Microtubule-regulatory phosphoproteins and NER system are involved in platinum and paclitaxel-based chemotherapy resistance in ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5567-5567
Author(s):  
R. Nadal ◽  
M. L. Romero ◽  
B. Ojeda ◽  
A. Gallardo ◽  
M. Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Excision Repair ◽  
Chemotherapy Resistance ◽  
Stage Iv ◽  
Figo Stage ◽  
Differential Sensitivity ◽  
Repair System ◽  
Mrna Levels ◽  
Intrinsic Resistance ◽  
Time To Recurrence

5567 Background: The treatment of ovarian cancer is hindered by intrinsic resistance to platinum and paclitaxel-based chemotherapy (CT). Nucleotide excision repair system plays a central role in DNA repair and is related with resistance to platinum compounds. Excision repair cross-complementation 1 (ERCC1) and 3 (ERCC3) genes confer a differential sensitivity to CT. OP18/stathmin and mDIA are involved in regulation of microtubules dynamics and may represent a mechanism of resistance to paclitaxel. Both mechanisms have been recently investigated in ovarian cancer (OC). Methods: Formalin and paraffin-embedded tissues obtained from 33 patients with advanced OC were retrospectively collected to investigate ERCC1, ERCC3, OP18, and mDIA mRNA levels by quantitative RT- PCR. All patients received a median of 6 cycles platinum based CT in combination with taxanes. Median age was 62 years. Tumors were classified: 52% serous, 9% endometrioid, 27% clear cell, and 12% poorly differentiated carcinomas. FIGO stage: 4 (12%) stage II, 19 (58%) stage III, and 10 (30%) stage IV. 12 chemoresistant tumors (time to recurrence (TTR) < 6 months) and 21 chemosensitive tumors (TTR = 6 months) were analyzed. Median follow-up was 31 months. Results: An increase in mRNA levels was consistently observed in the chemoresistent group: 1.9-fold increased in ERCC1 and 1.6-fold increased in ERCC3. Both genes exhibited comparable expression levels. Statistically significant differences on ERCC1 and ERCC3 mRNA levels were encountered when chemoresistant and chemosensitive tumors were compared (p=0.01 and p= 0.03, respectively). Statistically differences on OP18 mRNA levels were found when chemoresistant and chemosensitive tumors were compared (p=0.05). No differences in mDIA mRNA levels were encountered. Conclusions: Our results suggest that determination of ERCC1-ERCC3 before chemotherapy is potentially useful to predict the effectiveness of platinum-based therapy. Microtubule drug resistance in OC may be associated with altered OP18/stathmin expression. Novel treatment approaches based on molecular markers could be useful predictors of response and could identify targets for therapeutic strategies. Further studies are required. No significant financial relationships to disclose.

scholarly journals The FIGO Stage IVA Versus IVB of Ovarian Cancer: Prognostic Value and Predictive Value for Neoadjuvant Chemotherapy

2018 ◽  
Vol 28 (3) ◽  
pp. 453-458 ◽  
Author(s):  
Parvin Tajik ◽  
Roelien van de Vrie ◽  
Mohammad H. Zafarmand ◽  
Corneel Coens ◽  
Marrije R. Buist ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Neoadjuvant Chemotherapy ◽  
Epithelial Ovarian Cancer ◽  
Prognostic Value ◽  
Median Overall Survival ◽  
Stage Iv ◽  
Figo Stage ◽  
Figo Staging ◽  
Stage Ivb

ObjectiveThe revised version of the International Federation of Gynaecology and Obstetrics (FIGO) staging system (2014) for epithelial ovarian cancer includes a number of changes. One of these is the division of stage IV into 2 subgroups. Data on the prognostic and predictive significance of this classification are scarce. The effect of neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) in relation to the subclassification of FIGO stage IV is also unknown.MethodsWe used data of the EORTC 55971 trial, in which 670 patients with previous stage IIIC or IV epithelial ovarian cancer were randomly assigned to PDS or NACT; 160 patients had previous stage IV. Information on previous FIGO staging and presence of pleural effusion with positive cytology were used to classify tumors as either stage IVA or IVB. We tested the association between stage IVA/IVB and survival to evaluate the prognostic value and interactions between stage, treatment, and survival to evaluate the predictive performance.ResultsAmong the 160 participants with previous stage IV disease, 103 (64%) were categorized as stage IVA and 57 (36%) as stage IVB tumors. Median overall survival was 24 months in FIGO stage IVA and 31 months in stage IVB patients (P = 0.044). Stage IVB patients treated with NACT had 9 months longer median overall survival compared with IVB patients undergoing PDS (P = 0.025), whereas in IVA patients, no significant difference was observed (24 vs 26 months, P = 0.48).ConclusionsThe reclassification of FIGO stage IV into stage IVA or IVB was not prognostic as expected. Compared with stage IVA patients, stage IVB patients have a better overall survival and may benefit more from NACT.

