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1.
Front Oncol ; 9: 759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456944

RESUMO

Sensitivity to endocrine therapy of patients with estrogen receptor (ER)-positive metastatic breast cancer and germline BRCA1/2 mutations is not yet fully elucidated. Furthermore, the registration trials of CDK 4/6 inhibitors in combination with endocrine therapy lacked of a pre-specified subgroup analysis in BRCA1/2 mutation carriers. We report clinical history of two patients with BRCA-mutated, ER-positive metastatic breast cancer treated with letrozole plus the CDK 4/6 inhibitor palbociclib. Biological and clinical implications of the treatment outcome observed in the two cases are discussed with the knowledge of scientific evidence to date available. Overall, biological rationale, preclinical, and clinical data support the prominent role of CDK 4/6 inhibitors plus endocrine therapy, even in combination with PARP inhibitors, in the treatment of BRCA-mutated, ER-positive breast cancers. However, the interaction between Cyclin/CDK pathway, ER and BRCA is complex and evidences reported so far, albeit reliable, await confirmation in the context of future randomized clinical trials.

2.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Neoplasias/diagnóstico , Processamento Alternativo , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial , Neoplasias/genética
3.
Tumori ; 103(1): 66-71, 2017 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26391764

RESUMO

AIMS AND BACKGROUND: Bone flare reaction as a sign of response to antineoplastic treatment has been redefined, including the onset of new osteoblastic lesions. If misunderstood as skeletal progression, this finding could lead to erroneous therapy discontinuation, changing the disease clinical course. We aim to describe this clinical phenomenon in patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene-activating mutations treated with tyrosine kinase inhibitor (TKI). METHODS: We retrospectively reviewed the computed tomography scans of 43 EGFR-mutated patients with NSCLC treated with EGFR-TKI, analyzing the bone response in terms of increase in the quantity and/or density of lesions, and assessing objective tumor response to treatment. RESULTS: Osteoblastic reaction was detected in 10 cases (23%), showing different patterns: dimensional or density increase of known osteosclerotic metastases (pattern A, n = 4); response of previously lytic lesions (pattern B, n = 2); onset of new osteosclerotic lesions (pattern C, n = 4). Seven patients had partial response to TKI treatment, with response rate of 70%, vs 50% of patients with bone metastases without this reaction. No difference in terms of median overall survival or progression-free survival emerged between patients with or without osteoblastic reaction. CONCLUSIONS: The correct clinico-radiologic interpretation of osteoblastic reaction is crucial to avoid waste of therapeutic lines when TKI treatment has not yet exhausted its potential effectiveness. Clinical implications of ambiguous radiologic findings as described in this study deserve further discussion.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Osteoblastos/citologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Tomografia Computadorizada por Raios X
4.
Acta Biomed ; 87(1): 54-63, 2016 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-27163896

RESUMO

BACKGROUND AND AIM OF THE WORK: BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life-time risk of developing contralateral breast cancer (CBC). We performed a population-based study with the aim of estimating the proportion of CBC associated with BRCA1/BRCA2 mutations, and the contribution of germline mutations to both molecular and clinical features of these tumors. METHODS: Fifty-five women with invasive CBC consecutively seen at the at the Genetic Oncology Service of the University Hospital of Parma from 2000 to 2011 were subjected to BRCA1/2 testing. Fifty-five case-matched, unilateral breast cancer (UBC)  patients (pts), which tested negative for BRCA1/2 mutations, were selected as control group. RESULTS: BRCA mutations were detected in 13 (24%) of 55 CBC pts. Women with BRCA1 mutations, and to a lesser extent BRCA2 mutations, were significantly more likely to present with high histologic grade, negative hormone receptor status and high proliferation rate in both first and second primary breast cancers than BRCA-negative, CBC tumors. A diagnosis of triple-negative breast cancer (TNBC) was significantly more frequent in women with BRCA mutations in comparison with BRCA-negative, UBC controls. There were no survival differences between BRCA-positive and non-BRCA tumors. CONCLUSIONS: Results of the present study indicate that both first primary and second primary breast cancers in BRCA carriers are qualitatively distinct from BRCA negative CBC, and from sporadic UBC controls. These findings highlight relevant clinical considerations about the potential value of BRCA testing in women with CBC as well as therapeutic, preventive, and surveillance implications for patients carrying a mutation.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
5.
Tumour Biol ; 36(8): 5943-51, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25731731

