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Cancer Pharmacogenomics.

February - March 2013


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TÍTULO / TITLE:  - Cancer pharmacogenomics: early promise, but concerted effort needed.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Science. 2013 Mar 29;339(6127):1563-6. doi: 10.1126/science.1234139.

            ●● Enlace al texto completo (gratuito o de pago) 1126/science.1234139


INSTITUCIÓN / INSTITUTION:  - Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC 27599, USA. hmcleod@unc.edu

RESUMEN / SUMMARY:  - The past decade has brought together substantial advances in human genome analysis and a maturation of understanding of tumor biology. Although there is much progress still to be made, there are now several prominent examples in which tumor-associated somatic mutations have been used to identify cellular signaling  pathways in tumors. This in turn has led to the development of targeted therapies, with somatic mutations serving as genomic predictors of tumor response and providing new leads for drug development. There is also a realization that germline DNA variants can help optimize cancer drug dosing and predict the susceptibility of patients to the adverse side effects of these drugs-knowledge that ultimately can be used to improve the benefit:risk ratio of cancer treatment for individual patients.




TÍTULO / TITLE:  - Promising biomarkers for predicting the outcomes of patients with KRAS wild-type  metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: A systematic review with meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2013 Mar 11. doi: 10.1002/ijc.28153.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28153

AUTORES / AUTHORS:  - Yang ZY; Wu XY; Huang YF; Di MY; Zheng DY; Chen JZ; Ding H; Mao C; Tang JL

INSTITUCIÓN / INSTITUTION:  - Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China; The Hong Kong Branch of The Chinese Cochrane Centre, The Chinese University of Hong Kong, Hong Kong, China.

RESUMEN / SUMMARY:  - KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs). However, many patients with KRAS wild-type tumors still do not respond to the treatment. We conducted a systematic review with meta-analysis to assess whether  BRAF mutations, PIK3CA mutations, and PTEN loss can predict the outcomes of patients with KRAS wild-type mCRC treated with anti-EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression-free survival (PFS), overall survival (OS), and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random-effects model. BRAF mutations, PIK3CA exon 20 mutations, and PTEN loss were all associated with shorter PFS (HR=2.59, 95% CI 1.67-4.03; HR=2.52, 95% CI 1.33-4.78; and HR=1.75, 95% CI 1.19-2.56, respectively), shorter OS (HR=2.74, 95% CI 1.79-4.19; HR=3.29, 95% CI 1.60-6.75;  and HR=1.85, 95% CI 1.30-2.64, respectively), and lower ORR (RD=-36%, 95% CI -44% ~ -28%; RD=-38%, 95% CI -51% ~ -24%; and RD=-41%, 95% CI -68% ~ -14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power  of combined multiple biomarkers as compared with one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations, and PTEN loss are  predictive of better outcomes in KRAS wild-type mCRC treated with anti-EGFR MoAbs. However, the quality of included studies varied, and some of the meta-analyses were limited by significant between-study heterogeneity. In the future, well-designed large randomized controlled trials conducted in KRAS wild-type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20  and PTEN status are essential to fully assess the clinical relevance of these biomarkers. © 2013 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - Breast cancer susceptibility gene 1 (BRCA1) predict clinical outcome in platinum- and toxal-based chemotherapy in non-small-cell lung cancer (NSCLC) patients: a system review and meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Exp Clin Cancer Res. 2013 Mar 15;32:15. doi: 10.1186/1756-9966-32-15.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1756-9966-32-15

AUTORES / AUTHORS:  - Yang Y; Xie Y; Xian L

INSTITUCIÓN / INSTITUTION:  - Department of Cardiothoracic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China. Xianlei59@163.com.

RESUMEN / SUMMARY:  - The recent studies have evaluated the relationship between BRCA1 expression and clinical outcome of chemotherapy (mainly focused on platinum-based and toxal-based treatment) in NSCLC patients, but the results were inconclusive and controversial. Our aim of this study was to evaluate this association by literature based system review and meta-analysis.PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) databases were used to retrieve the relevant articles. The interested outcome included objective response rate (ORR), overall survival (OS) and event-free survival (EFS). The pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) ware estimated.After specific inclusion and exclusion criteria, 23 studies fulfilled the criteria and  were included in our analysis. In 17 platinum-based studies, low/negative BRCA1 was in favor of better ORR (OR = 1.70, 95%CI = 1.32-2.18), longer OS and EFS (HR  = 1.58, 95%CI = 1.27-1.97, and HR = 1.60, 95%CI = 1.07-2.39 for OS and EFS, respectively). In 4 toxal-based chemotherapy studies, the patients with high/positive BRCA1 had better ORR (OR = 0.41, 95%CI = 0.26-0.64), OS and EFS were not evaluated as the insufficient data available.Overall, BRCA1 might be a useful biomarker to predict clinical outcome for personal chemotherapy in NSCLC patients in the future.