ERCC1 and RRM1 but not EGFR gene expression is predictive of shorter survival in advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10030-10030
Author(s):  
G. Selvaggi ◽  
P. Ceppi ◽  
M. Volante ◽  
S. Saviozzi ◽  
S. Novello ◽  
...  
Keyword(s):  
Gene Expression ◽  
Excision Repair ◽  
Growth Factor Receptor ◽  
Needle Aspiration ◽  
Differential Sensitivity ◽  
Mrna Levels ◽  
Female Ratio ◽  
Expression Levels ◽  
Egfr Expression ◽  
Formalin Fixed Paraffin Embedded

10030 Background: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) has been recently deeply investigated in NSCLC. Methods: We retrospectively collected 70 formalin-fixed paraffin-embedded (FFPE) bronchoscopic/fine needle aspiration biopsies of NSCLC to investigate the expression levels of ERCC1, RRM1 and EGFR by Real-Time PCR (Lord R et al. Clin Cancer Research 2002, 8:2286–91). Results were correlated with survival using the Kaplan-Meier method. Results: Sixty-one (87%) specimens were successfully amplified. Median age was 62 years (range 26–75), male/ female ratio 44/17, stage III/IV 20/41; 43 patients received cisplatin-based chemotherapy; overall median survival (MS) was 13.3 months over a median follow-up time of 45 months. ERCC1 expression level ranged from 0.70 to 15.12, RRM1 0.60–17.82. By adopting cut-off values according to median expression levels, we found a strong correlation between ERCC1 and RRM1 mRNA levels (r=0.410; p<0.001). MS in patients with low ERCC1 was significantly longer (16.9 vs 11.3 months, p<0.006) as well as in patients with low RRM1 (13.9 vs 10.9 months, p<0.03). Concomitant high expression levels of ERCC1 and RRM1 (n=26) are predictive of a worse outcome (13.9 vs 10.9 months, p<0.05). Among patients treated with cisplatin-based regimens, low ERCC1 levels were also predictive of a significantly longer MS (23.0 vs 11.6 months, p<0.002). A lower median ERCC1 level (3.2 vs 4.7) and a correlation with a better outcome were also observed in females vs males. No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression levels (range 0.5–85.8) and survival was found, even when different cut-off values were tested. Conclusions: This retrospective study further validates ERCC1 and RRM1 as good candidates genes to customize chemotherapy. Prospective studies based on the selection of patients according to genes expression levels are a research priority in early and advanced stages of NSCLC. [Table: see text]

Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5500-5500 ◽  
Author(s):  
Sean Kehoe ◽  
Jane Hook ◽  
Matthew Nankivell ◽  
Gordon C. Jayson ◽  
Henry Charles Kitchener ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Controlled Trial ◽  
Advanced Ovarian Cancer ◽  
Pelvic Mass ◽  
Stage Iv ◽  
Figo Stage ◽  
Phase Iii ◽  
Initial Surgery ◽  
Platinum Based Chemotherapy ◽  
Optimal Debulking

