Andrés Redondo

Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.

BACKGROUND Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. FUNDING Amgen.

Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain)

Reactive Oxygen Species (ROS) result from cell metabolism as well as from extracellular processes. ROS exert some functions necessary for cell homeostasis maintenance. When produced in excess they play a role in the causation of cancer. ROS mediated lipid peroxides are of critical importance because they participate in chain reactions that amplify damage to biomolecules including DNA. DNA attack gives rise to mutations that may involve tumor suppressor genes or oncogenes, and this is an oncogenic mechanism. On the other hand, ROS production is a mechanism shared by many chemotherapeutic drugs due to their implication in apoptosis control. The ROS mediated cell responses depend on the duration and intensity of the cells exposing to the increased ROS environment. Thus the statusredox is of great importance for oncogenetic process activation and it is also implicated in tumor susceptibility to specific chemotherapeutic drugs. Phospholipid Hydroperoxide Glutathione Peroxidase (PH-GPx) is an antioxidant enzyme that is able to directly reduce lipid peroxides even when they are bound to cellular membranes. This article will review the relevance of oxidative stress, particularly of lipid peroxidation, in cell response with special focus in carcinogenesis and cancer therapy that suggests PH-GPx as a potentially important enzyme involved in the control of this processes.

Breast Cancer Prognosis Determined by Gene Expression Profiling: A Quantitative Reverse Transcriptase Polymerase Chain Reaction Study

PURPOSE We sought to reproduce with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) the results obtained with a 70-gene expression profile that has been described previously in breast cancer. PATIENTS AND METHODS Frozen breast cancer samples from patients who were operated on were used to isolate tumor RNA. Ninety-six patients with stage I to II disease were included. Median age was 57 years (range, 27 to 80 years). Forty-eight patients had lymph node-negative and 48 lymph node-positive disease. qRT-PCR amplifications were performed and the results were correlated with clinical data. RESULTS After a minimum follow-up of 5 years, 25 patients had a relapse. The gene profile divided patients into two groups with poor and good prognosis. Significant differences with regard to grade of differentiation, size and hormone receptors were seen between the two groups. The gene profile was significantly associated with relapse-free survival and overall survival in the whole group of 96 patients. Multivariate analysis showed that only lymph node status and gene profile were significantly correlated to overall survival. CONCLUSION qRT-PCR reproduced the results obtained with microarrays for a prognostic gene profile in women with early-stage breast cancer.

Molecular characterization of ovarian cancer by gene-expression profiling.

Ovarian cancer is the second most common gynecologic malignancy, and represents the fifth most common cause of cancer death in women in the United States. The age at diagnosis, extent of disease, success of primary surgery, and the histopathological features of the tumor are important prognostic markers. Epithelial ovarian carcinomas are classified into four major categories: serous, mucinous, endometrioid, and clear cell. Each subtypes of ovarian carcinoma are known to have different clinical characteristics and biological behaviour and response to chemotherapy. Molecular studies have supported for the notion that the different histological types of ovarian cancer likely represent histopathologically, genetically, and biologically distinct diseases. Microarray-based profiling technologies have provided an opportunity to simultaneously examine the relationship between thousands of genes and clinical phenotypes. In this review, we will summarise the current gene-expression profiles that address the classification of ovarian cancer into molecular subtypes with different outcomes.

Aurora kinases as prognostic biomarkers in ovarian carcinoma.

We investigated the expression of Aurora kinases A and B by immunohistochemistry in 68 ovarian carcinomas to analyze their prognostic value. The amplification of AURKA gene by fluorescence in situ hybridization was also assessed. Overall, 58.8% and 85.3% of ovarian carcinomas showed expression of Aurora A and B, respectively. Amplification of AURKA was found in 27.6% of cases examined. Tumors with Aurora A expression showed a lower rate of recurrence than those tumors without Aurora A expression (65% versus 91.7%, P = .019). In the univariate analysis, patients with Aurora A and B expression showed an increased progression-free survival (P = .023 and .06, respectively, log-rank test) and overall survival (P = .03 and .02, respectively, log-rank test). The multivariate analysis adjusted to optimal surgery by Cox proportional hazards regression showed Aurora A expression as an independent prognostic factor for progression-free survival (P = .03) and overall survival (P = .02). In conclusion, Aurora A expression seems to have a prognostic value in ovarian carcinoma.

