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Rodriguez-Antona C.,Hereditary Endocrine Cancer Group | Rodriguez-Antona C.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Garcia-Donas J.,Centro Integral Oncologico Clara Campal
Pharmacogenomics | Year: 2012

The development of specific angiogenesis inhibitors has drastically improved renal cancer treatment in recent years. Currently, four VEGF receptor inhibitors (sorafenib, sunitinib, pazopanib and axitinib), one anti-VEGF monoclonal antibody (bevacizumab) and two inhibitors of the mTOR pathway (temsirolimus and everolimus) have been approved to treat renal cell carcinoma (RCC), and several other molecules are under investigation. However, lack of response to antiangiogenic drugs and adverse drug reactions leading to treatment suspension are critical clinical problems that need to be solved. Because antiangiogenic drugs act on nonmalignant endothelial cells, the genetic background of the patient may play a crucial role determining the efficacy of these drugs. This article focuses on the identification of polymorphisms associated with antiangiogenic drugs outcome in RCC patients. It reviews and summarizes our current knowledge on this area and discusses future strategies to identify new biomarkers that could be used to personalize RCC management. © 2012 Future Medicine Ltd.

Diaz-Padilla I.,University of Toronto | Diaz-Padilla I.,Centro Integral Oncologico Clara Campal | Amir E.,University of Toronto | Marsh S.,University of Alberta | And 2 more authors.
Gynecologic Oncology | Year: 2012

Purpose: Numerous studies have explored the potential role of genetic polymorphisms as predictive or prognostic biomarkers in gynecologic malignancies. A systematic review for all eligible polymorphisms has not yet been reported. The aim of this study was to summarize the current status of the field and provide direction for future research. Design: We searched literature databases (MEDLINE, EMBASE, Cochrane) from 2006 to April 2011 to identify studies evaluating the association between gene polymorphisms and clinical outcome in ovarian, endometrial, cervical, or vulvar cancer. The main outcome measures were overall survival (OS) and progression-free survival (PFS). Studies reporting relationships between polymorphisms and toxicity were also included. Results: Sixty two studies met the inclusion criteria. The median sample size was 140. Most of the included studies (n = 50, 81%) were conducted in ovarian cancer patients. Almost a third assessed potential predictive associations between gene polymorphism and outcome in ovarian cancer. The most commonly evaluated genes were ERCC1, VEGF, ABCB1 (MDR), and GSTP1. Most studies (n = 44, 71%) were observational case-series. Only four studies (6%) included a validation arm and patient population ethnicity was explicitly stated only in 27% of included studies. Conclusion: No consistent association between any gene polymorphism and clinical outcome in gynecological cancers has been found across studies. There is incomplete adherence to the REMARK guidelines and inadequate methodology reporting in most studies. Moving forward, analysis of large trial-based clinical samples; adherence to the highest methodological standards, and focus on validation analyses are necessary to identify clinically useful pharmacogenomic biomarkers of outcome. © 2011 Elsevier Inc. All rights reserved.

Lluch A.,Hospital Clinico Universitario Of Valencia | Alvarez I.,Hospital Universitario Of Donostia | Munoz M.,Hospital Clinic | Segui M.T.,Corporacio Sanitaria Parc Tauli | And 2 more authors.
Critical Reviews in Oncology/Hematology | Year: 2014

In spite of recent advances in the treatment of metastatic breast cancer, this disease remains essentially incurable. Anthracyclines and taxanes have been widely demonstrated to be the most active cytotoxic drugs for the treatment of breast cancer. Paclitaxel and docetaxel are both hydrophobic drugs that need to be administered with detergent-like substances as solvents. In contrast, nanoparticle albumin-bound (nab) paclitaxel uses the natural characteristics of albumin to reversibly bind paclitaxel, transport it across endothelial cells and concentrate the active ingredient within the tumor. Several trials have demonstrated that nab-paclitaxel results in superior efficacy, with more complete responses, prolonged time to recurrence and survival, than paclitaxel and docetaxel in MBC. As second-line treatment, the novel formulation has almost doubled overall response rate, increased time to progression and overall survival in comparison with paclitaxel. Due to these results, to date nab-paclitaxel stands out as a promising treatment of metastatic breast cancer. © 2013.

Calvo E.,Centro Integral Oncologico Clara Campal | Grunwald V.,Hannover Medical School | Bellmunt J.,University of the Sea
European Journal of Cancer | Year: 2014

The mammalian target of rapamycin inhibitor (mTORI) everolimus and the tyrosine kinase inhibitor (TKI) axitinib are the only two post-first-line treatment options for metastatic renal cell carcinoma (mRCC) licensed at present. Extrapolation of robust phase III studies suggests that median progression-free survival (PFS) is similar between agents. This presents a dilemma for the physician planning treatment for their patients with mRCC: should they be treated with a TKI-mTORI or a TKI-TKI sequence? The lack of direct comparison between axitinib and everolimus leaves the clinician without clear guidance on the optimal choice in second-line therapy. In phase III studies, both post first-line everolimus and axitinib have been shown to delay disease progression; however, cumulative toxicity with sequential use of TKIs may result in more treatment interruptions or dose reductions or increased likelihood of adverse events. While everolimus exerts a tolerability advantage, axitinib is associated with higher response rate and a similar PFS benefit. Proven superiority cannot be used to guide treatment sequence selection in mRCC. Instead, therapeutic planning requires us to take a long-term view of our patient's treatment that includes quality of life and a balance between symptom control, adverse event management and avoidance of unnecessary drug interruptions or dose reductions. In the absence of curative therapies, sustaining a patient's quality of life is a major goal throughout the course of treatment and choosing a second-line agent that is able to adequately achieve this by limiting adverse events should be a priority. © 2014 Elsevier Ltd. All rights reserved.

Von Hoff D.D.,Translational Genomics Research Institute | Von Hoff D.D.,Virginia per Cancer Center | Ervin T.,Cancer Specialists | Arena F.P.,Arena Oncology Associates | And 20 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel- gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. Copyright © 2013 Massachusetts Medical Society.

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