TÍTULO / TITLE:  - Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genet Med. 2013 Feb 21. doi: 10.1038/gim.2012.184.

            ●● Enlace al texto completo (gratuito o de pago) 1038/gim.2012.184

AUTORES / AUTHORS:  - Calonge N; Fisher NL; Berg AO; Campos-Outcalt D; Djulbegovic B; Ganiats TG; Haddow JE; Klein RD; Lyman DO; Offit K; Pauker SG; Piper M; Richards CS; Strickland OL; Tunis SR; Veenstra DL

INSTITUCIÓN / INSTITUTION:  - EGAPP Working Group Chair; Colorado Department of Public Health and Environment.

RESUMEN / SUMMARY:  - Summary of recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use  of KRAS mutation analysis to determine which patients are KRAS mutation positive  and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net  health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.The EWG found insufficient evidence to recommend  for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low. The EWG encourages further studies of the potential value of testing in patients with mCRC who were found to have tumors that are wild type (mutation negative) for KRAS to predict responsiveness to therapy.The EWG found insufficient evidence to recommend for or against testing for mutations in NRAS, or PIK3CA, and/or loss of expression of PTEN or AKT proteins. The level of certainty for this evidence was low. In the absence of supporting evidence, and with consideration of other contextual issues, the EWG discourages the use of these tests in guiding decisions on initiating anti-EGFR therapy with cetuximab or panitumumab unless further evidence supports improved clinical outcomes.Rationale: It has been suggested that patients with mCRC whose  tumors harbor certain mutations affecting EGFR pathway signaling are typically unresponsive to therapy with anti-EGFR antibodies (cetuximab and panitumumab). The EWG identified recent evidence reviews that have addressed this topic, and this recommendation statement is based on results of these reviews. In developing these recommendations the EWG considered evidence in the areas described below.Analytic validity: Although no research syntheses that have formally evaluated analytic validity of these tests were found, the EWG was able to draw the following conclusions from assessments included in the evidence reviews under consideration. There is adequate evidence that KRAS mutation analysis reliably and accurately detects common mutations (codons 12 and 13), whereas evidence was  inadequate for less frequent KRAS mutations (e.g., codon 61). There is also adequate evidence that testing for BRAF V600E accurately and reliably detects the mutation. For common mutations in NRAS, PIK3CA, and expression of PTEN AKT, there is adequate evidence of accurate and reliable detection. However, much less data  exist in support. Furthermore, in the specific context of mCRC, no evidence was found on the analytic validity of immunohistochemistry (IHC) assays for PTEN or AKT expression.Clinical validity: For KRAS mutation analysis, the EWG found convincing evidence for association with treatment response to anti-EGFR therapy, independent of prognostic association. For BRAF V600E mutation testing, the EWG found insufficient evidence for association with treatment response to anti-EGFR  therapy independent of prognostic association. The EWG found insufficient evidence for association of results of testing for mutations in NRAS or PIK3CA, and loss of expression of PTEN or ATK proteins, with treatment response to anti-EGFR therapy.Clinical utility: For KRAS mutation analysis, the EWG found adequate evidence that improved health outcomes are achieved by avoiding ineffective chemotherapy and potential side effects and expediting access to the  next most effective treatment. Inadequate evidence was found regarding association of BRAF V600E mutation testing or loss of PTEN expression with improved health outcomes among patients with mCRC undergoing anti-EGFR therapy as compared with patients with tumors bearing wild-type BRAF sequence and PTEN expression levels, respectively. No evidence was found to support improved health outcomes associated with testing results for NRAS or PIK3CA variants, or AKT protein expression levels in this clinical scenario.Contextual issues: CRC is an  important and highly prevalent health problem. Improvements in mCRC outcomes associated with pharmacogenetic testing could have important clinical, and potentially public health, impacts. Adverse events related to cancer chemotherapy can be common and severe. Therefore, successfully optimizing treatment to maximize efficacy and minimize side effects is important for reducing mCRC-related morbidity and mortality.Gene Med advance online publication 21 February 2013Genetics in Medicine (2013); doi:10.1038/gim.2012.184.




TÍTULO / TITLE:  - Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: Current evidence and future perspectives.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Treat Rev. 2013 Mar 16. pii: S0305-7372(13)00035-2. doi: 10.1016/j.ctrv.2013.02.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ctrv.2013.02.004

AUTORES / AUTHORS:  - Custodio A; Barriuso J; de Castro J; Martinez-Marin V; Moreno V; Rodriguez-Salas N; Feliu J

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Department, IDiPAZ, RTICC (RD06/0020/1022), La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, España. Electronic address: anabcustodio@gmail.com.