RESUMO

Considering the role of carcinoembryonic antigen (CEA) serum levels as potential useful predictive marker during chemotherapy treatment, we studied its applicability in advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). Our retrospective cohort consists of 79 patients (33 EGFR mutated and 46 EGFR wild type or unknown) affected by advanced NSCLC, for whom CEA serum values at the beginning of TKI therapy and after the first month of treatment were available, regardless of treatment line. Baseline CEA value, percentage of CEA reduction after 1 month, and percentage of patients with ≥20 % CEA decrease after 1 month (CEA response) were correlated with disease control rate (DCR), progression-free (PFS), and overall (OS) survival, according to EGFR mutational status. Median baseline CEA levels were significantly higher in EGFR mutated (40.9 ng/ml; interquartile range (IQR) 8.9-197.6) than in wild-type cases (6.2 ng/ml; IQR 2.8-12.8; p = 0.003). Both percentage reduction in CEA levels (-10.7 vs. +13.4 %) and percentage of cases with CEA response (42 vs. 20 %) were significantly higher in mutated vs. wild-type/unknown patients (p = 0.007 and p = 0.027, respectively). In wild-type/unknown patients, CEA response was significantly correlated with DCR (p = 0.001) and resulted as a significant predictor of PFS both in univariate (p = 0.002) and in multivariate analyses (hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.11-0.66; p = 0.004); only a trend was found for OS prediction (p = 0.082). In EGFR-mutated group, CEA reduction did not show any correlation either with PFS or OS. CEA response after 1 month of EGFR-TKI therapy could be a useful marker, worthy to further studies, as early predictor of treatment outcome in EGFR wild-type/unknown unselected NSCLC cases for which no molecular predictor is yet available.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Receptores de Superfície Celular/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Detecção Precoce de Câncer , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Receptores de Superfície Celular/biossíntese , Resultado do Tratamento
6.
Lung Cancer ; 86(3): 324-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25453846

RESUMO

BACKGROUND: No target therapies are presently available in the treatment of small-cell lung cancer (SCLC). We investigated the presence of potentially drugable mutations in the EGFR, c-MET, BRAF, KRAS, PDGFRa and c-KIT genes in a retrospective series of SCLC from 2 Italian Institutions. Correlations with immunohistochemical, clinical and outcome features were evaluated. MATERIALS AND METHODS: Genes were studied by direct sequencing of DNA extracted from formalin-fixed paraffin-embedded tissues. Immunohistochemical expression of TTF-1, p63, chromogranin, synaptophysin, CD56 and bcl-2 was assessed. RESULTS: Samples from 113 SCLC patients were analyzed. All cases were wild-type for BRAF, KRAS, PDGFRa and c-KIT (data available for 82 patients). Two (1.8%) patients were EGFR-mutated (exon 19 delE746-A750 and exon 21 L858R); both were females, non-smoker and had limited disease. Overall survival of EGFR-mutated patients was 21 months as compared to 11 months in wild-type. Five (4.4%) patients were c-MET-mutated (4 on exon 14: 2 R988C, 1 D990N, 1 D102Y; 1 on exon 17 R1166Q); all were smokers, 3 were males and 4 had extensive disease. Their OS was comparable to wild-type cases (12 vs. 11 months). EGFR and c-MET mutations were mutually exclusive. Gene mutations did not correlate with immunophenotype. CONCLUSIONS: Targetable mutations are uncommon in SCLC. EGFR-mutated patients tended to be female and non-smoker and experienced a prolonged OS suggesting a possible positive prognostic effect. c-MET mutations did not affect survival. Target therapy might be considered in EGFR and c-MET-mutated patients.


Assuntos
Receptores ErbB/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-met/genética , Carcinoma de Pequenas Células do Pulmão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Receptores ErbB/biossíntese , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/biossíntese , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/biossíntese , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas p21(ras) , Receptor beta de Fator de Crescimento Derivado de Plaquetas/biossíntese , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Proteínas ras/biossíntese , Proteínas ras/genética
7.
Tumori ; 100(1): e20-3, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24675505

