M A Climent

Instituto Valenciano de Oncologia, Valenza, Valencia, Spain

Are you M A Climent?

Claim your profile

Publications (56)298.66 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years. Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required.
    10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR.
    International journal of clinical oncology. 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Among the many papers were presented at the 36th San Antonio Breast Cancer Symposium in 2013; the most important −mainly oral presentations−are summarized below. Notable for their clinical applicability were two studies on the management of the primary tumor in metastatic breast cancer and the PRIME II trial evaluating the impact of omitting adjuvant radiotherapy in elderly patients. The expected data from the BETH trial, evaluating the benefit of adding bevacizumab in the adjuvant treatment of HER2-positive tumors, were also reported, and interesting information was presented on the efficacy of carboplatin in triple-negative breast cancer. From the point of view of tumor biology, the organizers wanted to provide a platform for the potential role of immunity in the prognosis of breast cancer, and mutations in the estrogen receptor gene, which are emerging as a new mechanism of acquisition of hormone resistance.
    Revista de Senología y Patología Mamaria. 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access programmes (EAPs) were established worldwide, allowing access to cabazitaxel before its commercial availability. Preliminary results of the European CUP/EAP, focusing on the elderly population (aged ⩾70 years), are reported. Patients and methods Enrolled patients with progressive mCRPC received cabazitaxel (25 mg/m2) plus 10 mg oral prednisone/prednisolone every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. Safety was analysed by age group (<70, [70–75] and ⩾75 years). The influence of selected variables on grade ⩾3 neutropenia and/or neutropenic complications was analysed in multivariate analysis. Results 746 men were enrolled (<70 years, n = 421; [70–75], n = 180, ⩾75 years, n = 145). Number of cabazitaxel cycles, dose reductions for any cause, dose delays possibly related to cabazitaxel adverse events, and tolerability were similar in the three age groups. Prophylactic granulocyte colony-stimulating factor (G-CSF) use was more common in men aged ⩾70 years. In multivariate analysis, age ⩾75 years, treatment cycle 1, and neutrophil count <4000/mm3 before cabazitaxel injection were associated with increased risk of developing grade ⩾3 neutropenia and/or neutropenic complications. Prophylactic use of G-CSF at a given cycle significantly reduced this risk by 30% (odds ratio 0.70, p = 0.04). Conclusion The results suggest that cabazitaxel has a manageable safety profile in everyday clinical practice. Prophylactic use of G-CSF, especially at cycle 1 and in men aged ⩾75 years, is important and improves tolerability in senior adults treated with cabazitaxel.
    European journal of cancer (Oxford, England: 1990) 04/2014; · 4.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5·4 years (IQR 3·1-6·8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0·64 (95% CI 0·44-0·93; two-sided log-rank p=0·016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0·29 (95% CI 0·11-0·78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease. F Hoffmann-La Roche.
    The Lancet Oncology 03/2014; · 25.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
    PLoS ONE 01/2014; 9(1):e86263. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL).
    British Journal of Cancer 06/2013; 109(1):121-130. · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC). The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib. High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023). We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.
    Annals of Oncology 06/2013; · 7.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone metastases are a common complication of advanced prostate cancer and while they are less common in non-prostate genitourinary (GU) malignances, they have been reported in up to 35 % of patients with advanced renal cell carcinoma and bladder cancer. Furthermore, they may occur in more than two-thirds of those patients with bladder cancer who develop distant metastases. In the absence of bone-targeted therapies, approximately 50 % of all patients with metastatic bone disease from GU cancers experience at least one skeletal-related event within their lifetime. Zoledronic acid is a bisphosphonate that has been shown to delay or prevent the development of skeletal complications in patients with bone metastases and reduce bone pain in these patients. Furthermore, zoledronic acid has also demonstrated the ability to prevent osteopenia, which may occur with the prolonged use of some pharmacological interventions in patients with cancer.
