-sensitizing platinum-resistant ovarian cancer cells for platinum-based chemotherapy by inhibition of Wnt signaling seems to be mechanism visualized by the translocation of ß-Catenin from the nucleus towards the cell membrane. In this context, a dose-dependent response was noted for XAV939. Inhibition of Wnt Signaling appears to be a prospective therapeutic approach for platinum-resistant ovarian cancer patients.

scholarly journals 767P Retrospective analysis of the impact of bevacizumab dose-intensity on the survival of platinum-resistant ovarian cancer patients

2021 ◽  
Vol 32 ◽  
pp. S750-S751
Author(s):  
J.A. Bahena ◽  
L. Cetina-Pérez ◽  
D. Gallardo-Rincón ◽  
P. Cabrera-Galeana ◽  
G.C. Alamilla Garcia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Retrospective Analysis ◽  
Cancer Patients ◽  
Dose Intensity ◽  
Platinum Resistant ◽  
The Impact

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 Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252665
Author(s):  
Christine S. Walsh ◽  
Mitchell Kamrava ◽  
Andre Rogatko ◽  
Sungjin Kim ◽  
Andrew Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Interim Analysis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Free Survival ◽  
Platinum Resistant ◽  
Duration Of Response

Objective To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. Methods Patients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3–6 and as maintenance monotherapy in cycles 7–34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. Results An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. Conclusions The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.

scholarly journals Distinct genomic profiles are associated with treatment response and survival in ovarian cancer

2020 ◽  
Author(s):  
Chris J. de Witte ◽  
Joachim Kutzera ◽  
Arne van Hoeck ◽  
Luan Nguyen ◽  
Ingrid A. Boere ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Treatment Response ◽  
Survival Data ◽  
Genome Stability ◽  
Recurrent Disease ◽  
Single Nucleotide Variants ◽  
Homologous Recombination Deficiency ◽  
Resistant Disease ◽  
Platinum Based Chemotherapy

AbstractThe majority of patients with ovarian cancer ultimately develop recurrent chemotherapy resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy and time to recurrent disease. Here, we integrated clinical treatment, treatment response and survival data with whole genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability and duplications. The clusters exhibited distinct response rates and survival probabilities which according to our analysis could potentially be improved by genome-informed treatment stratification.

scholarly journals Impact of prior cancer history on the survival of patients with larynx cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kaiquan Zhu ◽  
Renyu Lin ◽  
Ziheng Zhang ◽  
Huanqi Chen ◽  
Xingwang Rao
Keyword(s):  
Overall Survival ◽  
Cancer Patients ◽  
Protective Factor ◽  
Larynx Cancer ◽  
Prior History ◽  
Second Primary ◽  
Cancer History ◽  
History Of ◽  
The Impact ◽  
History Of Cancer

Abstract Background Patients with a prior history of cancer are commonly excluded from clinical trial. Increasing number of studies implied that a prior cancer did not adversely affect the clinical outcome among various types of cancer patients. However, the impact of prior cancer on survival of larynx cancer patients remains largely unknown. The aim of this study was to evaluate the prevalence of prior cancer and assess its impact on survival of patients diagnosed with larynx cancer. Methods Patients with larynx cancer as the first or second primary malignancy diagnosed from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. Kaplan-Meier method, multivariate Cox proportional hazard model, and multivariate competing risk model were performed for survival analysis. Results A total of 24,812 eligible patients with larynx cancer were included in the study, wherein a total of 2436 patients (9.8%) had a prior history of cancer. Prostate (36%), lung and bronchus (10%), urinary bladder (7%), and breast (6%) were the most common types of prior cancer. A prior cancer history served as a risk factor for overall survival (AHR =1.30; 95% CI [1.21–1.41]; P < 0.001) but a protective factor for cancer-specific mortality (AHR = 0.83; 95% CI [0.72–0.94]; P = 0.004) in comparison with those without prior cancer. The subgroup analysis showed that a prior history of cancer adversely affected overall survival of patients with larynx cancer in most subgroups stratified by timing and types of prior cancer, as well as by different clinicopathologic features. Conclusion Our study indicated an adverse survival impact of a prior history of cancer on patients with larynx cancer. Except for a few particular prior cancer, clinical trials should be considered prudently for laryngeal cancer patients with prior cancers.

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