Progression-free Survival In Ovarian Cancer Research Articles

ITGA7 loss drives the differentiation of adipose-derived mesenchymal stem cells to cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) represent a major cellular component of the tumor (pre-)metastatic niche and play an essential role in omental dissemination of ovarian cancer. The omentum is rich in adipose, and adipose-derived mesenchymal stem cells (ADSCs) have been identified as a source of CAFs. However, the molecular events driving the phenotype shift of ADSCs remain largely unexplored. In this research, we focus on integrins, transmembrane receptors that have been widely involved in cellular plasticity. We found that integrin α7(ITGA7) was the only member of the integrin family that positively correlated with both overall survival and progression-free survival in ovarian cancer through GEPIA2. The immunohistochemistry signal of ITGA7 was apparent in the tumor stroma, and a lower omental ITGA7 level was associated with metastasis. Primary ADSCs were isolated from the omentum of patients with ovarian cancer and identified by cellular morphology, biomarkers, and multilineage differentiation. The conditional medium of ovarian cancer cells induced ITGA7 expression decrease and phenotypic changes in ADSCs. Downregulation of ITGA7 in primary omental ADSCs led to decrease in stemness properties and emerge of characteristic morphology and biomarkers of CAFs. Moreover, the conditioned medium of ADSCs with ITGA7 depletion exhibited enhanced abilities to improve the migration and invasion of ovarian cancer cells in vitro. Overall, these findings indicate that loss of ITGA7 may induce the differentiation of ADSCs to CAFs that contribute to a tumor-supportive niche.

Prognostic value of neutrophil-to-lymphocyte ratio and fibrinogen levels in ovarian cancer

BACKGROUND High neutrophil-to-lymphocyte ratio (NLR) and fibrinogen levels have been associated with mortality in several malignancies. However, the studies on the association between NLR or fibrinogen levels and ovarian cancer prognosis are inconsistent. This study aimed to investigate the prognostic roles of NLR and fibrinogen in ovarian cancer.
 METHODS A systematic search of electronic databases was performed to analyze studies on the association of pre-treatment NLR and fibrinogen levels with overall survival (OS) and progression-free survival (PFS) among patients with ovarian cancer. The hazard ratio (HR) and corresponding 95% confidence intervals [CIs] were analyzed. All statistical analyses were done using RevMan version 5.4 (Cochrane, United Kingdom).
 RESULTS A total of 7,312 patients from 27 studies were included. The median cut-off for high NLR was 3.6 for OS among 17 studies and 3.23 for PFS among 11 studies reporting an NLR HR. The median cut-off for fibrinogen levels was 4.0 in 9 studies reporting fibrinogen levels HR. High NLR was associated with lower OS (HR 1.35, 95% CI 1.18 to 1.55, p<0.0001, I2 = 76%) and PFS (HR 1.35, 95% CI 1.14 to 1.60, p = 0.0005, I2 = 71%). High fibrinogen levels were associated with lower OS (HR 1.44, 95% CI 1.14 to 1.82, p = 0.002, I2 = 81%) and PFS (HR 1.34, 95% CI 1.17 to 1.55, p<0.0001, I2 = 15%). This association occurred in all ovarian cancer types.
 CONCLUSIONS High pre-treatment NLR and plasma fibrinogen levels were related to poor OS and PFS in ovarian cancer.

The Plasticity of Circulating Tumor Cells in Ovarian Cancer During Platinum-containing Chemotherapy.