    Clinical and Translational Oncology 04/2013; · 1.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus.Objective To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety.Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (oncologist and urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease.Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG).Conclusions With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.ResumenContextoEn el manejo integral del cáncer de próstata avanzado resistente a la castración siguen existiendo incertidumbres y controversias a pesar de la existencia de numerosas guías de práctica clínica basadas en la evidencia, internacionalmente consensuadas.ObjetivoElaborar un documento en el que se revise el manejo de controversias en el cáncer de próstata avanzado resistente a la castración con recomendaciones desde su definición hasta el manejo de maniobras hormonales y el tratamiento de primera y segunda línea con nuevos fármacos como cabacitaxel y abiraterona, así como el abordaje multidisciplinar de la patología con el objetivo de buscar la alternativa más eficiente, el mejor momento de actuar y la mayor seguridad.Adquisición de la EvidenciaSe realizaron 2 reuniones de un grupo de expertos multidisciplinares implicados en el manejo de esta enfermedad (urólogos y oncólogos) donde se pusieron en común el análisis bibliográfico de artículos originales y se consensuó este documento de recomendaciones sobre el cáncer de próstata resistente a la castración, revisando e intentando dar respuesta a las actuales controversias de la enfermedad.Síntesis de la EvidenciaEste documento está avalado por las principales Sociedades Científicas y grupos de trabajo implicados en el manejo actual de los tumores genitourinarios: la Asociación Española de Urología (AEU), el Grupo de Urología Oncológica (GUO) y el Grupo Español de Oncología Genitourinaria (SOGUG).ConclusionesCon la adaptación e implementación de este Documento de Recomendaciones a la práctica clínica se dispone, por primera vez, de una verdadera hoja de ruta de calidad, eficiencia y seguridad del manejo de los pacientes con cáncer de próstata avanzado resistente a la castración.
    Actas urologicas españolas 12/2012; 36(10):569–577. · 1.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Aromatase inhibitors (AIs) may promote ovarian function recovery (OFR). True incidence, predictors and impact on the outcome of OFR are unknown.Patients and methodsWe carried out a prospective study to assess ovarian function in estrogen receptor (ER)-positive BC patients on tamoxifen who had at least 2 years of chemotherapy-induced amenorrhea (CIA) and postmenopausal E2 levels. Patients switched to exemestane and underwent a series of investigations including vaginal ultrasound, antimullerian hormone, follicle stimulating hormone (FSH), and E2. E2 measurements were made using a clinical assay (direct) and a highly sensitive (indirect) immunoassay for comparison.ResultsBoth E2 assays (indirect versus direct) showed a similar incidence of OFR 32% (95% CI 19.5-44.5) versus 30% (95% CI 17.7-42.3) and median time to OFR 5.4 months (95% CI 1.2-9.6) versus 6.0 months (95% CI 4.8-7.1).On multivariate analysis, the mean age at the start of exemestane treatment was the only marker associated with probability of OFR (OR: 0.44, 0.24-0.78; P = 0.006). According to a receiver operating characteristic (ROC) analysis, age <48 years predicted for OFR (sensitivity: 59%; 1-specificity: 17%; AUC: 0.796; P = 0.001). Patients with OFR had higher mean E2 levels (43.6 versus 5.76 pmol/l; P = 0.001) and a reduced disease-free survival [DFS; HR 9.3 (95% CI 3.3-48.0; P = 0.04)] than those without it.Conclusion Even with a clinical and biochemical profile compatible with menopause, switching from tamoxifen to an AI should be avoided in patients <48 with CIA.
    Annals of Oncology 10/2012; · 7.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome.
    CANCER AND METASTASIS REVIEW 06/2012; 31 Suppl 1:S3-9. · 9.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy. To evaluate the efficacy and safety of everolimus in elderly patients (those ≥ 65 and ≥ 70 yr of age) enrolled in RECORD-1. The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n=416). Everolimus 10mg once daily (n=277) or placebo (n=139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity. Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety. In RECORD-1, 36.8% of patients were ≥ 65 yr and 17.5% were ≥ 70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation. Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.
    European Urology 04/2012; 61(4):826-33. · 10.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PCa) is the most common cancer in the male population in Western countries, second to skin cancer. Hormonal therapy allows long-lasting and effective control of cancer-related symptoms in advanced stages; however, in almost all patients with metastatic PCa the disease will progress when it becomes castration-resistant (CRPC). Chemotherapy with docetaxel was a turning point in CRPC, as, for the first time, it resulted in an increased survival time in comparison with mitoxantrone and prednisone. Combination therapy with docetaxel and prednisone is the first-line treatment of choice. Once the cancer has progressed, there is no clear alternative, although some new agents have shown promise in the treatment of this type of cancer. This review will provide an overview of the current status of CRPC, including clinical status, prognosis, firstline treatment and new second-line treatment options.