5500 Background: First line treatment of advanced ovarian cancer (OC) is accepted to be primary surgery (PS) followed by adjuvant platinum-based chemotherapy (P-CT). However, the EORTC55971 trial suggested neoadjuvant chemotherapy (NACT) is an alternative, showing increased optimal debulking rates and reduced surgical complications without detriment to survival. CHORUS (CRUK 07/009) is the 2nd phase III randomized controlled trial to investigate timing of initial surgery in OC. Methods: Patients (pts) with clinical FIGO stage III-IV OC (pelvic mass, extrapelvic metastases and CA125/CEA ratio >25) were randomized to standard treatment (PS followed by 6 cycles P-CT) or NACT (3 cycles P-CT either side of surgery). CHORUS was designed to demonstrate non-inferiority of NACT, excluding a 6% absolute detriment in 3yr survival from 50% expected with PS (1-sided alpha 10%). Primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), toxicity and quality of life. Results: 550 women (276 PS, 274 NACT) were randomized from 74 centres (72 UK, 2 NZ) between Mar 2004 and Aug 2010. Baseline characteristics were well balanced: median age 65yrs, median tumor size 80mm, 25% FIGO stage IV, 19% WHO PS 2. Median follow-up was 3yrs, 410 pts have died. Treatment data are summarized in the Table. 3yr survival in the control arm was 32%. Intention to treat analysis showed a median OS of 22.8 months for PS vs 24.5 months for NACT (hazard ratio (HR) 0.87 in favor of NACT, 80% CI 0.76 – 0.98) and median PFS of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). OS results represent a 5% absolute benefit in 3yr survival for NACT to 37% and the upper 80% CI allows us to exclude a survival benefit for PS. Conclusions: NACT was associated with increased optimal debulking, less early mortality and similar survival in this poor prognosis group. CHORUS results are consistent with EORTC55971 and strengthen evidence that NACT is a viable alternative to PS. Clinical trial information: ISRCTN74802813. [Table: see text]

Use of clinical classification software to differentiate good versus poor prognostic patients with ovarian cancer: A SEER-Medicare database analysis from the viera study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18069-e18069
Author(s):  
Gboyega Adeboyeje ◽  
Kaushal Desai ◽  
Shahed Iqbal ◽  
Jinghua He ◽  
Matthew J. Monberg
Keyword(s):  
Ovarian Cancer ◽  
Liver Disease ◽  
Stage Iv ◽  
Figo Stage ◽  
The United States ◽  
Baseline Period ◽  
Good Prognosis ◽  
Clinical Classification ◽  
Clinical Classification Software ◽  
Medicare Database

e18069 Background: Historically, recurrence in ovarian cancer (OC) following first-line (1L) chemotherapy (CT) occurs in up to 80% of patients within 2 years. The Clinical Classification Software (CCS) systematically classifies thousands of ICD-9 codes into a smaller number of clinically meaningful categories. We sought to use CCS and other routinely collected variables to differentiate the clinical and demographic profiles of patients with good prognosis (GP) versus poor prognosis (PP) in the United States (US). Methods: This was a retrospective cohort study of newly diagnosed (FIGO stage II - IV), treatment-naïve patients, ≥ 66 years, who received 4-10 cycles of platinum-based 1L CT between Jan 2009 - Dec 2015 using the SEER-Medicare database, a nationally representative cancer registry. Patient were assumed to have progressed to a subsequent line of therapy following a gap between consecutive CT cycles ≥ 63 days. Patients were classified as GP if alive ≥4 years with no further treatment following 1L CT; PP was defined as receipt of ≥2L CT within 12 months of initial 1L CT. Demographic and prognostic characteristics were assessed during a 6-month baseline period prior to initiation of 1L CT. We assessed clinically meaningful differences in baseline characteristics with absolute standardized differences (ASD) using a threshold of 0.1 (indicating negligible difference between two cohorts). Results: There were a total of 2,262 patients (mean age: 74.6 ±6.2 years) including 251 GP (11%) and 209 PP (9%) patients (table below). PP patients were significantly more likely to be older than 70 years, and present at stage IV, liver disease and ascites, and anemia at diagnosis. PP patients were also less likely to have primary debulking surgery. Conclusions: Approximately one tenth of OC patients received no further treatment 4 years after the initial treatment with contemporary standard of care. GP may be differentiated from PP on the basis of commonly used clinical characteristics such as stage and also specific comorbidities such as liver disease and ascites. [Table: see text]

scholarly journals Niraparib in ovarian cancer: results to date and clinical potential

2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Repair System ◽  
Gynaecological Malignancy ◽  
Platinum Based Chemotherapy ◽  
Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

scholarly journals Control of malignant ascites using HIPEC in 2 patients with ovarian cancer: A case-report

2020 ◽  
Author(s):  
Vladislav Nikulin ◽  
Amir Abdullaev ◽  
Mikhail Davydov ◽  
Alexey Rumyantsev ◽  
Vladislav Kirsanov ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Clinical Trials ◽  
Stage Iv ◽  
Figo Stage ◽  
Malignant Ascites ◽  
Investigational Treatment ◽  
Long Time ◽  
Platinum Refractory