RESUMO

The identification of activating EGFR gene mutations and the availability of effective target therapies such as gefitinib and erlotinib have radically changed the therapeutic approach and prognosis for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, despite an initial response to EGFR tyrosine kinase inhibitors (TKIs), acquired resistance inevitably develops and the way to overcome it is an open challenge. We report the first case, to our knowledge, of a patient affected by metastatic EGFR-mutated NSCLC with T790M-driven acquired TKI resistance who obtained a significant response to afatinib. Considering the improvement achieved in all disease sites but those in the brain, this case puts a strain on afatinib's activity on brain metastases.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Afatinib , Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Metionina , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Treonina , Tomografia Computadorizada por Raios X
8.
Lung Cancer ; 83(2): 265-71, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24388705

RESUMO

OBJECTIVES: An association between skin toxicity and outcome has been reported for NSCLC patients treated with erlotinib. Several explanations have been suggested, including pharmacokinetic and pharmacogenomic variability. The purposes of this study were to characterize erlotinib pharmacokinetic and to correlate drug serum and urine levels to toxicity and outcomes in advanced NSCLC patients. METHODS: Patients with stage IV NSCLC consecutively treated with erlotinib in second- or third-line were enrolled. Biological samples (blood, urine and tumor specimens) were collected. Erlotinib levels in serum and urine samples of all patients after 7 (T1) and 30 (T2) days of treatment were quantified by LC-MS/MS analysis, along with urinary 6ß-hydroxycortisol/cortisol ratio, as marker of metabolic phenotype of the CYP3A4/5 enzyme. RESULTS: 56 patients were recruited and for 46 all samples were available. At T1 erlotinib levels were 3.90 [2.13] µmol/l and 0.37 [2.90]µmol/mol creat in serum and urinary samples, respectively; at T2 drug concentrations were significantly lower (2.02 [4.05] µmol/l and 0.23 [4.47] µmol/mol creat, respectively). Patients with grade 3 skin toxicity showed serum T1 drug levels significantly higher than those with grade 0-2 (6.84 [2.28] vs. 3.08 [1.97] µmol/l, respectively, p=0.004) and had longer progression-free and overall survival. An inverse correlation between erlotinib serum levels and urinary 6ß-hydroxycortisol/cortisol ratio was observed in patients with grade 3 skin toxicity. CONCLUSIONS: These findings suggest that the pharmacokinetics and metabolism of erlotinib are related to skin toxicity and may support further studies where erlotinib dosing is tailored according to pharmacokinetic parameters.


Assuntos
Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacocinética , Pele/efeitos dos fármacos , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cloridrato de Erlotinib , Feminino , Humanos , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Quinazolinas/sangue , Quinazolinas/urina , Pele/patologia , Análise de Sobrevida , Resultado do Tratamento
9.
Cancer Chemother Pharmacol ; 73(2): 299-307, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24258456

RESUMO

BACKGROUND: [18F]fluorodeoxyglucose (FDG)-PET is being evaluated as a tool for the early detection of response to various targeted agents in solid tumors. The aim of this study was to evaluate the predictive value of PET response after 2 days of erlotinib in unselected pretreated patients with stage IV NSCLC. PATIENTS AND METHODS: FDG-PET/CT scans were conducted at baseline and after 2 days of erlotinib, with a CT evaluation performed at baseline and after 45-60 days of therapy. PET responses were evaluated by quantitative changes on SUVmax tumor/non-tumor ratio and classified according to EORTC criteria. PET responses were compared with RECIST responses and related to progression-free (PFS) and overall (OS) survival. Erlotinib effects on glucose uptake were also studied in a panel of NSCLC cell lines. RESULTS: Fifty-three patients were enrolled. At 2 days of erlotinib, 20 (38 %) patients showed partial metabolic response (PMR), 25 (47 %) had stable metabolic disease (SMD) and 8 (15 %) had progressive metabolic disease (PMD). All patients with PMD had confirmed RECIST progression at 45-60 days. Patients with early PMR and SMD had significantly longer PFS (p < 0.001 and p = 0.001, respectively) and OS (p = 0.001 for both) than PMD patients. CONCLUSIONS: FDG-PET assessment after 2 days of erlotinib could be useful to identify early resistant patients and to predict survival in unselected NSCLC pretreated population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Intervalo Livre de Doença , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos Radiofarmacêuticos , Resultado do Tratamento
10.
Lung Cancer ; 80(1): 35-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23352033