Targeting the endothelin axis in prostate carcinoma

Prostate cancer is the most common malignancy in men in Western countries. Until the last decade, the main available therapeutic options were based on hormonal therapy. For castration-refractory prostate carcinoma, from 2004, the combination of chemotherapy with docetaxel and prednisone has shown to improve survival in this subset of patients. Many agents have been tested either alone or in combination with this standard therapy, trying to find synergistic effects between drugs, and to target specific pathways that influence tumor growth, invasiveness, angiogenesis, and the development of distant metastasis. Endothelin antagonists have been recently studied, as they can get involved in many of these oncogenic pathways, and results are encouraging; nevertheless, the right setting to use them, whether to use them in monotherapy or in combination with other agents, and if they really improve the survival of our patients, are questions that remain to be addressed. In this review, we summarize the role of endothelins in tumoral biology and specifically in prostate carcinoma natural history, and the results obtained in the clinical trials involving this new therapeutic group.

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2☆☆☆☆☆☆

PURPOSE Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). PATIENTS AND METHODS Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. RESULTS Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (14.5 versus 12.3months; HR, 0.72; 95% CI, 0.55-0.93; P=0.011) in patients with ascites at baseline (n=295). In the intent-to-treat population, trebananib significantly improved median PFS-2 compared with placebo (12.5 versus 10.9months; HR, 0.85; 95% CI, 0.74-0.98; P=0.024). The incidence and type of adverse events in this updated analysis was consistent with that described in the primary analysis; no new safety signals were detected. CONCLUSIONS OS was not significantly longer in the intent-to-treat population, although there was an improvement in OS in patients with ascites receiving trebananib. PFS-2 confirmed that the PFS benefit associated with trebananib was maintained through the second disease progression independent of the choice of subsequent therapy.

An 8-gene qRT-PCR-based gene expression score that has prognostic value in early breast cancer

BackgroundGene expression profiling may improve prognostic accuracy in patients with early breast cancer. Our objective was to demonstrate that it is possible to develop a simple molecular signature to predict distant relapse.MethodsWe included 153 patients with stage I-II hormonal receptor-positive breast cancer. RNA was isolated from formalin-fixed paraffin-embedded samples and qRT-PCR amplification of 83 genes was performed with gene expression assays. The genes we analyzed were those included in the 70-Gene Signature, the Recurrence Score and the Two-Gene Index. The association among gene expression, clinical variables and distant metastasis-free survival was analyzed using Cox regression models.ResultsAn 8-gene prognostic score was defined. Distant metastasis-free survival at 5 years was 97% for patients defined as low-risk by the prognostic score versus 60% for patients defined as high-risk. The 8-gene score remained a significant factor in multivariate analysis and its performance was similar to that of two validated gene profiles: the 70-Gene Signature and the Recurrence Score. The validity of the signature was verified in independent cohorts obtained from the GEO database.ConclusionsThis study identifies a simple gene expression score that complements histopathological prognostic factors in breast cancer, and can be determined in paraffin-embedded samples.

Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx) expression is downregulated in poorly differentiated breast invasive ductal carcinoma

Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx) is the only known enzyme able to reduce lipid peroxides bound to cell membranes. Moreover it has been involved in apoptosis and can influence intracellular signaling. To investigate the possible relationship between PHGPx and human cancer we have quantified PHGPx expression levels by real-time quantitative PCR and immunohistochemistry in tissue samples of human breast invasive ductal carcinoma from 34 patients compared with their own controls of benign breast tissue. PHGPx expression levels were compared with the clinical and pathological data of these patients. The results showed that PHGPx expression levels are downregulated in poorly differentiated (grade 3) breast invasive ductal carcinoma (P = 0.0043). PHGPx expression levels decreased gradually with tumor grade from grade 1 to grade 3.We also found a downregulation of PHGPx in cases that showed p53 accumulation compared with cases without p53 immunostaining (P = 0.0011). PHGPx was also downregulated in cases without progesterone receptors (PR) immunostaining compared with cases with PR immunostaining (P = 0.0165). Grade 3, p53 immunostaining and absence of PR immunostaining are poor prognostic factors. These results suggest that PHGPx downregulation could be related with a poorer prognosis in breast invasive ductal carcinoma.

SEOM guidelines for cervical cancer

Cervical cancer (CC) is the second most common cancer worldwide, strongly linked to high-risk human papilloma virus infection. Although screening programs have led to a relevant reduction in the incidence and mortality due to CC in developed countries, it is still an important cause of mortality in undeveloped countries. Clinical stage is still the most relevant prognostic factor. In early stages, the primary treatment is surgery or radiotherapy, whereas concomitant chemo-radiotherapy is the conventional approach in locally advanced stages. In the setting of recurrent or metastatic CC, for the first time ever, the combination of chemotherapy plus bevacizumab prolongs the overall survival beyond 12 months. Therefore, this regimen is considered by most of the oncologist a new standard of care for metastatic/recurrent CC.