Abstract Objective: to demonstrate an efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in management of malignant ascites (MA) in patients with platinum-refractory ovarian cancer (OC).Background: MA in OC patients can dramatically affect quality of life. HIPEC is an investigational treatment modality that can be effective in MA setting but evidence-based data supporting this method are lacking. Cases presentation: 2 women 50-year-old, FIGO stage IV and 60-year-old, FIGO stage IIIC presented at our center, both had recurrent MA. Patients were treated with HIPEC after platinum-refractory recurrence. The first one had total control of MA with no evidence of disease at the time of last follow-up examination. The 2nd had 9 months of disease control – a relatively long time considering her MA recurrence rate.Conclusions: HIPEC can be successfully used for MA management in selected patients with epithelial OC refractory to standard chemotherapy, however more data are needed from randomized clinical trials.

scholarly journals The capacity of the ovarian cancer tumor microenvironment to integrate inflammation signaling conveys a shorter disease-free interval

2020 ◽  
Author(s):  
Kimberly R. Jordan ◽  
Matthew J. Sikora ◽  
Jill E. Slansky ◽  
Angela Minic ◽  
Jennifer K Richer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Early Response ◽  
Mrna Levels ◽  
Inflammatory Signaling ◽  
Resistant Disease ◽  
Time To Recurrence ◽  
Before And After ◽  
Cancer Tumor ◽  
Induced Changes

ABSTRACTOvarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is typically effective, but most patients will develop chemo-resistant disease. Mechanisms driving clinical chemo-response and -resistance in ovarian cancer are not well understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant platinum/taxane-based chemotherapy (NACT). NACT offers a window to profile pre-versus post-therapy tumor specimens, which we used to identify chemotherapy-induced changes to the tumor microenvironment. We hypothesized changes in the immune microenvironment correlate with tumor chemo-response and disease progression. We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient n=6). We measured mRNA levels of 770 genes (NanoString), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in additional pre-NACT ascites samples (n=39) by multiplex ELISA. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multi-spectral immunohistochemistry. In NanoString analyses, transcriptional profiles segregated based on pre- and post-NACT status. The most upregulated gene post-NACT was IL6 (17.1-fold, adjusted p = 0.045). RPPA data were highly concordant with mRNA, consistent with elevated immune infiltration. Elevated IL-6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString, RPPA, and cytokine studies identified an activated inflammatory signaling network and induced IL6 and IER3 (Immediate Early Response 3) post-NACT, associated with poor chemo-response and decreased time to recurrence. Taken together, multi-omic profiling of ovarian tumor samples before and after NACT provides unique insight into chemo-induced changes to the tumor and microenvironment. We integrated transcriptional, proteomic, and cytokine data and identified a novel IL-6/IER3 signaling axis through increased inflammatory signaling which may drive ovarian cancer chemo-resistance.

scholarly journals A Practical Nomogram to Predict Early Death in Advanced Epithelial Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zixuan Song ◽  
Yangzi Zhou ◽  
Xue Bai ◽  
Dandan Zhang
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Stage Iv ◽  
Early Death ◽  
Premature Death ◽  
Figo Stage ◽  
Stage Iii ◽  
Internal Validation ◽  
Gynecological Malignancy ◽  
Clinical Pragmatism

Background: Ovarian cancer is a common gynecological malignancy, most of which is epithelial ovarian cancer (EOC). Advanced EOC is linked with a higher incidence of premature death. To date, no effective prognostic tools are available to evaluate the possibility of early death in patients with advanced EOC.Methods: Advanced (FIGO stage III and IV) EOC patients who were enrolled in the Surveillance, Epidemiology, and End Results database between 2004 and 2015 were regarded as subjects and studied. We aimed to construct a nomogram that can deliver early death prognosis in patients with advanced EOC by identifying crucial independent factors using univariate and multivariate logistic regression analyses to help deliver accurate prognoses.Results: In total, 13,403 patients with advanced EOC were included in this study. Three hundred ninety-seven out of a total of 9,379 FIGO stage III patients died early. There were 4,024 patients with FIGO stage IV, 414 of whom died early. Nomograms based on independent prognostic factors have the satisfactory predictive capability and clinical pragmatism. The internal validation feature of the nomogram demonstrated a high level of accuracy of the predicted death.Conclusions: By analyzing data from a large cohort, a clinically convenient nomogram was established to predict premature death in advanced EOC. This tool can aid clinicians in screening patients who are at higher risk for tailoring treatment plans.

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