Circulating Tumor Cells (CTCs) are a potential source of metastases and relapses. The data on molecular characteristics of Ovarian Cancer (OC) CTCs are limited. This study aims to assess the TGFβ, CXCL2, VEGFA and ERCC1 expressions in two OC CTC subpopulations before and during chemotherapy (CT), and their relation to clinical characteristics. Two CTCs subpopulations (EpCAM+CK18+E-cadherin+; EpCAM+CK18+Vimentin+) were enriched using immunomagnetic separation before treatment and after 3 cycles of platinumcontaining CT. The expression of mRNA was assessed using RT-qPCR. The study included 31 I-IV stage OC patients. During CT, TGFβ levels increased in both fractions (p=0.054) compared with the initial levels. ERCC1 expression in E-cadherin+ CTCs was higher during neoadjuvant than adjuvant CT (p=0.004). CXCL2 level in E-cadherin+ CTCs increased (p=0.038) during neoadjuvant CT compared with the initial. TGF-β expression in vimentin+ CTCs during CT was negatively correlated to disease stage (p=0.003). Principal component analysis before CT revealed a component combining VEGFA, TGFβ, CXCL2, and a component with ERCC1 and VEGFA; during CT, component 1 contained ERCC1 and VEGFA, and component 2 - TGFβ and CXCL2 in both fractions. Increased ERCC1 expression in E-cadherin+ CTCs during CT was associated with decreased Progression-Free Survival (PFS) (HR 1.11 (95% CI 1.03-1.21, p=0.009) in multivariate analysis. EpCAM+ OC CTCs are phenotypically heterogeneous, which may reflect variability in their metastatic potential. CT changes the molecular characteristics of CTCs. Expression of TGFβ in EpCAM+ CTCs increases during CT. High ERCC1 expression in EpCAM+CK18+E-cadherin+ CTCs during CT is associated with decreased PFS in OC.

Multiple genetic variants predict the progression-free survival of bevacizumab plus chemotherapy in advanced ovarian cancer: A retrospective study.

Bevacizumab (BV) plus chemotherapy is broadly used in advanced ovarian cancer (OC). However, the efficacy of BV-based regimens for advanced OC patients is not satisfactory. Therefore, it is urgent to explore the predictive genetic biomarkers for BV.Tumor tissues from advanced OC patients receiving BV-based regimens were analyzed with a 150-gene targeted panel for next generation sequencing. The associations between gene alterations or clinicopathology features and progression-free survival (PFS) were analyzed by Kaplan–Meier curves or Cox regression. The association of the genetic alteration in potential predictive genes and expressions of 11 vascular endothelial growth factor-related genes were analyzed in The Cancer Genome Atlas cohort using 292 OC cases.Sixty two Chinese advanced OC patients treated with BV-based therapy were included. The median PFS of was 6.9 months, and objective response rate was 14.5%. In multivariate Cox regression analysis, the status of endothelial growth factor receptor (EGFR) (hazard ratio = 6.39, 95% confidence interval [CI] 2.25–18.13, P < .001) and human epidermal growth factor receptor 2 (HER2) (hazard ratio = 3.58, 95% CI 1.27–10.08, P = .016) were significantly correlated with PFS. MYC Proto-Oncogene amplification seemed to have a positive trend (hazard ratio = 0.21, 95% CI 0.05–1.02, P = .052). Moreover, EGFR and HER2 alterations were not prognostic factors of overall survival for OC in The Cancer Genome Atlas OC cohort. The vascular endothelial growth factor-related signature analysis indicated vascular endothelial factor A expression was upregulated with EGFR alterations (P = .034) which may be involved in BV resistance, and HER2 alterations were associated with hypoxia inducible factor 1 subunit alpha overexpression significantly (P = .029).EGFR or HER2 alterations are negative predictors of PFS for OC patient treated with BV plus chemotherapy. Therefore, the clinicians may consider to use alternative regimens such as anti-EGFR or anti-HER2 targeted therapy instead of BV-based regimens on these patients when standard care fail.

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors

BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with...

GAB2 and GAB3 are expressed in a tumor stage-, grade- and histotype-dependent manner and are associated with shorter progression-free survival in ovarian cancer.

