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1.
Anticancer Res ; 40(1): 305-313, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892581

RESUMO

BACKGROUND: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines. PATIENTS AND METHODS: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months. RESULTS: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m2), trauma history, renal insufficiency and bevacizumab use. CONCLUSION: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning.


Assuntos
Neoplasias/complicações , Trombose/etiologia , Trombose/terapia , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Fatores de Risco
2.
Cancer Genomics Proteomics ; 16(3): 195-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31018950

RESUMO

BACKGROUND/AIM: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. MATERIALS AND METHODS: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of "grey zone" tumors with low and very low PTEN protein expression. RESULTS: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned "grey zone" tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations,single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. CONCLUSION: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida
3.
Clin Breast Cancer ; 18(1): 53-62.e3, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28870680

RESUMO

BACKGROUND: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer. PATIENTS AND METHODS: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively. RESULTS: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy-8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028). CONCLUSION: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Amplificação de Genes , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Antraciclinas/uso terapêutico , Mama/citologia , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Núcleo Celular/metabolismo , Quimioterapia Adjuvante/métodos , Instabilidade Cromossômica , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adulto Jovem
4.
Transl Oncol ; 10(4): 589-598, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28666187

RESUMO

BACKGROUND: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription-polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS: Median age was 52.7years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P=.002 and P<.001, respectively). In the univariate analysis, low RANKL mRNA expression was found to be an unfavorable factor for DFS [hazard ratio (HR)=1.33, 95% confidence interval (CI) 1.05-1.68, Wald's P=.018] and bone metastasis-free survival (HR=1.67, 95% CI 1.09-2.56, P=.018), although it did not retain its significance in the multivariate analysis. CONCLUSIONS: Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts.

5.
J Transl Med ; 15(1): 30, 2017 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-28193231

RESUMO

BACKGROUND: The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively. RESULTS: OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00-1.59, Wald's p = 0.050) and OS (HR 1.37, 95% CI 1.05-1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10-1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61-2.05, p = 0.003) in the multivariate analysis. CONCLUSIONS: We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202.


Assuntos
Neoplasias da Mama/genética , Osteopontina/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Osteopontina/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
PLoS One ; 11(10): e0164013, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27695115

RESUMO

BACKGROUND-AIM: Early breast cancer is a heterogeneous disease, and, therefore, prognostic tools have been developed to evaluate the risk for distant recurrence. In the present study, we sought to develop a risk for recurrence score (RRS) based on mRNA expression of three proliferation markers in high-risk early breast cancer patients and evaluate its ability to predict risk for relapse and death. In addition the Adjuvant! Online score (AOS) was also determined for each patient, providing a 10-year estimate of relapse and mortality risk. We then evaluated whether RRS or AOS might possibly improve the prognostic information of the clinical treatment score (CTS), a model derived from clinicopathological variables. METHODS: A total of 1,681 patients, enrolled in two prospective phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Sufficient RNA was extracted from 875 samples followed by multiplex quantitative reverse transcription-polymerase chain reaction for assessing RACGAP1, TOP2A and Ki67 mRNA expression. The CTS, slightly modified to fit our cohort, integrated the prognostic information from age, nodal status, tumor size, histological grade and treatment. Patients were also classified to breast cancer subtypes defined by immunohistochemistry. Likelihood ratio (LR) tests and concordance indices were used to estimate the relative increase in the amount of information provided when either RRS or AOS is added to CTS. RESULTS: The optimal RRS, in terms of disease-free survival (DFS) and overall survival (OS), was based on the co-expression of two of the three evaluated genes (RACGAP1 and TOP2A). CTS was prognostic for DFS (p<0.001), while CTS, AOS and RRS were all prognostic for OS (p<0.001, p<0.001 and p = 0.036, respectively). The use of AOS in addition to CTS added prognostic information regarding DFS (LR-Δχ2 8.7, p = 0.003), however the use of RRS in addition to CTS did not. For estimating OS, the use of either AOS or RRS in addition to CTS added significant prognostic information. Specifically, the use of both CTS and AOS had significantly better prognostic value vs. CTS alone (LR-Δχ2 20.8, p<0.001), as well as the use of CTS and RRS vs. CTS alone (LR-Δχ2 4.8, p = 0.028). Additionally, more patients were scored as high-risk by AOS than CTS. According to immunohistochemical subtypes, prognosis was improved in the Luminal A (LR-Δχ2 7.2, p = 0.007) and Luminal B (LR-Δχ2 8.3, p = 0.004) subtypes, in HER2-negative patients (LR-Δχ2 23.4, p<0.001) and in patients with >3 positive nodes (LR-Δχ2 23.9, p<0.001) when AOS was added to CTS. CONCLUSIONS: The current study has shown a clear benefit in predicting overall survival of high-risk early breast cancer patients when combining CTS with either AOS or RRS. The combination of CTS and AOS adds significant prognostic information compared to CTS alone for DFS, while the combination of CTS with either AOS or RRS has better prognostic value than CTS alone for OS. These findings could possibly add on the information needed for the best risk prediction strategy in high-risk early breast cancer patients in a rather simple and inexpensive way, especially in Luminal A and B subtypes, HER2-negative patients and those with >3 positive nodes.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Neoplasias da Mama/diagnóstico , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
7.
BMC Neurol ; 16(1): 190, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27716097