RESUMEN / SUMMARY:  - Angiogenesis is a universal requirement for the growth of solid tumours beyond the limits of oxygen diffusion from the existing vasculature. The expression and  function of proangiogenic and antiangiogenic factors are altered in solid malignancies to drive net neoangiogenesis. Vascular endothelial growth factor (VEGF) has been confirmed in several clinical trials as an important therapeutic  target in colorectal cancer (CRC) treatment. However, given that the efficacy of  antiangiogenic agents appears to be limited to a subset of patients, the identification of who will obtain the greater benefit from this therapy or suffer from specific toxicities and when or for how long they should be administered in  the treatment algorithm are major open questions for clinicians and challenges for present and future research. Current evidence indicates some predictive value for particular circulating measures, such as an increase in VEGF, a decrease in vascular endothelial growth factor receptor 2 (VEGFR-2) or circulating endothelial cells, tissue biomarkers, microvessel density, KRAS and BRAF gene mutations or polymorphisms affecting components of the VEGF pathway. Many questions relating to these and other surrogate biomarkers, however, remain unanswered and their clinical usefulness has yet to be proven. This review will focus on the present status of knowledge and future perspectives for developing molecular tools to foresee and monitor antiangiogenic therapy activity in CRC patients.




TÍTULO / TITLE:  - KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in  rectal cancer: A systematic review and meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Surg Oncol. 2013 Mar 5. pii: S0960-7404(13)00019-4. doi: 10.1016/j.suronc.2013.02.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.suronc.2013.02.001

AUTORES / AUTHORS:  - Clancy C; Burke JP; Coffey JC

INSTITUCIÓN / INSTITUTION:  - Department of Colorectal Surgery, University Hospital Limerick, Graduate Entry Medical School, University of Limerick, Ireland.

RESUMEN / SUMMARY:  - INTRODUCTION: The current management of locally advanced rectal cancer involves total mesorectal excision, which may be preceded by neo-adjuvant chemoradiotherapy (CRT). Individual patient response to CRT is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of  the current study was to systematically appraise the effect of KRAS mutation on outcomes following CRT for rectal cancer. METHODS: A comprehensive search for published studies examining the effect of KRAS mutation on outcome after neo-adjuvant CRT in rectal cancer was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. RESULTS: Data was retrieved from 8 series describing 696 patients. Neo-adjuvant treatment regimens  varied in usage of chemotherapeutic agents and interval to surgery. KRAS mutation was present in an average of 33.2 +/- 11.8% of patients with rectal cancer. KRAS  mutation was not associated with decreased rates of pathological complete response (odds ratio (OR): 0.778, 95% confidence interval (CI): 0.424-1.428, P =  0.418), tumor down-staging (OR: 0.846, 95% CI: 0.331-2.162, P = 0.728) or an increase in cancer related mortality (OR: 1.239, 95% CI: 0.607-2.531, P = 0.555). CONCLUSIONS: Based on these data, the presence of KRAS mutation does not affect tumor down-staging or cancer specific survival following neo-adjuvant CRT and surgery for rectal cancer.




TÍTULO / TITLE:  - Prognostic significance of IDH mutation in adult low-grade gliomas: a meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 16.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1107-5

AUTORES / AUTHORS:  - Sun H; Yin L; Li S; Han S; Song G; Liu N; Yan C

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, 10093, People’s Republic of China.

RESUMEN / SUMMARY:  - Mutations in the gene encoding isocitrate dehydrogenase (IDH) have been identified in approximately 65-90 % of low-grade gliomas (LGGs). Various studies  examining the relationship between IDH mutation with the clinical outcome in patients with LGGs have yielded inconclusive results. The purpose of the present  meta-analysis of literature is to determine this effect. We conducted a meta-analysis of 10 studies (937 patients) that evaluated the correlation between IDH mutation and overall survival (OS). For the quantitative aggregation of the survival results, the IDH mutation effect was measured by hazard ratio (HR). Overall, the pooled HR was 0.585 (95 % CI, 0.376-0.911, p = 0.025, random effect  model) for patients with IDH mutation vs patients without IDH mutation. IDH mutation was associated with better overall survival of LGGs. At least this trend was observed in our analysis.




TÍTULO / TITLE:  - Erratum to Azacitidine: a review of its use in the management of myelodysplastic  syndromes/acute myeloid leukaemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Drugs. 2012 Jul;72(11):1578.