Ovarian cancer is the most lethal gynecological malignancy and molecular mechanisms of its progression and metastasis are not completely understood. Some members of GAB (GRB2-associated binding) protein family have been reported to be involved in tumor cell proliferation and metastasis in various cancer types. In the present study, we analyzed the expression of GAB proteins (GAB1, GAB2 and GAB3) in ovarian cancer compared to normal ovarian tissue, in terms of tumor stage, tumor grade and histological type. Differential expression analyses performed in R programming environment using multiple transcriptome datasets (n = 1449) showed that GAB1 expression is decreased in ovarian cancer independently of tumor stage, grade and histotype. Unlike GAB1, expression of GAB2 and GAB3 are increased from early stage to late stage and from low grade to high grade in epithelial ovarian cancer. GAB2 and GAB3 also showed histotype-dependent expression. GAB3 was computed as a top gene whose expression most significantly changed between tumor cells from primary tumor, metastases and ascites. High expression of GAB2 and GAB3 was shown to be associated with shorter progression-free survival in ovarian cancer. This study shows that GAB2 and GAB3 can be important regulators of tumor progression and metastasis in ovarian cancer.

EZH2/H3K27Me3 and phosphorylated EZH2 predict chemotherapy response and prognosis in ovarian cancer.

BackgroundEZH2 acts as an oncogene through canonical pathway EZH2/H3K27Me3 and uncanonical pathway pAkt1/pS21EZH2 in many solid tumors including ovarian cancer. However, the clinical value of EZH2/H3K27Me3 and pAkt1/pS21EZH2 remain unclear. In the current study, we aim to investigate the correlation between these two pathways to clinical-pathological parameters and prognosis.MethodsEZH2, H3K27Me3, pAkt1 and pS21EZH2 expression were evaluated by tissue micro-array and immunohistochemistry in a cohort of ovarian cancer patients. The results were analyzed based on clinical characteristics and survival outcomes.ResultsEZH2, H3K27Me3, pAkt1 and pS21EZH2 were universally expressed in ovarian cancer specimens with a positive expression rate of 81.54% (53/65), 88.89% (48/54), 63.07% (41/65) and 75.38% (49/65). EZH2-pS21EZH2 (Spearman r = 0.580, P < 0.0001) and pS21EZH2-pAkt1 (Spearman r = 0.546, P < 0.0001) were closely correlated while EZH2- H3K27Me3 were less closely correlated (Spearman r = 0.307, P = 0.002). Low pS21EZH2 associated with better chemotherapy response (OR = 0.184; 95% CI [0.052–0.647], P = 0.008) according to logistic regression with an area under the curve of 0.789 (specificity 89.36%, sensitivity 68.42%) by ROC analysis and predicted improved progression-free survival (HR = 0.453; 95% CI [0.229–0.895], P = 0.023) as indicated by multivariate cox regression. A combination of EZH2low/H3K27Me3low status predicted better chemotherapy response (OR = 0.110; 95% CI [0.013–0.906], P = 0.040) and better progression-free survival (HR = 0.388; 95% CI [0.164–0.917], P = 0.031). The results suggested that EZH2/H3K27Me3 and pEZH2 predicted chemotherapy response and progression-free survival in ovarian cancer.

Comparison of PARPis with Angiogenesis Inhibitors and Chemotherapy for Maintenance in Ovarian Cancer: A Network Meta-Analysis.