RESUMO

BACKGROUND: Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored. METHODS: We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3-4 months and 6-8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR). RESULTS: At the 3-4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6-8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected. CONCLUSIONS: Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.


Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Nervoso Autônomo/induzido quimicamente , Sistema Nervoso Autônomo/efeitos dos fármacos , Carboplatina/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade
8.
Oncotarget ; 7(22): 32731-53, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27129168

RESUMO

BACKGROUND: We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era. RESULTS: TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009). MATERIALS AND METHODS: TP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off). CONCLUSIONS: TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Trastuzumab/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Classe I de Fosfatidilinositol 3-Quinases/análise , Classe I de Fosfatidilinositol 3-Quinases/genética , Ensaios Clínicos como Assunto , Progressão da Doença , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Grécia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/análise , Adulto Jovem
9.
Anticancer Res ; 36(5): 2365-78, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27127145

RESUMO

Wnt and epidermal growth factor receptor (EGFR) pathway abnormalities and de-stabilization of cell adhesion are all important aspects of the pathogenesis of triple-negative breast cancer (TNBC). Herein we investigated how the expression of related protein markers may affect the outcome of patients bearing TNBC treated in the adjuvant setting. Immunohistochemistry for beta-catenin, Myc (Wnt pathway), E-cadherin, P-cadherin (cell-adhesion), EGFR and cytokeratin 5 (CK5) (identification of basal-like tumors) was carried out in 364 centrally confirmed TNBCs. Survival analysis was performed with Cox-regression models according to dichotomized continuous protein expression data and marker interactions. In 352 evaluable tumors, 81.5% were basal-like TNBC. E-cadherin and P-cadherin were positively associated, with co-expression being present in 68% of tumors. Individual markers did not affect patient outcome. However, a statistically significant interaction was shown such that low expression of beta-catenin in the cell membrane, defined as expression below the median of the H-score distribution, was associated with unfavourable disease-free survival among tumors that expressed EGFR, but not in the absence of EGFR expression (interaction p=0.0085). The interaction persisted after correcting for clinicopathological variables. A considerable number of TNBC co-expresses E-cadherin and P-cadherin, while membranous localization of beta-catenin may predict patient outcome in an EGFR-dependent manner. This novel interaction seems worthy for validating with regards to its biological and clinical relevance.


Assuntos
Fator de Crescimento Epidérmico/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , beta Catenina/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Ligação Proteica , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Mol Clin Oncol ; 4(2): 211-220, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26893865

RESUMO

Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients WHO had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)-based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration FOR CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels <12 mg/dl at baseline and 47.9% received ESA prophylactically (1:1 randomization). The major tumor types included colorectal (36.0%), breast (20.6%), non-prostate genitourinary (11.0%) and lung CANCER (8.4%). After a median follow-up of 85.4 months, 358 patients had relapsed and 380 had succumbed to the disease. Patients in the prophylactic ESA group (GROUP A; experimental arm), as compared with those in the Hb-based group (GROUP B; iron supplementation alone), exhibited A significantly more prominent increase in median Hb levels, particularly in the subset of patients with non-metastatic disease (two-sided P<0.01) among patients receiving chemotherapy for advanced cancer, those who received ESAs prophylactically exhibited a lower incidence of CIA (all grades: P=0.014, grades 3-4: P=0.034) and fatigue (all grades: P<0.001, grades 3-4: P=0.055), but a higher rate of a composite outcome encompassing all thrombosis-related events (all grades: P=0.043, grades 3-4: P=0.099). These differences were less prominent in the group of patients who received adjuvant treatment. There were no significant differences in overall mortality and relapse/progression rates between the two groups. therefore, prophylactic, compared with Hb-based, administration of ESAs for CIA in patients with solid tumors, was found to be associated with a significantly lower incidence of anemia and fatigue, but with a marginally higher rate of thrombosis-related adverse events, particularly in patients receiving first-line chemotherapy for advanced cancer.