            ●● Enlace al texto completo (gratuito o de pago) 2165/11635530-000000000-00000






TÍTULO / TITLE:  - Current evidence for histone deacetylase inhibitors in pancreatic cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - World J Gastroenterol. 2013 Feb 14;19(6):813-28. doi: 10.3748/wjg.v19.i6.813.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v19.i6.813

AUTORES / AUTHORS:  - Koutsounas I; Giaginis C; Patsouris E; Theocharis S

INSTITUCIÓN / INSTITUTION:  - First Department of Pathology, Medical School, National and Kapodistrian University of Athens, GR-11527 Athens, Greece.

RESUMEN / SUMMARY:  - Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which  HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.




TÍTULO / TITLE:  - Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast. 2013 Apr;22(2):121-9. doi: 10.1016/j.breast.2013.01.014. Epub 2013 Feb 23.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.breast.2013.01.014


INSTITUCIÓN / INSTITUTION:  - Istanbul University, Institute of Oncology, 34390 Istanbul, Turkey. Electronic address: adnanaydiner@superonline.com.

RESUMEN / SUMMARY:  - The present meta-analysis examines randomized trials of third-generation aromatase inhibitors (AIs) as alternatives to tamoxifen in three treatment settings: monotherapy, sequenced therapy and extended therapy. Eleven randomized  controlled trials (RCTs) were chosen based on their similarity in terms of study  design and included 34,070 post-menopausal women who had undergone surgery for estrogen-sensitive early breast cancer. DFS was significantly improved by AI monotherapy (Hazard Ratio (HR): 0.89, p = 0.001), sequenced therapy (HR: 0.7, p < 0.00001) and extended therapy (HR: 0.62, p < 0.00001). All of the patients benefited significantly from sequenced therapy (HR: 0.81, p = 0.003), and hormone receptor-positive patients benefited from AI monotherapy (HR = 0.92, p = 0.046) with respect to OS. AI monotherapy conferred significantly lower risks for thromboembolic events (OR = 0.61; p < 0.001) and endometrial cancer (OR = 0.26; p < 0.001) compared with tamoxifen monotherapy; however, there was a greater risk of cardiovascular events (OR = 1.20; p = 0.030). Sequenced therapy was also superior in terms of endometrial cancer but was inferior with respect to fractures, thromboembolic and cardiovascular events.




TÍTULO / TITLE:  - Neoadjuvant trastuzumab for breast cancer. Better to stick with proven treatments.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Prescrire Int. 2013 Feb;22(135):39.

RESUMEN / SUMMARY:  - No documented increase in overall survival with neoadjuvant trastuzumab, given the lack of trials versus chemotherapy in combination with adjuvant trastuzumab.




TÍTULO / TITLE:  - Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmacogenomics J. 2013 Mar 26. doi: 10.1038/tpj.2013.10.

            ●● Enlace al texto completo (gratuito o de pago) 1038/tpj.2013.10

AUTORES / AUTHORS:  - Liu X; Cheng D; Kuang Q; Liu G; Xu W

INSTITUCIÓN / INSTITUTION:  - 1] Ontario Cancer Institute, Toronto, ON, Canada [2] School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China.

RESUMEN / SUMMARY:  - A meta-analysis in Caucasians was conducted to investigate the possible association of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms with irinotecan (IRI)-induced neutropenia and diarrhoea in colorectal cancer (CRC). We searched PubMed and Embase until May 2012 to identify eligible studies, extracted data, assessed methodological quality, and performed  statistical analysis using REVMAN 5.1 and R software. Subgroups meta-analyses were performed in groups representing different IRI combination regimens and IRI  doses. Sixteen trials were included. UGT1A1*28/*28 genotype was associated with more than fourfold (odds ratio (OR)=4.79, 95% confidence intervals (CI): 3.28-7.01; P<0.00001) and threefold (OR=3.44, 95% CI: 2.45-4.82; P<0.00001) increases in the risk of neutropenia when compared with wild type and with at least one UGT1A1*1 allele, respectively. UGT1A1*1/*28 genotype had an OR of 1.90  (95% CI: 1.44-2.51; P<0.00001) for an increased risk of neutropenia. A twofold increase in risk of diarrhoea was associated with UGT1A1*28/*28 genotype (OR=1.84, 95% CI: 1.24-2.72; P=0.002). In subgroup meta-analysis, the higher incidence of diarrhoea in UGT1A1*28/*28 patients was limited to studies where when IRI was given at higher doses (OR=2.37, 95% CI: 1.39-4.04; P=0.002) or combined with 5-fluorouracil (FU or analogue) (OR=1.78, 95% CI: 1.16-2.75; P=0.009). Genotyping of UGT1A1*28 polymorphism before treatment for CRC can tailor IRI therapy and reduce the IRI-related toxicities. IRI-combined 5-FU (or analogue) and a high-dose IRI therapy enhance IRI-induced diarrhoea among patients bearing the UGT1A1*28 allele. Although the toxicity relationships were much stronger with the UGT1A1*28 homozygous variant, associations were also found with the UGT1A1*28 heterozygous variant.The Pharmacogenomics Journal advance online publication, 26 March 2013; doi:10.1038/tpj.2013.10.




