RESUMO
Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in <5% of tumor cells and 1 (0.5%) showed focal membranous staining. All histologic mimics were negative. In conclusion, diffuse and/or at least focally strong nuclear pan-TRK staining is a sensitive and specific marker for secretory carcinoma of the breast.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama/enzimologia , Carcinoma/enzimologia , Fusão Gênica , Imuno-Histoquímica , Receptores de Fator de Crescimento Neural/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Carcinoma/genética , Carcinoma/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Paris , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-ets/genética , Receptores de Fator de Crescimento Neural/genética , Proteínas Repressoras/genética , Estados Unidos , Adulto Jovem , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
BACKGROUND: Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. METHODS: A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab. RESULTS: The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. DISCUSSION: This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/enzimologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Lapatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
BACKGROUND: Glutathione peroxidase 1 gene (GPX1) is one of the antioxidant enzyme that remove the reactive oxygen species in a continuous process. Since the identification of a well-characterized functional polymorphism named p.Pro198Leu (rs1050450 C>T) in GPX1 gene, abundant studies have evaluated the association between p.Pro198Leu polymorphism and tumor risk in diverse population. But, the available results related to breast cancer are conflicting and absent in Africa. The present case-control study was planned to assess the presence of GPX1 Pro198Leu polymorphism in Rwanda population to determine whether it is associated with the risk of developing breast cancer. METHODS: Genomic DNA from peripheral blood leukocytes of 41 patients with breast cancer and 42 healthy controls were enrolled and genotyped GPX1 Pro198Leu polymorphism by PCR amplification and DNA sequencing. RESULTS: No significant difference in the frequencies of Pro/Pro (49%) and Pro/Leu (51%) genotypes in cancer cases and in controls (50% each) were found. The allelic frequencies of Pro and Leu were 74% versus 26% and 75% versus 25% in breast cancer cases and controls respectively. No association was observed in allele frequencies of Pro and Leu, and familial history. Only an overall association of GPX1 Pro198Leu with grade of cancer (Pro/Leu vs. Pro/Pro: p = .0200) was detected. CONCLUSION: The result of this study suggested that GPX1 Pro198Leu polymorphism could not be a risk factor for breast cancer in Rwanda. However, large-scale studies on the effect of this polymorphism on the factors disturbing the redox homeostasis are needed for conclusive understanding.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Glutationa Peroxidase/genética , Adulto , Alelos , Sequência de Bases , Neoplasias da Mama/epidemiologia , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Estudos de Casos e Controles , Códon , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Glutationa Peroxidase/sangue , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Fatores de Risco , Ruanda/epidemiologia , Glutationa Peroxidase GPX1RESUMO
BACKGROUND: In 2011, the NABON Breast Cancer Audit (NBCA) was instituted as a nation-wide audit to address quality of breast cancer care and guideline adherence in the Netherlands. The development of the NBCA and the results of 4 years of auditing are described. METHODS: Clinical and pathological characteristics of patients diagnosed with invasive breast cancer or in situ carcinoma (DCIS) and information regarding diagnosis and treatment are collected in all hospitals (n = 92) in the Netherlands. Thirty-two quality indicators measuring care structure, processes and outcomes were evaluated over time and compared between hospitals. RESULTS: The NBCA contains data of 56,927 patients (7,649 DCIS and 49,073 invasive cancers). Patients being discussed in pre- and post-operative multidisciplinary team meetings improved (2011: 83% and 91%; 2014: 98% and 99%, respectively) over the years. Tumour margin positivity rates after breast-conserving surgery for invasive cancer requiring re-operation were consistently low (â¼5%). Other indicators, for example, the use of an MRI-scan prior to surgery or immediate breast reconstruction following mastectomy showed considerable hospital variation. CONCLUSIONS: Results shown an overall high quality of breast cancer care in all hospitals in the Netherlands. For most quality indicators improvement was seen over time, while some indicators showed yet unexplained variation. J. Surg. Oncol. 2017;115:243-249. © 2016 Wiley Periodicals, Inc.