11.
Oncotarget ; 7(4): 5074-87, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26506242

RESUMO

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are considered in the prognosis of breast cancer (BC) patients. Here, we investigated the prognostic/predictive effect of TILs in patients treated in the frame of four prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab era. METHODS: TILs density was histologically assessed as percentage of stromal area on whole routine sections of 2613 BC (1563 Luminal A/B; 477 Luminal HER2; 246 HER2-enriched; 327 triple negative [TNBC]) and were evaluated as high/low at three cut-offs (c/o; 50% [lymphocytic predominance, LP], 35% and 25%), in separate training and validation sets. RESULTS: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively. TILs status did not interact with BC subtypes or trastuzumab treatment. LPBC patient outcome was not affected by nodal status, while high TILs were favorable in TNBC with unfavorable nodal status. When adjusted for standard clinicopathological parameters and treatment, high TILs independently predicted for favorable outcome, e.g., disease-free survival with the 35% c/o in the entire cohort (HR = 0.44, 95% CI 0.28-0.69, p < 0.001) and in specific subtypes. CONCLUSIONS: High TILs tumors, especially LPBC seem worthy validating as a separate entity of favorable prognosis in breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Metanálise como Assunto , Estudos Multicêntricos como Assunto , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
12.
PLoS One ; 10(10): e0140293, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26452060

RESUMO

BACKGROUND: The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer. METHODS: Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors. RESULTS: PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified. CONCLUSIONS: The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Pessoa de Meia-Idade , Taxa de Mutação , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais , Adulto Jovem
13.
J Transl Med ; 13: 171, 2015 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-26021752

RESUMO

BACKGROUND: The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as a validation analysis of another previously published HeCOG study. METHODS: RNA was extracted from 663 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples of high-risk early breast cancer patients enrolled in the randomized HE10/00 trial. Relative mRNA expression of all four HER family members was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: In compliance with our previous study, the overall agreement between qRT-PCR and IHC/FISH for HER2 status determination was good (69%). Likewise, the overall concordance between qRT-PCR and IHC for EGFR status was high (81%). In line with our previously reported data, we demonstrated a positive association between HER2 and HER3 mRNA expression. Similarly, mRNA expression of HER3 and HER4 was positively associated with each other and negatively associated with EGFR. Regarding relationships with clinico-pathological parameters, our findings are also in agreement with our previous results. Generally, increased EGFR and HER2 mRNA expression was related to unfavorable, whereas high HER3 and HER4 mRNA expression was associated with favorable clinico-pathological parameters. In univariate analysis, no significant association between EGFR, HER2 and HER3 mRNA expression and overall survival (OS) or disease-free survival (DFS) was demonstrated. However, high EGFR protein expression was associated with significantly shorter OS (log-rank, p = 0.015). In compliance with our previously published data, increased HER4 mRNA expression had a significantly favorable prognostic value in terms of OS (p = 0.044) and DFS (p = 0.047). In multivariate analysis, among all HER receptors, only EGFR protein expression was found to affect OS (Wald's p = 0.028) and DFS (p = 0.015) independently. Concerning the combined expression of all four HER family receptors, the combination of high EGFR, high HER2, low HER3 and low HER4 mRNA expression was associated with a trend for shorter OS (log-rank, p = 0.065) and significantly worse DFS (p = 0.033), compared with all other co-expression profiles. CONCLUSIONS: These data indicate that qRT-PCR may represent a valid alternative method for evaluating the expression of HER family members in FFPE breast carcinoma tissue samples. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609001036202.


Assuntos
Neoplasias da Mama/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Grécia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Reprodutibilidade dos Testes , Fatores de Risco , Adulto Jovem
14.
Pathol Oncol Res ; 21(2): 273-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25098276

RESUMO

To investigate the immunohistochemical expression of p85 in a cohort of trastuzumab-treated HER2-positive and HER2-negative metastatic breast cancer patients. The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients. Samples were evaluated by immunohistochemistry for p85, estrogen receptors (ER), progesterone receptors (PgR), HER2, Ki67, PTEN and phosphorylated Akt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization, as well. PIK3CA mutational status was also evaluated. Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients (50.7 months) compared to HER2-negative patients (36.6 months) both treated with trastuzumab, but this difference has not reached significance (p = 0.068). In total, 62% of the patients were found positive for p85, however the p85 protein was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was however associated with poor survival in trastuzumab-treated HER2-positive patients. In our cohort of trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/metabolismo , Índice de Gravidade de Doença , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Mama/metabolismo , Neoplasias da Mama/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estudos Retrospectivos , Transdução de Sinais/fisiologia , Taxa de Sobrevida , Resultado do Tratamento
15.
BMC Cancer ; 14: 515, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25026897

