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BACKGROUND: This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. METHODS: Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. RESULTS: A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9-9.9] and 27.0 months [95% CI, 23.9-30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). CONCLUSIONS: The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed.
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INTRODUCTION: The purpose of this investigation was to evaluate the efficacy of cisplatin chemotherapy in BRCA1 mutation carriers with metastatic breast cancer. METHODS: In a phase II, open-label study, 20 patients with metastatic breast cancer who carried a mutation in BRCA1 were treated with cisplatin 75 mg/m2 intravenously every 3 weeks as part of a 21-day cycle for 6 cycles. Restaging studies to assess response were performed after cycles 2 and 6, and every three months thereafter. RESULTS: Between July 2007 and January 2009, 20 patients were enrolled. Baseline characteristics were as follows: 65% had prior adjuvant chemotherapy, 55% had prior chemotherapy for metastatic breast cancer; mean age was 48 years (ranges 32 to 70); 30% estrogen receptor (ER) or progesterone receptor (PR)+, 70% ER/PR/Human Epidermal Growth Factor Receptor 2 (HER2)- and 0% HER2+. Overall response rate was 80%; nine patients experienced a complete clinical response (45%) and seven experienced a partial response (35%). Overall survival was 80% at one year, 60% at two years and 25% at three years. Four of the 20 patients are alive four years after initiating treatment. The median time to progression was 12 months. The median survival from the start of cisplatinum treatment was 30 months. Cisplatin-related adverse events, including nausea (50%), anemia (5%) and neutropenia (35%) were mostly mild to moderate in severity. CONCLUSIONS: This phase II study demonstrates that cisplatin chemotherapy has high activity in women with a BRCA1 mutation and metastatic breast cancer and is generally well tolerated. TRIAL REGISTRATION: This trial is registered retrospectively on the clinical trials website ClinicalTrials.gov. The identifier is NCT01611727.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cisplatino/uso terapêutico , Genes BRCA1 , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. METHODS: The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. RESULTS: A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). CONCLUSIONS: These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Receptor ErbB-2/biossíntese , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Encefálicas/induzido quimicamente , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/genética , Fatores de Risco , TrastuzumabRESUMO
Sarcopenia is common in metastatic colorectal cancer (mCRC), increases the risk of treatment-related toxicity and reduces survival. Trifluridine/tipiracil (TT) chemotherapy significantly improved survival in refractory mCRC patients, but the prognostic and predictive role of pretherapeutic sarcopenia and variation in the skeletal muscle index (SMI) during this treatment has not been investigated so far. In this retrospective, observational study, clinical data on mCRC patients treated with TT at six cancer centres in Poland were collected. Computed tomography (CT) scans acquired at the time of initiation of TT (CT1) and on the first restaging (CT2), were evaluated. SMI was assessed based on the skeletal muscle area (SMA) at the level of the third lumbar vertebra. Progression-free survival (PFS) and overall survival (OS) were calculated from the treatment start. Neither initial sarcopenia nor ≥5% skeletal mass loss (SML) between CT1 and CT2 had a significant effect on PFS in treated patients (p = 0.5526 and p = 0.1092, respectively). In the multivariate analysis, reduced OS was found in patients with ≥5% SML (HR: 2.03 (1.11-3.72), p = 0.0039). We describe the prognostic role of sarcopenia beyond second line treatment and analyze other factors, such as performance status, tumor histological differentiation or carcinoembryonic antigen level that could predict TT treatment response.
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BACKGROUND: Triple-negative breast cancer (TNBC) lacks expression of steroid hormone receptors (estrogen receptor α and progesterone) and epidermal growth factor receptor type 2. This phenotype shows high metastatic potential, with particular predilection to lungs and brain. Determination of TNBC transcriptomic profiles associated with high risk of brain metastasis (BM) might identify patients requiring alternative, more aggressive, or specific preventive and therapeutic approaches. PATIENTS AND METHODS: Using a cDNA-mediated annealing, selection, extension, and ligation assay, we investigated expression of 29,369 gene transcripts in primary TNBC tumor samples from 119 patients-71 in discovery cohort A and 48 in independent cohort B-that included best discriminating genes. Expression of mRNA was correlated with the occurrence of symptomatic BM. RESULTS: In cohort A, the difference at the noncorrected P < .005 was found for 64 transcripts (P = .23 for global test), but none showed significant difference at a preset level of false-discovery rate of < 10%. Of the 30 transcripts with the largest differences between patients with and without BM in cohort A, none was significantly associated with BM in cohort B. CONCLUSION: Analysis based on the primary tumor gene transcripts alone is unlikely to predict BM development in advanced TNBC. Despite its negative findings, the study adds to the knowledge on the biology of TNBC and paves the way for future projects using more advanced molecular assays.
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Neoplasias Encefálicas/diagnóstico , Perfilação da Expressão Gênica , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/secundário , Receptor alfa de Estrogênio/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
UNLABELLED: Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015). IN CONCLUSION: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.