    Clinical and Translational Oncology 03/2012; 14(3):169-76. · 1.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer is the most prevalent urogenital malignancy. However, despite initial disease control using androgen deprivation, most of patients eventually develop progressive disease that is resistant to further hormone manipulation. For these patients with castration-resistant prostate cancer (CRPC), and particularly patients with metastatic disease, options have been limited, and prognosis is grim. However, as newer regimens and agents become available, higher rates of objective and biochemical response are being achieved, providing renewed hope for the management of these patients. With the aim of facilitating the treatment of these patients, the Spanish Oncology Genitourinary Group (SOGUG) has issued a series of the recommendations which have been collected in this review. Each recommendation is accompanied by the appropriate level of evidence and grade of recommendation on the basis of the characteristics of the data available.
    Critical reviews in oncology/hematology 01/2012; 83(3):341-52. · 5.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus.Objective To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety.Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (Oncologist and Urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease.Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG).Conclusions With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.
    Actas urologicas españolas 01/2012; 36(10):569–577. · 1.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hormonal therapy allows effective control of cancer-related symptoms in advanced stages. However, the disease will progress in almost all these metastatic prostate cancer patient until becoming resistant to androgen suppression. The emergence of new drugs will most probably have open up new expectations regarding the treatment of this cancer. The aim of the present review has been to provide an overview of the current status of castration-resistant prostate cancer and to share the high expectations created with the new treatments. Evidence was obtained from multidisciplinary meetings with the participation of urologists and oncologists, where they pooled the analysis of original articles in the literature and defined the content of the article. Chemotherapy with docetaxel was a turning point in castration-resistant prostate cancer after the failure of hormonal therapy failure. For the first time, it achieved increased survival time in comparison with mitoxantrone and prednisone. Combination therapy with docetaxel and prednisone is the first-line choice treatment. Once the cancer has progressed, there is no clear alternative, although some novel agents have created expectations for the treatment of this type of cancer. The range of therapeutic options for castration-resistant prostate cancer has increased dramatically with the arrival of new drugs. At present, cabazitaxel, and in the near future, abiraterone, have been found to be effective drugs in second-line treatment after progression to docetaxel, increasing survival by 2-4 months and reducing risk of death by 30-35%.
    Actas urologicas españolas 12/2011; 36(6):367-74. · 1.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The field of urothelial carcinoma has shown considerable advances in terms of diagnosis, staging, and treatment. The increasing knowledge of molecular pathways and genes involved in the occurrence of this tumor has encouraged the search for new, more effective and less toxic therapies, and has prompted the design and development of clinical trials. However, the speed at which results are published makes it difficult for clinicians to cover the vast amount of information available. Moreover, in clinical practice some gaps remain concerning treatment options for patients who have progressed after first-line cisplatin-based combinations, who cannot tolerate cisplatin-based chemotherapy, or who have received platinum-based neoadjuvant or adjuvant therapy, and thus cannot be offered this option on disease progression. The purpose of this review is to issue a series of recommendations on the optimal management of early and advanced urothelial carcinoma based on current evidence and the available updated guidelines.
    Cancer Treatment Reviews 11/2011; 38(5):431-41. · 6.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. In our observational, prospective study we enrolled previously untreated adults (≥ 18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75-7·30; p(unadjusted)=0·00049, p(adjusted)=0·0079) and rs307821 (3·31, 1·64-6·68; p(unadjusted)=0·00085, p(adjusted)=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67-8·41; p(unadjusted)=0·0014, p(adjusted)=0·022). No other SNPs were associated with sunitinib response or toxicity. Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. Pfizer.
    The Lancet Oncology 11/2011; 12(12):1143-50. · 25.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metastatic renal cell carcinoma is resistant to conventional treatment with chemotherapy. Recently the use of molecular-targeted therapies with multikinase inhibitors has been recommended as first-choice therapy because they inhibit cell proliferation and tumour angiogenesis. Sorafenib is a well tolerated tyrosine kinase inhibitor that initially demonstrated efficacy in the treatment of patients with metastatic RCC who progressed after immunotherapy. Expanded-access studies in Europe and North America showed the safety and efficacy of sorafenib in special populations such as elderly, renal failure and cerebral metastases, as well as patients with no prior therapy. No cross-resistance has been suggested in non-randomized trials when used in second line treatment after other targeted therapies. Ongoing clinical trials will better define the role of sorafenib in first and second line either as monotherapy or in combination, as well as the best strategies for the sequential use of this drug.
    Critical reviews in oncology/hematology 03/2011; 80(2):314-22. · 5.27 Impact Factor