RESUMO

BACKGROUND: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet. METHODS: From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation. RESULTS: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020). CONCLUSIONS: No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Trastuzumab , Adulto Jovem
16.
Breast ; 23(3): 234-43, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24703723

RESUMO

The Androgen Receptor (AR) is a potential prognostic marker and therapeutic target in breast cancer. We evaluated AR protein expression in high-risk breast cancer treated in the adjuvant setting. Tumors were subtyped into luminal (ER+/PgR±/AR±), molecular apocrine (MAC, [ER-/PgR-/AR+]) and hormone receptor negative carcinomas (HR-negative, [ER-/PgR-/AR-]). Subtyping was evaluated with respect to prognosis and to taxane therapy. High histologic grade (p < 0.001) and increased proliferation (p = 0.001) more often appeared in MAC and HR-negative than in luminal tumors. Patients with MAC had outcome comparable to the luminal group, while patients with HR-negative disease had increased risk for relapse and death. MAC outcome was favorable upon taxane-containing treatment; this remained significant upon multivariate analysis for overall survival (HR 0.31, 95%CI 0.13-0.74, interaction p = 0.035) and as a trend for time to relapse (p = 0.15). In conclusion, AR-related subtyping of breast cancer may be prognostic and serve for selecting optimal treatment combinations.


Assuntos
Antagonistas de Receptores de Andrógenos , Neoplasias da Mama , Receptores Androgênicos/metabolismo , Taxoides , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Gradação de Tumores/estatística & dados numéricos , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Receptores Estrogênicos/metabolismo , Medição de Risco , Análise de Sobrevida , Taxoides/farmacologia , Taxoides/uso terapêutico
17.
PLoS One ; 9(3): e91407, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24637962

RESUMO

INTRODUCTION: We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes. PATIENTS AND METHODS: Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers. RESULTS: After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035). CONCLUSION: Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptores de Somatomedina/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptores de Somatomedina/genética , Reprodutibilidade dos Testes , Resultado do Tratamento , Adulto Jovem
18.
PLoS One ; 8(7): e69256, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23935969

RESUMO

UNLABELLED: To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR-positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00790894.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Epotilonas/administração & dosagem , Epotilonas/uso terapêutico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Intervalo Livre de Doença , Esquema de Medicação , Epotilonas/efeitos adversos , Epotilonas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Cooperação do Paciente , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resultado do Tratamento , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
19.
PLoS One ; 8(7): e70634, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23923010

RESUMO

BACKGROUND: Discrepant data have been published on the incidence and prognostic significance of ESR1 gene amplification in early breast cancer. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tumor blocks were collected from women with early breast cancer participating in two HeCOG adjuvant trials. Messenger RNA was studied by quantitative PCR, ER protein expression was centrally assessed using immunohistochemistry (IHC) and ESR1 gene copy number by dual fluorescent in situ hybridization probes. RESULTS: In a total of 1010 women with resected node-positive early breast adenocarcinoma, the tumoral ESR1/CEP6 gene ratio was suggestive of deletion in 159 (15.7%), gene gain in 551 (54.6%) and amplification in 42 cases (4.2%), with only 30 tumors (3%) harboring five or more ESR1 copies. Gene copy number ratio showed a significant, though weak correlation to mRNA and protein expression (Spearman's Rho <0.23, p = 0.01). ESR1 clusters were observed in 9.5% (57 gain, 38 amplification) of cases. In contrast to mRNA and protein expression, which were favorable prognosticators, gene copy number changes did not obtain prognostic significance. When ESR1/CEP6 gene ratio was combined with function (as defined by ER protein and mRNA expression) in a molecular classifier, the Gene Functional profile, it was functional status that impacted on prognosis. In univariate analysis, patients with functional tumors (positive ER protein expression and gene ratio normal or gain/amplification) fared better than those with non-functional tumors with ESR1 gain (HR for relapse or death 0.49-0.64, p = 0.003). Significant interactions were observed between gene gain/amplification and paclitaxel therapy (trend for DFS benefit from paclitaxel only in patients with ESR1 gain/amplification, p = 0.066) and Gene Functional profile with HER2 amplification (Gene Functional profile prognostic only in HER2-normal cases, p = 0.029). CONCLUSIONS: ESR1 gene deletion and amplification do not constitute per se prognostic markers, instead they can be classified to distinct prognostic groups according to their protein-mediated functional status.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Adulto Jovem
20.
PLoS One ; 8(3): e58182, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23536787

RESUMO

Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.


Assuntos
Genes BRCA1 , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Éxons , Família , Feminino , Genes BRCA2 , Grécia/epidemiologia , Heterozigoto , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Linhagem , Fenótipo , Prevalência , Adulto Jovem
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