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1.
Fam Cancer ; 20(1): 49-53, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32451744

RESUMO

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514-522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A [c.444 + 1G > A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5-11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T > C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8-2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T > C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.


Assuntos
Alelos , Quinase do Ponto de Checagem 2/genética , Deleção de Genes , Mutação em Linhagem Germinativa/genética , Perda de Heterozigosidade , Neoplasias Testiculares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Embrionário/genética , Criança , Pré-Escolar , Tumor do Seio Endodérmico/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Federação Russa , Seminoma/genética , Teratoma/genética , Adulto Jovem
2.
J Gastroenterol Hepatol ; 33(4): 814-824, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28960444

RESUMO

BACKGROUND AND AIM: REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤ 45 and < 65 years) and elderly (≥ 65, ≥ 70, and ≥ 75 years) patients. METHODS: Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo. RESULTS: The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤ 45 years (HR: 0.59, 95% confidence interval: 0.27-1.26), < 65 years (0.80, 0.59-1.10), ≥ 65 years (0.72, 0.48-1.08), ≥ 70 years (0.73, 0.44-1.23), and ≥ 75 years (0.59, 0.25-1.37); and RAINBOW ≤ 45 years (0.56, 0.33-0.93), < 65 years (0.78, 0.63-0.97), ≥ 65 years (0.88, 0.66-1.18), and ≥ 70 years (0.88, 0.60-1.28). The exception was elderly patients aged ≥ 75 years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n = 36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥ 3) were not associated with age. CONCLUSIONS: In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Junção Esofagogástrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Efeito Placebo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem , Ramucirumab
3.
Br J Cancer ; 115(8): 974-982, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27623234

RESUMO

BACKGROUND: Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma. METHODS: A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3. RESULTS: None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression. CONCLUSIONS: REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.


Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/sangue , Neoplasias Gástricas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/sangue , Adenocarcinoma/sangue , Adenocarcinoma/química , Adulto , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Junção Esofagogástrica , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/análise , Estudos Retrospectivos , Método Simples-Cego , Neoplasias Gástricas/sangue , Neoplasias Gástricas/química , Neoplasias Gástricas/mortalidade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Ramucirumab
4.
Future Oncol ; 12(11): 1359-67, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27020170

RESUMO

AIM: This randomized, double-blind trial compared proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer (PROTECT-1). PATIENTS & METHODS: Women (≥18 years) were randomized to receive LA-EP2006 (n = 159) or reference (n = 157) pegfilgrastim (Neulasta(®), Amgen) for ≤6 cycles of (neo)-adjuvant TAC chemotherapy. Primary end point was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10(9)/l) with equivalence confirmed if 90% and 95% CIs were within a ±1 day margin. RESULTS: For DSN, LA-EP2006 was equivalent to reference (difference: 0.07 days; 90% CI: -0.09-0.23; 95% CI: -0.12-0.26). CONCLUSION: LA-EP2006 and reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving chemotherapy.


Assuntos
Medicamentos Biossimilares/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/prevenção & controle , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Filgrastim , Humanos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Polietilenoglicóis , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
5.
Lancet ; 383(9911): 31-39, 2014 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-24094768

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. METHODS: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. FINDINGS: 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. INTERPRETATION: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. FUNDING: ImClone Systems.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Junção Esofagogástrica , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Método Duplo-Cego , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto Jovem , Ramucirumab
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