RESUMO

INTRODUCTION: Molecular profiling of advanced non-small cell lung cancer (NSCLC) has become essential for predicting customized medical treatment decision. In light of recent advances in non-invasive diagnostic procedures in NSCLC, we aimed to demonstrate the reliability of assessing molecular tests for epidermal growth factor receptor (EGFR) and KRAS genes on cytological samples by comparing the molecular profile obtained on cells from scraped smears with that on paired needle washing in a series of NSCLC cases. METHODS: Thirty-two cytological specimens obtained by fine-needle aspiration biopsy procedures from primary or metastatic lesions of NSCLCs were Giemsa stained for a rapid on-site evaluation and, in case of an adequate sampling, the cellular material obtained from needle washing was collected into a saline solution. Scraped smears and needle washings were tested for EGFR and KRAS by polymerase chain reaction followed by direct sequencing. RESULTS: The concordance between EGFR and KRAS mutational status in 29 paired scraped smears and needle washing was 100%, with 7 paired samples showing the same EGFR mutation (4 L858R mutation, 2 E746_A750 deletion and 1 A767_V769 duplication) and 8 paired samples showing the same KRAS mutations (4 G12D, 1 G12A, 1 G12V and 2 G12C). Three scraped smears, uninformative for poor DNA quality, resulted EGFR mutated on paired needle washings. CONCLUSIONS: Needle washing obtained in the course of NSCLC non-invasive fine needle diagnostic procedures allows reliable mutation testing and can be regarded as an additional important source of biological material for molecular profiling of advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Pulmão/metabolismo , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Substituição de Aminoácidos , Biópsia por Agulha Fina , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Análise Mutacional de DNA/métodos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas p21(ras) , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Deleção de Sequência
11.
Diagn Cytopathol ; 41(7): 595-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22833420

RESUMO

Epidermal growth factor receptor (EGFR) and Kras gene mutations are crucial for discriminating patients responsive to anti-EGFR drugs in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), respectively. The majority of NSCLCs come to clinical attention at an advanced stage when surgery is no longer recommended and a considerable number of them are diagnosed by cytology only. A large number of metastatic CRCs are also diagnosed by imaging and minimally invasive techniques such as fine-needle aspiration biopsy. Here, we report our experience in the mutation analysis of EGFR and Kras on cytological material obtained from superficial and deep lesions of NSCLC and CRC. Our series included 63 cytological specimens from primary or metastatic lesions of 42 NSCLCs and 21 CRCs. The cytological material was adequate for the mutation analysis in 39/42 (93%) NSCLCs and in 20/21(95%) CRCs. EGFR and Kras mutations were found in 9 (23%) and 9 (23%) NSCLC cases, respectively. Kras mutations were found in 9/20 (45%) CRC specimens. Histological samples from the primary tumors were available in 9/42 NSCLCs and in 17/21 CRCs. The agreement of EGFR and Kras mutational status in cytological vs. histological samples was 100% for NSCLC and 88% for CRC. Our results suggest that standard cytology provides adequate material for the assessment of EGFR and Kras mutational status in NSCLC and CRC patients and could be specifically indicated in patients not eligible for surgery but candidate to anti-EGFR therapy.


Assuntos
Adenocarcinoma/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Expressão Gênica , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Análise Mutacional de DNA , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Linfonodos/patologia , Metástase Linfática , Proteínas Proto-Oncogênicas p21(ras) , Reprodutibilidade dos Testes
12.
Appl Immunohistochem Mol Morphol ; 20(4): 356-62, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22710815

RESUMO

INTRODUCTION: Epidermal growth factor receptor (EGFR) gene mutations are usually detected by direct sequencing to identify patients with advanced pulmonary adenocarcinomas as candidates for tyrosine kinase inhibitor therapy. The aim of the study was to evaluate the efficacy of EGFR mutation-specific antibodies in identifying EGFR-mutated adenocarcinomas. MATERIALS AND METHODS: Thirty-three consecutive cases of pulmonary adenocarcinomas sequenced for EGFR mutations were retrieved from our files. Immunohistochemistry was performed with the rabbit monoclonal antibodies E746-A750del (6B6) and L858R (43B2). The results obtained using the 2 procedures were statistically compared by Coehn κ and by calculation of sensitivity and specificity. RESULTS: There were 21 women and 12 men, ranging in age from 48 to 78 years. All cases were lung adenocarcinomas, 23 primaries and 10 metastatic. The mutational spectrum was as follows: 12 cases mutated in exon 19 (9 with E746-A750del, 1 with homozygote L747-T751del, 1 with L747-P753del, 1 with E747-S752del), 6 in exon 21 (5 with L858R, 1 with L861Q+L862L), and 15 EGFR wild type. Immunohistochemistry detected 6/9 cases with an E746-A750del mutation (κ=0.744, sensitivity: 66.7%, specificity: 100%) and 5/5 cases with an L858R mutation (κ=1, sensitivity: 100%, specificity: 100%). Four cases showed faint and focal immunostaining and were interpreted as negative. All other cases were negative. Overall, the 2 antibodies had 61.1% sensitivity and 100% specificity for EGFR mutations. CONCLUSIONS: EGFR mutation-specific antibodies may represent a first-line screening tool to identify patients as candidates for tyrosine kinase inhibitor therapy.