Seventy-five percent of ovarian cancer would relapse within 18-28months after platinum-base chemotherapy. Evidence suggests that maintenance chemotherapy is effective in prolonging remission. Recent target therapies such as poly(ADP-ribose) polymerase inhibitors (PARPis) and angiogenesis inhibitors (AIs) are known to ease burden and recurrence of ovarian cancer. There is limited data for head-to-head comparison of PARPis, AIs, and chemotherapeutic agents (CTAs) as maintenance treatment. This network meta-analysis thus assessed the effectiveness and toxicity of these three maintenance therapies in patients with ovarian cancer. We searched relevant sources (PubMed, EMBASE) to identify randomized controlled trials assessing efficacy and safety of maintenance therapy in patients with ovarian cancer. Primary outcome was progression-free survival (PFS) as assessed by blinded review; safety and tolerability were secondary outcomes. A network meta-analysis to compare three drug classes was performed using statistical software R. We included 24 trials (11,366 patients) assessing efficacy and safety of PARPis (n = 4), AIs (n = 12), and CTAs (n = 8). PARPis [hazard ratio (HR) 0.64; 95% credible intervals (CrI) 0.55-0.73] and AIs (HR 0.87; 95% CrI 0.81-0.93) showed significant improvement in PFS compared to placebo but not CTA (HR 1.00; 95% CrI 0.86-1.15). PARPis showed significant improvement in PFS compared to AIs (HR 0.73; 95% CrI 0.63-0.86) and CTA (HR 0.64; 95% CrI 0.52-0.78). Adverse events (AEs) leading to treatment discontinuation and dose reduction were lower in PARPis [incidence rate ratio (IRR) 0.60; CrI 0.31-1.18 and IRR 0.73, 95% CrI 0.50-1.06, respectively] compared to AIs, but the differences were not significant. PARPi as maintenance treatment improved PFS in ovarian cancer and was relatively safer in terms of implications caused by AEs when compared to AIs. This network meta-analysis provides valuable evidence and significant insights into treatment of ovarian cancer.

Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer

BackgroundHigh-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histologic type of ovarian cancer. To date, there are no reliable biomarkers to effectively predict patient prognosis. Studies have demonstrated inflammation and tumor infiltrating lymphocytes (TILs) correlate with a bad and good prognosis, respectively. Here, we sought to evaluate systemic inflammation and TILs as early prognostic markers of survival. MethodsNeutrophil-to-lymphocyte ratio (NLR) and serum Lactate Dehydrogenase (LDH) were used as indicators of systemic inflammation. NLR, serum LDH, tumor infiltrating lymphocytes (TILs), PDL1 and quality of debulking surgery were evaluated as determinants of progression-free survival (PFS) and overall survival (OS) in a cohort of 128 HGSOC patients. ResultsInitial univariate analysis showed that systemic inflammation measures (NLR and serum LDH), debulking surgery, and intra-epithelial TILs have a significant impact on both PFS and OS. After adjustment for several variables, multivariate analyses confirmed intraepithelial CD4+ T-cells, systemic inflammation measures, PDL1 and debulking surgery as determinants of better OS and PFS. ConclusionsSystemic inflammation and TILs are early determinants of OS in HGSOC. Other variables such as the quality of debulking surgery and PDL1 also improve survival of patients. Regarding TIL sub-populations, intraepithelial CD4+ cells are associated to an increase in both PFS and OS. We also confirmed previous reports that demonstrate intraepithelial CD8+ cells correlate with an increase on PFS in ovarian cancer. A combined score using systemic inflammation and TILs may be of prognostic value for HGSOC patients.

Significant overall survival improvement in proliferative subtype ovarian cancer patients receiving bevacizumab.

5520Background: We previously demonstrated that bevacizumab may differentially improve ovarian cancer progression-free survival (PFS) depending on TCGA molecular subtypes. Despite recent progress i...

Perirenal Adiposity is Associated With Lower Progression-Free Survival From Ovarian Cancer.