TÍTULO / TITLE:  - EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(2):e56205. doi: 10.1371/journal.pone.0056205. Epub 2013 Feb 18.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0056205

AUTORES / AUTHORS:  - Jiang Z; Li C; Li F; Wang X

INSTITUCIÓN / INSTITUTION:  - Department of Colorectal Cancer Surgery, The 2nd Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.

RESUMEN / SUMMARY:  - BACKGROUND: The epidermal growth factor receptor (EGFR) gene copy number (GCN) has been previously demonstrated to correlate with the clinical outcome of colorectal cancer (CRC) treated with anti-EGFR monoclonal antibodies (mAbs), although it remains controversial. We conducted a systematic review and meta-analysis to assess EGFR GCN as a potential biomarker of survival for patients with advanced CRC receiving treatment with anti-EGFR mAbs. METHODS: We systematically identified articles investigating EGFR GCN by fluorescent or chromogenic in situ hybridization or other detection techniques in patients with  metastatic CRC treated with panitumumab or cetuximab, (last search: 10 August 2012). Eligible studies had to report on overall survival (OS), progression-free  survival (PFS) or time-to-progression (TTP), stratified by EGFR GCN. Summary hazard ratios (HRs) were calculated using random-effects models. RESULTS: Among 13 identified studies, 10 (776 patients, 302 with increased GCN), 8 (893 patients, 282 with increased GCN) and 3 (149 patients, 66 with increased GCN) were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR GCN was associated with increased OS (HR = 0.62; 95% CI 0.50-0.77; P<0.001), PFS  (HR = 0.65; 95% CI 0.47-0.89; P = 0.008) but not TTP (HR = 0.71; 95% CI 0.44-1.14; P = 0.157). It was also shown that EGFR GCN is independent of other factors such as KRAS status. Among those populations received second-line or higher treatment, increased EGFR GCN was strongly associated with improved survival (for OS, HR = 0.60; 95% CI 0.47-0.75; P<0.001; for PFS, HR = 0.59; 95% CI 0.47-0.75; P<0.001), whereas it did not influence survival in patients that received first-line therapy. CONCLUSION: Among the anti-EGFR-treated patients, increased EGFR GCN appears to be associated with improved survival outcomes. The  effect on survival appears to be related to patients receiving the line of treatment.



TÍTULO / TITLE:  - Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Future Oncol. 2013 Feb;9(2):255-69. doi: 10.2217/fon.12.173.

            ●● Enlace al texto completo (gratuito o de pago) 2217/fon.12.173

AUTORES / AUTHORS:  - Qiu T; Zhou L; Zhu W; Wang T; Wang J; Shu Y; Liu P

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, First Affiliated Hospital of Nanjing Medical University,  300 Guangzhou Road, Nanjing 210029, China.

RESUMEN / SUMMARY:  - It has been found that the epigenetic silence of tumor suppressor genes induced by overexpression of histone deacetylases (HDACs) plays an important role in carcinogenesis. HDAC inhibitors (HDACi) that block the activity of specific HDACs have emerged as the accessory therapeutic agents for multiple human cancers. To better understand the effects of HDACi in cancer treatment, we carried out a review based on 30 published clinical trials to determine whether HDACi will benefit patients with solid tumors. Information of complete response, partial response, stable disease, objective responses and objective response rate was collected to assess clinical outcomes. A lack of therapeutic effects was observed when HDACi was used as a single agent. However, when HDACi treatment was combined with other agents, it appeared to increase the anti-tumor activity. High-quality  studies are required to better understand the clinical effects of HDACi.



TÍTULO / TITLE:  - The prognostic value of epigenetic silencing of p16 gene in NSCLC patients: a systematic review and meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e54970. doi: 10.1371/journal.pone.0054970. Epub 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0054970

AUTORES / AUTHORS:  - Lou-Qian Z; Rong Y; Ming L; Xin Y; Feng J; Lin X

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.

