INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes.
Background and objective: SN-38 is the active metabolite of irinotecan (CPT-11) and mainly responsible of hematological and intestinal toxicity after CPT-11 treatments. SN-38 is inactivated into SN-38G by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Some polymorphism of these enzymes leads lower clearance (CL) of SN-38 and therefore bigger exposition and bigger risk of hematological and/or intestinal toxicity (1). Therefore, the goal of this study has been to evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of CPT-11 and its metabolites, SN-38 and SN-38G on Caucassian cancer population. Methods: Plasma concentrations of CPT-11, SN-38 and SN-38G from 72 patients were pooled to develop a joint population pharmacokinetic model using NONMEM 7. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. Results: The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. Clearance in patients with some allele (heterozygous or homozygous) associated with low enzymatic activity of UGT1A1*28 was a 35,7% lower (CI 95%: 6,7 - 64,7; p=0,003) than in wild-type patients. Additionally, linkage dissequilibrium indicates a strong interaction between functional UGT1A1, UGT1A7 and UGT1A9 polymorphisms related to the alteration of the UGT enzyme activity. Conclusion: The impact of UGT1A1*28 genotype on the systemic exposure of SN-38 justifies its routine determination in patients receiving CPT-11 and subsequent dose adjustment. Citation Format: Belen Valenzuela, Mario González-Sales, Vanessa Escudero, Elena Navarro, Carlos Perez-Ruixo, Joseba Rebollo, Ramon González-Manzano, Juan José Pérez-Ruixo. Influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on irinotecan, SN-38 and SN-38G pharmacokinetics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2213. doi:10.1158/1538-7445.AM2013-2213
Sunuuary In order to test whether circumvention of clinical resistance can be obtained in common solid tumours by targeting different drug resistance mechanisms, a phase I chnical and immunological study was designed. The purpose of the study was to determine the dose of cyclosporin A (CsA), in combination with doxorubicin (DOX) and ifosfamide (IFX), needed to achieve steady-state whole-blood levels of 2000 ng ml-' and the associated toxicity of this combination. Treatment consisted of CsA 5 mg kg-' as a 2 h loading infusion, followed by a CsA 3 day continuous infusion (c.i.) (days 1 -3) at doses that were escalated from 10 to 18 mg kg-' day-'.
e22120 Background: Genomic-based profiling of tumors is a promising approach that allows the selection of the optimal chemotherapy regimen minimizing the possibility of futile therapies. Preliminary clinical results by our group showing a 23% response rate were presented at ASCO’12 (abstract 3,064). However, RNA isolation is a challenging technical step that requires a high quality specimen and takes 2-4 weeks interval to be finished. For this reason we analyzed the feasibility conditions in our series. Methods: Patients (pts) with R/R solid tumors had immediately frozen biopsies, underwent RNA isolation and quality validation after a pathologic confirmation of viable tumor in more than 30% of the sample. Results: From August 2010 to December 2012, 138 patients accepted the MAGE chemotherapy profiling. The median time from biopsy to MAGE analysis has been 4 weeks (ranging 2 to 6). In 17 (12%) pts the procedure was aborted for technical reasons. In these cases tumor samples were obtained from liver in 7 pts, local recurrence in 3 pts, soft tissues in 3 pts, peritoneum in 2 pts, and nodes in 2 pts. Reasons for canceling the assay were mainly a very low tumor cells rate (less than 30%) in 10 pts (fibrotic changes in 5 pts and predominance of necrosis in 5 pts), 2 pts with no tumor, 1 pt with a non-radiologically identifiable lesion, 1 pt with radiofrequency deterioration of the specimen and 3 pts with poor quality RNA. Among the remaining 121 pts who completed the procedure only 74 (61.2%) were treated according to the selected chemotherapy agents achieving a clinical benefit rate of 60%. The high attrition rate (38.8%) was due to poor clinical condition, refusal of recommendations and/or short life expectancy. Conclusions: MAGE-based chemotherapy profiling of tumors was feasible to guide antitumor therapy in selected patients. We recommend performing the study in untreated patients or earlier in the course of their disease (i.e. after failure to first line chemotherapy) in patients with a life expectancy of more than 3 months.
Treinta enfermos con tumores testiculares avanzados fueron tratados con PVB o BEP. Ninguno recibió previamente tratamiento citostático. Se practicó citorreducción tumoral de enfermedad "bulky" antes de la quimioterapia en cuatro pacientes y durante la administración de la misma en dos. Se obtuvieron 27 (90%) respuestas completas (RC), dos (6,7%) respuestas parciales (RP) y un enfermo (3,3%) permaneció en no cambios. Con cirugía de enfermedad residual los pacientes con RP inicial lograron RC. En cuatro enfermos se evidenció progresión tumoral a PVB o BEP, en tres de los cuales se objetivó desarrollo de neoplasias de histología no germinal. Se registró una muerte tóxica y tres patrones radiológicos de neumonitis intersticial reversible atribuibles a bleomicina. Con una mediana de seguimiento de 38,5 meses, límites entre 2,5 y 130 meses, el 83,3% de los pacientes permanecen vivos y libres de enfermedad. La supervivencia global actuarial es del 85,6%. Se confirman una vez más las buenas expectativas de curación que tienen estos enfermos.
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