Abdominal obesity is linked with a higher risk of developing ovarian cancer. However, the link between abdominal obesity and survival after diagnosis of ovarian cancer is unknown. The purpose of this study was to determine the impact of abdominal obesity on progression-free survival in patients with ovarian cancer. Among 258 patients, visceral and subcutaneous adipose tissue volume, along with perirenal adipose tissue thickness (a visceral adiposity proxy measure) was retrospectively measured from abdominal computed tomography (CT) scans obtained within 6 months of ovarian cancer diagnosis. Progression-free survival was computed using the Kaplan-Meier method and log-rank tests. Univariate and multivariate Cox proportional hazards analysis was used to determine relationships between measures of abdominal obesity and clinical variables in relation to progression-free survival. Patients with perirenal adipose tissue thickness greater than 5 mm(median) had lower rates of progression-free survival at 5 years compared with patients with perirenal adipose tissue thickness less than 5 mm (45.6% vs 53.8%, respectively). Perirenal adipose tissue thickness less than 5 mm was associated with lower rates of progression-free survival on multivariate analysis (hazard ratio = 1.37; 95% confidence interval, 1.03-1.82). There was no correlation with other metrics of abdominal adiposity on progression-free survival in univariate or multivariate analysis. Our data suggest that perirenal adipose, but not body mass index, visceral, or subcutaneous fat volume that were measured within 6 months from diagnosis, is associated with lower rates of progression-free survival in ovarian cancer.

Prognostic Role of Neutrophil to Lymphocyte Ratio in Ovarian Cancer: A Meta-Analysis

Objective:The aim of the study was to investigate the prognostic role of neutrophil to lymphocyte ratio in ovarian cancer. Growing number of articles reported the relationship between neutrophil to lymphocyte ratio and prognosis in ovarian cancer, but the results remains inconclusive. The meta-analysis was conducted to analyze the association of pretreatment neutrophil to lymphocyte ratio with overall survival and progression-free survival.Methods:We performed a systematic literature research of PubMed, EMBASE, Medline, and Cochrane library for relevant studies up to October 8, 2017. The quality of included studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. The hazard ratio and corresponding 95% confidence intervals were calculated. We checked the heterogeneity by the Q test and Higgins I-squared statistic. Begg funnel plot and Egger linear regression test were also applied for ascertain publication bias. All of the statistical analyses were performed using STATA version 12.0.Results:A total of 12 studies with 4046 patients were included in our study. The results indicated that depressed neutrophil to lymphocyte ratio was significantly correlated with higher overall survival (hazard ratio = 1.409, 95% confidence intervals = 1.112-1.786, P = .005) and progression-free survival (hazard ratio = 1.523, 95% confidence intervals = 1.187-1.955, P = .001) in ovarian cancer. Subgroup analysis by ethnicity of overall survival and progression-free survival showed that the prognostic effect of neutrophil to lymphocyte ratio was found both in Asians and Caucasians.Conclusion:Patients with depressed neutrophil to lymphocyte ratio had a higher overall survival and progression-free survival in ovarian cancer. This meta-analysis provided neutrophil to lymphocyte ratio as an available predictor of overall survival and progression-free survival for patients with ovarian cancer.

Identification of long non-coding RNA signature for paclitaxel-resistant patients with advanced ovarian cancer.

Ovarian cancer is the most lethal gynecologic malignancy, characterized by late diagnosis, frequent relapse, and easy development of chemoresistance. Recent studies suggest that lncRNAs are involved in ovarian cancer onset and progression, as well as the resistance in paclitaxel-containing chemotherapy. However, the genome-wide expression pattern and associated functional implications of lncRNAs in paclitaxel-resistant ovarian cancer cells remain undetermined. In the present study, we identified a panel of lncRNAs aberrantly expressed in both paclitaxel resistant ovarian cancer tissues and cell lines, including XR_948297, XR_947831, XR_938728, XR_938392, NR_103801, NR_073113, and NR_036503. Moreover, the seven-lncRNA signature showed a relatively high predictive accuracy of chemoresistance with an area under the ROC curve (AUC) of 0.93, and was associated with progression-free survival inovarian cancer patients (HR=2.05, p=0.015). Our function prediction demonstrated that the seven-lncRNA signature was positively correlated with a cluster containing 129 genes enriched in insulin secretion-related pathway. Our findings suggest that the seven-lncRNA signature may be utilized as potent biomarkers for predicting chemoresistance for ovarian cancer patients with paclitaxel-containing chemotherapy.