Assuntos
Adenocarcinoma/enzimologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/imunologia , Neoplasias Pulmonares/enzimologia , Adenocarcinoma/tratamento farmacológico , Idoso , Anticorpos/imunologia , Análise Mutacional de DNA , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Sensibilidade e Especificidade , Análise de Sequência de DNA
13.
J Thorac Oncol ; 3(10): 1104-11, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18827605

RESUMO

INTRODUCTION: Epidermal growth factor receptor (EGFR) gene intron 1 contains a polymorphic single sequence dinucleotide repeat (CA)n whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)n polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC). METHODS: Blood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron 1 gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron 1 polymorphism was also studied. RESULTS: EGFR intron 1 polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)16 and with a (CA)else genotype, respectively; p = 0.044). Patients with a (CA)16 genotype had a longer survival compared with those with a (CA)else genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)16 allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)16 allele (p = 0.003). CONCLUSIONS: This study supports a potential role of EGFR intron 1 polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Íntrons/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/genética , Repetições de Dinucleotídeos/genética , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Dosagem de Genes , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento
14.
J Clin Oncol ; 26(11): 1789-96, 2008 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-18347005

RESUMO

PURPOSE: The anti-HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [Fc gamma R]IIIa; Fc gamma RIIa) and inhibitory (Fc gamma RIIb) antibody receptors and Fc gamma R polymorphisms have been identified that may affect the antibody-dependent cell-mediated cytotoxicity (ADCC) of natural-killer cells/monocytes. In this study, we tested whether Fc gamma R polymorphisms are associated with clinical outcome of patients with breast cancer who received trastuzumab. PATIENTS AND METHODS: Fifty-four consecutive patients with HER-2/neu-amplified breast cancer receiving trastuzumab plus taxane for metastatic disease were evaluated for genotype for the Fc gamma RIIIa-158 valine(V)/phenylalanine(F), Fc gamma RIIa-131 histidine(H)/arginine(R), and Fc gamma RIIb-232 isoleucine(I)/threonine(T) polymorphisms. Trastuzumab-mediated ADCC of patients' peripheral blood mononuclear cells (PBMCs) was measured by chromium-51 release using a HER-2/neu-expressing human breast cancer cell line as a target. Controls comprised thirty-four patients treated with taxane alone. RESULTS: Our population was in Hardy-Weinberg equilibrium except for the Fc gamma RIIb polymorphism. The Fc gamma RIIIa-158 V/V genotype was significantly correlated with objective response rate (ORR) and progression-free survival (PFS). Also, there was trend significance in ORR and PFS for the Fc gamma RIIa-131 H/H genotype. The combination of the two favorable genotypes (VV and/or H/H) was independently associated with better ORR and PFS compared with the other combinations. The ADCC analysis showed that V/V and/or H/H PBMCs had a significantly higher trastuzumab-mediated cytotoxicity than PBMCs harboring different genotypes. CONCLUSION: These data support for the first time the hypothesis that Fc gamma R-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of Fc gamma R polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Polimorfismo Genético , Receptor ErbB-2/metabolismo , Receptores de IgG/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Receptores de IgG/metabolismo , Transdução de Sinais , Taxoides/administração & dosagem , Trastuzumab , Resultado do Tratamento
15.
Clin Cancer Res ; 13(21): 6518-26, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17975165