RESUMEN / SUMMARY:  - BACKGROUND: The prognostic significance of p16 promoter hypermethylation in patients with non-small cell lung cancer (NSCLC) is still controversial. This analysis presents pooled estimates of the association to better elucidate whether p16 methylation has a prognostic role in NSCLC. METHODS: Relevant studies were identified by searching PubMed, Embase and Web of Science databases until June 2012. The association of p16 methylation with both overall survival (OS) and disease-free survival (DFS) was preformed. Studies were pooled and summary hazard ratios (HR) were calculated. Subgroup analyses, sensitivity analysis and publication bias were also conducted. RESULTS: A total of 18 studies containing 2432 patients met the inclusion criteria and had sufficient survival data for quantitative aggregation. The results showed that p16 methylation was an indicator of poor prognosis in NSCLC. The HR was 1.36 (95% CI: 1.08-1.73, I(2) =  56.7%) and 1.68 (95% CI: 1.12-2.52, I(2) = 38.7%) for OS and DFS, respectively. Subgroup analyses were carried out. The HRs of fresh and paraffin tissue were 1.50 (95% CI: 1.11-2.01) and 1.10 (95% CI: 0.77-1.57). The pooled HR was 1.40 (95% CI: 1.02-1.92) for methylation-specific PCR (MSP) and 1.26 (95% CI: 0.87-1.82) for quantitative MSP (Q-MSP). The combined HR of the 16 studies reporting NSCLC as a whole indicated that patients with p16 hypermethylation had  poor prognosis. No significant association was found when adenocarcinoma subtype  pooled. When seven studies on DFS were aggregated, the HR was 1.68 (95% CI: 1.12-2.52) without significant heterogeneity. Moreover, no obvious publication bias was detected on both OS and DFS. CONCLUSION: The meta-analysis findings support the hypothesis that p16 methylation is associated with OS and DFS in NSCLC patients. Large well-designed prospective studies are now needed to confirm the clinical utility of p16 methylation as an independent prognostic marker.



TÍTULO / TITLE:  - Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - PLoS One. 2013;8(1):e55128. doi: 10.1371/journal.pone.0055128. Epub 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1371/journal.pone.0055128

AUTORES / AUTHORS:  - Liu HB; Wu Y; Lv TF; Yao YW; Xiao YY; Yuan DM; Song Y

INSTITUCIÓN / INSTITUTION:  - Respiratory Department, Jinling Hospital, Nanjing University School of Medicine,  Nanjing, China.

RESUMEN / SUMMARY:  - BACKGROUND: The aim of this study was to assess the role of skin rash in predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the prognosis of patients with non-small cell lung cancer (NSCLC). METHOD: We systematically searched for eligible articles investigating the association between rash and the efficacy of EGFR-TKIs and the  prognosis of patients with NSCLC. The summary risk ratio (RR) and hazard ratio (HR) were calculated using meta-analysis. RESULTS: We identified 33 eligible trials involving 6,798 patients. We used two different standards to group the patients [standard 1: rash vs. no rash, standard 2: rash (>/= stage 2) vs. rash (stage 0, 1)]. For standard 1, the objective response rate (ORR) and disease control rate (DCR) of the rash group were significantly higher than the no rash group [RR = 3.28; 95% CI: 2.41-4.47(corrected RR = 2.225, 95% CI: 1.658-2.986); RR = 1.96, 95% CI: 1.58-2.43]. The same results were observed for standard 2. For standards 1 and 2, the progression-free survival (PFS) (HR = 0.45, 95% CI: 0.37-0.53; HR = 0.57, 95% CI: 0.50-0.65) and overall survival (OS) (HR = 0.40, 95% CI: 0.28-0.52; HR = 0.53, 95% CI: 0.35-0.71) of the rash group were significantly longer than the control group, and the same results were observed in the subgroup analysis. CONCLUSIONS: skin rash after EGFR-TKI treatment may be  an efficient clinical marker for predicting the response of patients with NSCLC to EGFR-TKIs. Furthermore, skin rash is also the prognostic factor of patients with NSCLC. Patients with skin rash have a longer PFS and OS.



TÍTULO / TITLE:  - High expression of epidermal growth factor receptor might predict poor survival in patients with colon cancer: a meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genet Test Mol Biomarkers. 2013 Apr;17(4):348-51. doi: 10.1089/gtmb.2012.0421. Epub 2013 Feb 6.

            ●● Enlace al texto completo (gratuito o de pago) 1089/gtmb.2012.0421

AUTORES / AUTHORS:  - Hong L; Han Y; Zhang H; Zhao Q; Yang J; Ahuja N

INSTITUCIÓN / INSTITUTION:  - 1 Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University , Xi’an, China .

RESUMEN / SUMMARY:  - Background and Aims: The epidermal growth factor receptor (EGFR) has been recognized as a molecular target for antibody-based therapy in various cancer types. Here we aimed to analyze the relation between high expression of EGFR and  postoperational survival in patients with colon cancer. Methods: A meta-analysis  was performed by searching PubMed, Cochrane Library, EMBASE, and Science Direct databases from 1960 to June 2012. Data were extracted from studies comparing survival in colon cancer patients having higher EGFR expression with those having lower levels. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were  calculated. Results: Four studies including 815 colon cancer patients were subjected to final analysis. Comparing to patients with low expression of EGFR, the HR of postoperational survival for patients with high EGFR expression was 2.34 (95% CI: 1.83-2.99), which could significantly predict poorer survival. Conclusions: High expression of EGFR might predict poor survival for patients with colon cancer.