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Neoplasias da Mama/tratamento farmacológico , Imuno-Histoquímica/métodos , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclina E/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Lapatinib , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Fosforilação/efeitos dos fármacos , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Adulto JovemRESUMO
BACKGROUND: Hereditary ovarian cancer in BRCA1 constitutional mutation carriers shows a characteristic clinical pattern. AIM OF THE STUDY: Evaluation of the type of mutation, age of onset, clinical stage (FIGO) and morphological grade (G) of ovarian cancers in BRCA1 mutation carriers. MATERIAL AND METHOD: We analyzed 16 cases of hereditary ovarian cancers from 14 families. The cases were included into studied group as a result of evaluation of pedigree criteria and molecular-genetic analyses detecting constitutional mutation--5382insC, C61G, 4153delA--founder mutations dominating the Polish population. The following features were compared between studied and control group: C1--age of onset of ovarian cancer in 5-year intervals (below 35, 40, 45, 50 and 55 years of age); C2--clinical staging (FIGO) I/II or III/IV: C3--grading (G1-G3). The data were analyzed statistically. RESULTS: Age of onset < 50, OR--2.52 is highly characteristic for BRCA1 mutation carries. Similarly the staging III/IV is more often observed in studied group--OR 2.71. The most characteristic of studied group is high morphological grading--OR 12.38. CONCLUSIONS: 1. Features of HOC in studied material and in other populations are similar 2. High morphological grading is the most characteristic for HOC in BRCA1 carriers.
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Efeito Fundador , Genes BRCA1 , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , DNA de Neoplasias/genética , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Ovarianas/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Hereditary ovarian cancer (HOC), as any genetic disease, may display clinical characteristics that depends on population. AIM OF THE STUDY: The aim of the study was to describe clinical characteristics of HOC in Polish population basing on analysis of the following features: age at onset, clinical staging, morphological grading and prevalence of serous adenocarcinoma. MATERIAL AND METHOD: The cases were selected basing on analysis of pedigree/clinical features and molecular studies of founder mutations of BRCA1 gene in Poland. RESULTS: The patient's age at diagnosis was ca 49-52 and was similar in all groups. The exception was the subgroup without mutations in group II (breast and ovarian cancers found in families) with mean age at diagnosis ca 46 years (n = 9). In patients with HOC without mutation of BRCA1 gene, lower FIGO stage and lower morphological grade were detected more frequently. The majority of HOC showed histopathological pattern of serous adenocarcinoma. CONCLUSIONS: Clinical features of HOC in Poland and in other countries are similar. 2. Introduction of DNA tests to the clinical and pedigree diagnostic criteria allows detection of subgroups of HOC with different clinical features.
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Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adulto , Idade de Início , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cistadenocarcinoma Seroso/epidemiologia , DNA de Neoplasias/genética , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Ovarianas/epidemiologia , Polônia/epidemiologia , Prevalência , Estudos RetrospectivosRESUMO
PURPOSE: P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients. EXPERIMENTAL DESIGN: In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions. RESULTS: In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes. CONCLUSIONS: The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/imunologia , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Intervalo Livre de Doença , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos Testes , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Receptores de Progesterona/metabolismo , Reprodutibilidade dos Testes , Estudos Retrospectivos , Trastuzumab , Resultado do TratamentoRESUMO
INTRODUCTION: The aim of this study was to assess the efficacy of Tc-99m sestamibi scintimammography in the prediction and evaluation of tumour response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS: The subjects consisted of 14 female patients with unilateral locally advanced breast cancer eligible for anthracycline-based neoadjuvant chemotherapy followed by surgery. The patients underwent mastectomies with pathologic evaluation of the residual tumour size. The early and delayed static imaging were undertaken in all subjects at 10 and 120 minutes after intravenous injection with 720-1080 MBq of Tc-99m MIBI. Patients lay prone on the scintimammographic pad (provided by the IAEA). The acquisition included three positions: both lateral prone and anterior supine. Early, delayed tumour to background ratios (TBR) and washout rate (WOR) were calculated. Three sets of scintimammography images were obtained: baseline study (BL), the first follow-up study (FF) after two cycles of chemotherapy and the second follow-up (SF) scan on completion of chemotherapy and prior to surgery. Clinical response was evaluated following WHO criteria and classified as complete response (CR), partial response (PR), stable disease (StD) and progressive disease (PD). All patients underwent BS, seven of them FF and eight completed the study with SF. RESULTS: The only statistically significant differences in Student's t-test for matched pairs were found between mean values of TBR10 and TBR120 in BL and FF study however in the SF study it was not significant. Other differences between the mean values of TBR10, TBR120 and WOR in BL/FF, BL/SF and FF/SF studies were not statistically significant. CONCLUSION: The results obtained are encouraging, but further investigations are needed.
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Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Tecnécio Tc 99m Sestamibi , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Seguimentos , Humanos , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Cintilografia , Resultado do TratamentoRESUMO
There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.