RESUMO

PURPOSE: To evaluate the role of pretreatment and posttreatment expression in buccal mucosa cells of signal transduction proteins activated by epidermal growth factor receptor, including phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated mitogen-activated protein kinase (p-MAPK), and phosphorylated AKT (p-AKT), in predicting gefitinib activity in advanced non-small cell lung cancer patients. Expression of the same proteins was also assessed on corresponding tissue samples for comparison. Moreover, EGFR gene mutations and copy number were analyzed. EXPERIMENTAL DESIGN: Protein expression was evaluated by standard immunocytochemistry in buccal smears, obtained by scraping immediately before and after 2 weeks of gefitinib treatment, and in the available archival tumor specimens. EGFR gene mutations were evaluated by direct sequencing and gene copy number was determined by fluorescence in situ hybridization. Data were correlated with gefitinib toxicity and objective response. RESULTS: Fifty-eight patients with pretreated advanced non-small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses). Toxicity (P = 0.025) and baseline p-AKT expression in buccal mucosa cells (P = 0.061) showed a potential predictive role. On the contrary, the probability of achieving an objective response was not affected by pretreatment expression of EGFR, p-EGFR, and p-MAPK, either in buccal mucosa or in tumor tissue. Responders showed a nonstatistically significant trend toward a more pronounced reduction in the expression of p-EGFR, p-MAPK, and p-AKT after gefitinib treatment. Among responders, five of six (83%) tumors showed EGFR gene mutation, whereas none of the tumors from patients with stable or progressive disease did (P < 0.001). CONCLUSIONS: Epithelial cells obtained from buccal mucosa may be used to assess the pharmacodynamic effect of EGFR-targeted agents, and pretreatment p-AKT expression may be a possible predictive biomarker of in vivo gefitinib activity.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Pulmonares/tratamento farmacológico , Mucosa Bucal/citologia , Mucosa Bucal/metabolismo , Quinazolinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Receptores ErbB/metabolismo , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Fatores de Tempo
16.
Breast ; 16(3): 280-92, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17257844

RESUMO

Early age at onset is generally considered an indicator of genetic susceptibility to breast cancer. To address both the proportion of early-onset breast cancer associated with BRCA-1 or BRCA-2 germline mutation and the contribution of germline mutations to the clinical features and outcome of these tumors, we analyzed molecular status and clinical variables of a population-based sample of 66 Italian women diagnosed with breast cancer before the age of 40 who were unselected for family history. BRCA mutations were screened by automated sequencing of the entire BRCA-1 and BRCA-2 coding regions and splice junctions. Twenty-eight late-onset (over 45 years), sporadic, breast cancers were designated as "control group" for comparisons with early-onset cases. BRCA mutations (10 BRCA-1 and 6 BRCA-2) were detected in 15 (22.7%) out of 66 tested patients. The combination of ER, PR, HER-2/neu negativity and p53 positivity was significantly more frequent in BRCA-1 positive tumors than in BRCA-2 positive and non-BRCA tumors (P=0.03). Taken collectively, BRCA-positive tumors correlated with high histologic grade and ER negativity compared with non-BRCA and sporadic tumors (P=0.05 and 0.003, respectively). There were no significant differences between BRCA-associated breast cancers (BABC) and non-BABC in relapse-free, event-free, and overall survival. Our data confirm that the combination of age at onset and tumor phenotype can provide an efficient model for identifying individuals with a high probability of carrying BRCA mutations and support the hypothesis that breast cancer in BRCA carriers is qualitatively distinct from other early-onset breast cancers and from late-onset, sporadic, breast carcinomas. Further studies on incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Adulto , Idade de Início , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Proteína Supressora de Tumor p53/análise
17.
Breast Cancer Res Treat ; 91(2): 203-5, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15868448

RESUMO

We report the first case in Italy of a non-Ashkenazi double heterozygote for BRCA1 and BRCA2 genes. This finding is predictably rare, with a maximum frequency of 1/250,000. The proband and her mother were diagnosed with early-onset breast cancer. No other relatives with breast and/or ovarian cancer were observed. The implications of this case in regard to genetic testing and counseling are substantial.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Adulto , Feminino , Heterozigoto , Humanos , Itália , Linhagem
18.
Tumori ; 91(6): 505-12, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16457150

RESUMO

PURPOSE: To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. PATIENTS AND METHODS: We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. RESULTS: Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P < 0.001), and more likely to be histological grade 3 (100% vs 14%, P < 0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P < 0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors (P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. CONCLUSION: In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/genética , Genes BRCA1 , Mutação em Linhagem Germinativa , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Proliferação de Células , Intervalo Livre de Doença , Feminino , Frequência do Gene , Aconselhamento Genético , Predisposição Genética para Doença , Heterozigoto , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Valor Preditivo dos Testes , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/análise
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