TÍTULO / TITLE:  - Prognostic significance of beta-catenin expression in patients with non-small cell lung cancer: A meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biosci Trends. 2013 Feb;7(1):42-9.

AUTORES / AUTHORS:  - Mei XD; Su H; Song J; Dong L

INSTITUCIÓN / INSTITUTION:  - Department of Pulmonary Medicine, Qilu Hospital, Shandong University, Ji’nan, Shandong, China.

RESUMEN / SUMMARY:  - beta-Catenin has been reported to play a crucial role in the invasion and metastasis of lung cancer. However, the value of beta-catenin as a prognostic factor for non-small cell lung cancer (NSCLC) remains controversial. The present  study systematically reviewed the evidence of predicting significance of beta-catenin expression in NSCLC patients with meta-analysis. Twelve literatures  were included by searching PubMed, Cochrane library, and EMBASE databases. Separate hazard ratio estimates and a 95% confidence interval (CI) for the prognostic value of beta-catenin in NSCLC were extracted and merged from the included literatures. The summary hazard ratios were 1.91 (95% CI 1.60-2.28), indicating a worse overall survival for NSCLC patients with reduced beta-catenin  expression. There was no significant heterogeneity among the studies (X(2) = 12.41, p = 0.413, I(2) = 3.3%). Publication bias was not statistically significant. Sensitivity analysis showed that omission of any single study had little effect on the combined risk estimates. This meta-study revealed that decreased beta-catenin expression denoted a poor prognosis in NSCLC patients.



TÍTULO / TITLE:  - Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Curr Oncol. 2013 Feb;20(1):48-61. doi: 10.3747/co.20.1316.

            ●● Enlace al texto completo (gratuito o de pago) 3747/co.20.1316

AUTORES / AUTHORS:  - Pritchard KI; Gelmon KA; Rayson D; Provencher L; Webster M; McLeod D; Verma S

INSTITUCIÓN / INSTITUTION:  - Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, ON.

RESUMEN / SUMMARY:  - Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor  receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk  of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.



TÍTULO / TITLE:  - Study protocol of the B-CAST study: a multicenter, prospective cohort study investigating the tumor biomarkers in adjuvant chemotherapy for stage III colon cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BMC Cancer. 2013 Mar 25;13(1):149.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1471-2407-13-149

AUTORES / AUTHORS:  - Ishiguro M; Kotake K; Nishimura G; Tomita N; Ichikawa W; Takahashi K; Watanabe T; Furuhata T; Kondo K; Mori M; Kakeji Y; Kanazawa A; Kobayashi M; Okajima M; Hyodo I; Miyakoda K; Sugihara K

RESUMEN / SUMMARY:  - BACKGROUND: Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy. Several oral fluorouracil (5-FU) derivatives with different properties are available in Japan, but which drug is the most appropriate for each patient has not been established. Although efficacy prediction of 5-FU derivatives using expression of 5-FU activation/metabolism enzymes in tumors has been studied, it has not been clinically applied.Methods/design: The B-CAST study is a multicenter, prospective cohort study aimed to identify the patients who benefit from adjuvant chemotherapy with each 5-FU regimen, through evaluating the relationship between  tumor biomarker expression and treatment outcome. The frozen tumor specimens of patients with stage III colon cancer who receives postoperative adjuvant chemotherapy are examined. Protein expression of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) are evaluated using enzyme-linked immunosorbent assay (ELISA). mRNA expression of TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyl transferase (OPRT) are evaluated using reverse transcription polymerase chain reaction (RT-PCR). The patients’ clinical data reviewed are as follow: demographic and pathological characteristics, regimen, drug doses and treatment duration of adjuvant therapy, types and severity of adverse events, disease free survival, relapse free survival and overall survival. Then, relationships among the protein/mRNA expression, clinicopathological characteristics and the treatment outcomes are analyzed for each 5-FU derivative. DISCUSSION: A total of 2,128 patients from the 217 institutions were enrolled between April 2009 and March 2012. The B-CAST study demonstrated that large-scale, multicenter translational research using frozen samples was feasible when the sample shipment and Web-based data collection were  well organized. The results of the study will identify the predictors of benefit  from each 5-FU derivative, and will contribute to establish the “personalized therapy” in adjuvant chemotherapy for colon cancer.Trial registration: ClinicalTrials.gov: NCT00918827UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002013.