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer

ObjectiveTo investigate the association of tumor glucocorticoid receptor (GR) expression and patient outcome in ovarian cancer. MethodsGR expression was evaluated by immunohistochemistry using tissue microarrays of specimens from 481 patients with ovarian cancer and 4 patients with benign conditions. Low GR expression was defined as an intensity of 0 or 1+ and high GR as 2+ or 3+ in >1% of tumor cells. Analyses were performed to evaluate the relationship of GR expression with clinical characteristics, progression-free survival (PFS) and overall survival (OS). ResultsGR protein was highly expressed in 133 of 341 (39.0%) tumors from patients who underwent upfront cytoreduction surgery followed by adjuvant chemotherapy. High GR expression was more common in serous tumors (p<0.001), high grade tumors (p<0.001), and advanced stage tumors (p=0.037). Median PFS was significantly decreased in cases with high GR (20.4months) compared to those with low GR (36.0months, HR=1.66, 95% CI 1.29–2.14, p<0.001). GR remained an independent prognostic factor for PFS in multivariate analysis. OS was not associated with GR status. ConclusionsThese data suggest that high GR expression correlates with poor prognosis and support the hypothesis that modulating GR activity in combination with chemotherapy may improve outcomes.

Expression of zinc finger E-box-binding homeobox factor 1 in epithelial ovarian cancer: A clinicopathological analysis of 238 patients.

A growing body of evidence indicates that aberrant activation of epithelial-to-mesenchymal transition (EMT) plays a key role in tumor cell invasion and metastasis. Zinc finger E-box-binding homeobox factor 1 (ZEB1), as a crucial mediator of EMT, contributes to the malignant progression of various epithelial tumors. To determine whether ZEB1 is involved in the progression of ovarian cancer, we immunohistochemically evaluated the expression of ZEB1 in 238 cases of epithelial ovarian cancer (EOC) and analyzed its associations with clinicopathological parameters. Positive expression of ZEB1 was observed in 32.8% (78/238) of EOCs and it was found to be significantly associated with advanced tumor stage (P=0.001). The survival analysis indicated that the expression of ZEB1 was associated with a poor 5-year progression-free survival (PFS) (P=0.021). A similar tendency was also observed between the expression of ZEB1 and 5-year overall survival, although it did not reach statistical significance (P=0.118). Moreover, the multivariate analysis demonstrated that ZEB1 expression was an independent risk factor for 5-year PFS in ovarian cancer. Taken together, our data provide evidence that ZEB1 may play a crucial role in promoting aggressive ovarian carcinoma progression. Therefore, ZEB1 may serve as an effectively predictive marker and a potential target for therapeutic intervention in EOC.

A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer

Complex focal chromosomal rearrangements in cancer genomes, also called “firestorms”, can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER−) cases. We found only a modest correlation between CAAI and the overall rate of genomic instability (GII) and number of breakpoints (r = 0.27 and r = 0.42, p < 0.001). Breast cancer specific survival (BCSS), overall survival (OS) and ovarian cancer progression free survival (PFS) were used as clinical end points in Cox proportional hazard model survival analyses. CAAI positive breast cancers (43%) had higher mortality: hazard ratio (HR) of 1.94 (95%CI, 1.62–2.32) for BCSS, and of 1.49 (95%CI, 1.30–1.71) for OS. Representations of the 70-gene and the 21-gene predictors were compared with CAAI in multivariable models and CAAI was independently significant with a Cox adjusted HR of 1.56 (95%CI, 1.23–1.99) for ER+ and 1.55 (95%CI, 1.11–2.18) for ER− disease. None of the expression-based predictors were prognostic in the ER− subset. We found that a model including CAAI and the two expression-based prognostic signatures outperformed a model including the 21-gene and 70-gene signatures but excluding CAAI. Inclusion of CAAI in the clinical prognostication tool PREDICT significantly improved its performance. CAAI positive ovarian cancers (52%) also had worse prognosis: HRs of 1.3 (95%CI, 1.1–1.7) for PFS and 1.3 (95%CI, 1.1–1.6) for OS. This study validates CAAI as an independent predictor of survival in both ER+ and ER− breast cancer and reveals a significant prognostic value for CAAI in high-grade serous ovarian cancer.