TÍTULO / TITLE:  - Predictive and prognostic biomarkers with therapeutic targets in breast, colorectal, and non-small cell lung cancers: A systemic review of current development, evidence, and recommendation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Oncol Pharm Pract. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 1177/1078155212474047

AUTORES / AUTHORS:  - Chung C; Christianson M

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Kennewick General Hospital, WA, USA.

RESUMEN / SUMMARY:  - Appropriate evidence-based roles of prognostic and predictive biomarkers of known therapeutic targets in breast, colorectal, and non-small cell lung cancers in adults are reviewed, with summary of evidence for use and recommendation. Current development in biomarker studies is also discussed. Computerized literature searches of PubMed (National Library of Medicine), the Cochrane Collaboration Library, and commonly accepted US and international guidelines (American Society  of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network) were performed from 2001 to 2012. Literature published before 2001 was noted for historical interest but not evaluated. Literature review was focused on available systematic reviews and meta-analyses of published predictive (associated with treatment response and/or efficacy) and  prognostic (associated with disease outcome) biomarkers of known therapeutic targets in colorectal, breast, and non-small cell lung cancers. In general, significant health outcomes (e.g. predicted response to therapy, overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used for making recommendations. Four breast cancer biomarkers were evaluated, two of which (2D6 genotyping, Oncotype Dx) were considered emerging with insufficient evidence. Seven colorectal cancer biomarkers were evaluated, five of which (EGFR gene expression, K-ras G13D gene mutation, B-raf V600E gene mutation, dihydropyrimidine dehydrogenase deficiency,  and UGT1A1 genotyping) were considered emerging. Seven non-small cell lung cancer biomarkers were evaluated, five of which were emerging (EGFR gene expression, ERCC gene expression, RRM1 gene expression, K-ras gene mutation, and TS gene expression). Of all 18 biomarkers evaluated, the following showed evidence of clinical utility and were recommended for routine use in practice: ER/PR and HER2 for breast cancer; K-ras gene mutation (except G13D gene mutation) for colorectal cancer; mismatch repair deficiency or microsatellite instability for colorectal cancer; and EGFR and EML4-ALK gene mutations for non-small cell lung. Not all recommendations for these biomarkers were uniformly supported by all guidelines.



TÍTULO / TITLE:  - Safety and efficacy of calcium and magnesium infusions in the chemoprevention of  oxaliplatin induced sensory neuropathy in digestive tract cancers: A meta-analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Dig Dis. 2013 Feb 21. doi: 10.1111/1751-2980.12050.

            ●● Enlace al texto completo (gratuito o de pago) 1111/1751-2980.12050

AUTORES / AUTHORS:  - Xu XT; Dai ZH; Xu Q; Qiao YQ; Gu Y; Nie F; Zhu MM; Tong JL; Ran ZH

INSTITUCIÓN / INSTITUTION:  - Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao Tong University), Shanghai, China.

RESUMEN / SUMMARY:  - OBJECTIVE: Published data on the safety and efficacy of calcium and magnesium (Ca/Mg) infusions in prevention of oxaliplatin-induced sensory neuropathy has yet to be confirmed. To derive a more precise estimation of the association, we conducted a meta-analysis. METHODS: The odds ratio (OR) and its 95% confidence interval (CI) were used to assess the strength of association. A total of 16 separate studies including 1765 individuals based on the search criteria were involved in this meta-analysis. RESULTS: The difference in oxaliplatin-induced neuropathy grade >/=1 incidence was statistically significant between the Ca/Mg infusions treatment group and the no treatment group (national cancer institute common toxicity criteria, NCI CTC: OR 0.44, 95% CI 0.31-0.62, P=0.000; oxaliplatin-specific scale, OSS: OR 0.30, 95% CI 0.20-0.45, P=0.000). Similar results were found in oxaliplatin-induced neuropathy grade >/= 2 incidences (NCI  CTC: OR 0.60, 95% CI 0.46-0.77, P=0.000; OSS: OR 0.45, 95% CI 0.30-0.67, P=0.000). However, we did not detect a trend of fewer oxaliplatin-induced neuropathy grade >/= 3 incidences in Ca/Mg infusions treatment group than the no  treatment group (NCI CTC: OR 0.67, 95% CI 0.44-1.01, P=0.054; OSS: OR 0.66, 95% CI 0.34-1.29, P=0.224).There is no difference in the response rate (RR) between the Ca/Mg treated group and the untreated group (OR 0.89, 95% CI 0.67-1.17, P=0.391). CONCLUSION: The meta-analysis suggests that Ca/Mg infusions do not alter the efficacy of oxaliplatin-based chemotherapy in digestive tract cancers,  it may be reasonable to add them to lessen the incidence of neuropathy.