Metformin, at Concentrations Corresponding to the Treatment of Diabetes, Potentiates the Cytotoxic Effects of Carboplatin in Cultures of Ovarian Cancer Cells

The use of the type 2 diabetics drug metformin has been correlated with enhanced progression-free survival in ovarian cancer. The literature has speculated that this enhancement is due to the high concentration of metformin directly causing cancer cell death. However, this explanation does not fit with clinical data reporting that the women exposed to constant micromolar concentrations of metformin, as present in the treatment of diabetes, respond better to chemotherapy. Herein, our aim was to examine whether micromolar concentrations of metformin alone could bring about cancer cell death and whether micromolar metformin could increase the cytotoxic effect of commonly used chemotherapies in A2780 and SKOV3 cell lines and primary cultured cancer cells isolated from the peritoneal fluid of patients with advanced ovarian cancer. Our results in cell lines demonstrate that no significant loss of viability or change in cell cycle was observed with micromolar metformin alone; however, we observed cytotoxicity with micromolar metformin in combination with chemotherapy at concentrations where the chemotherapy alone produced no loss in viability. We demonstrate that previous exposure and maintenance of metformin in conjunction with carboplatin produces a synergistic enhancement in cytotoxicity of A2780 and SKOV3 cells (55% and 43%, respectively). Furthermore, in 5 (44%) of the 11 ovarian cancer primary cultures, micromolar metformin improved the cytotoxic response to carboplatin but not paclitaxel or doxorubicin. In conclusion, we present data that support the need for a clinical study to evaluate the adjuvant maintenance or prescription of currently approved doses of metformin during the chemotherapeutic treatment of ovarian cancer.

Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer

Background:Ovarian cancer is frequently advanced at presentation when treatment is rarely curative. Response to first-line platinum-based chemotherapy significantly influences survival, but clinical response is unpredictable and is frequently limited by the development of drug-resistant disease.Methods:We used qRT–PCR analysis to assess intertumour differences in the expression of fibroblast growth factor 1 (FGF1) and additional candidate genes in human ovarian tumours (n=187), and correlated individuality in gene expression with tumour histology, chemotherapy response and survival. We used MTT assays to assess platinum chemosensitivity in drug-sensitive and drug-resistant ovarian cell lines.Results:Marked intertumour differences in gene expression were observed, with each tumour having a unique gene expression profile. Nine genes, including FGF1 (P=1.7 × 10−5) and FGFR2 (P=0.003), were differentially expressed in serous and nonserous tumours. MDM2 (P=0.032) and ERBB2 (P=0.064) expression was increased in platinum-sensitive patients, and FGF1 (adjusted log-rank test P=0.006), FGFR2 (P=0.04) and PDRFRB expression (P=0.037) significantly inversely influenced progression-free survival. Stable FGF1 gene knockdown in platinum-resistant A2780DPP cells re-sensitised cells to both cisplatin and carboplatin.Conclusion:We show for the first time that FGF1 is differentially expressed in high-grade serous ovarian tumours, and that individuality in FGF1 expression significantly influences progression-free survival and response to platinum-based chemotherapy.

Adding bevacizumab to chemotherapy improves progression-free survival in ovarian cancer

British Journal of Hospital MedicineVol. 73, No. 7 Clinical NewsAdding bevacizumab to chemotherapy improves progression-free survival in ovarian cancerSusan MayorSusan MayorSearch for more papers by this authorSusan MayorPublished Online:16 Aug 2013https://doi.org/10.12968/hmed.2012.73.7.371aAboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article FiguresReferencesRelatedDetails 1 July 2012Volume 73Issue 7ISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 16 August 2013 Published in print 1 July 2012 Information© MA Healthcare LimitedPDF download