Assuntos
Neoplasias da Mama Masculina/cirurgia , Neoplasias da Mama/cirurgia , Carcinoma in Situ/cirurgia , Auditoria Médica/métodos , Melhoria de Qualidade , Oncologia Cirúrgica/normas , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Carcinoma in Situ/epidemiologia , Carcinoma in Situ/patologia , Prática Clínica Baseada em Evidências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Países Baixos/epidemiologia , Indicadores de Qualidade em Assistência à Saúde , Oncologia Cirúrgica/métodos , Oncologia Cirúrgica/estatística & dados numéricosRESUMO
BACKGROUND: Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers. METHODS: Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes. RESULTS: Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours. CONCLUSIONS: This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.
Assuntos
Neoplasias da Mama Masculina/genética , Genes p53 , Mutação , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/metabolismo , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MasculinoRESUMO
We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , TrastuzumabRESUMO
Anaplastic large-cell lymphoma is an extremely rare lymphoma subtype. We describe the mammographic and ultrasonographic findings in a 51-year-old male patient who suffered from a palpable lump caused by this rare disease.
Assuntos
Neoplasias da Mama Masculina/diagnóstico por imagem , Linfoma Anaplásico de Células Grandes/diagnóstico por imagem , Quinase do Linfoma Anaplásico , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Humanos , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Pessoa de Meia-Idade , Radiografia , Receptores Proteína Tirosina Quinases/análise , UltrassonografiaRESUMO
INTRODUCTION: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC). METHODS: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs. RESULTS: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC. CONCLUSIONS: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.
Assuntos
Arilamina N-Acetiltransferase/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama Masculina/enzimologia , Carcinoma Ductal de Mama/enzimologia , Carcinoma Intraductal não Infiltrante/enzimologia , Isoenzimas/metabolismo , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Arilamina N-Acetiltransferase/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/classificação , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/mortalidade , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/mortalidade , Carcinoma Intraductal não Infiltrante/classificação , Carcinoma Intraductal não Infiltrante/diagnóstico , Carcinoma Intraductal não Infiltrante/mortalidade , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Isoenzimas/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , Prognóstico , Estatísticas não Paramétricas , Análise Serial de Tecidos , Adulto JovemRESUMO
INTRODUCTION: Her2/neu is a biomarker which is amplified and/or overexpressed in a subset of breast cancer patients who are eligible to receive trastuzumab. Her-2 gene amplification analysed by fluorescence in situ hybridisation (FISH) and/or protein over-expression detected by immunohistochemistry (IHC) are the two main methods used to detect Her-2 status in clinical practice. The concordance rate between the two techniques is controversial. METHODS: FISH analysis were performed on 104 tumoural samples from breast cancer patients with known IHC results to determine the Her2 gene status. The FISH/IHC analyses results were then compared and the concordance rate was determined. RESULTS: Her2 gene amplification was detected in 0 of IHC score 1+, 24/86 (27.91%) 2+, and 8/13 (61.54%) 3+. The IHC and FISH results concordance rates were 100%, 27.9%, and 61.5% for IHC scores of 1+, 2+, and 3+ respectively. CONCLUSION: The results of this study suggest that IHC 1+ should be considered as negative while IHC 2+ results need further confirmative analysis by FISH. Further quality control and standardization of IHC technique are required to improve the concordance rate between the two methods.
Assuntos
Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Amplificação de Genes , Genes erbB-2 , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente/métodos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genéticaRESUMO
PURPOSE: Response to neoadjuvant chemotherapy (NACT) for breast cancer patients cannot be predicted; however, polymorphism of the glutathione S-transferase genes GSTM1 and GSTT1 can modify the response to chemotherapy. The aim of this study was to establish whether there is an association between the polymorphism of GSTM1 and GSTT1 and response to NACT. METHODS: The subjects of this study were 45 patients with locally advanced breast cancer (LABC), who received the cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) regimen as NACT. We analyzed the relationship between the genotypes and responses to chemotherapy. RESULTS: The response rates to chemotherapy were better, although not significantly so, in patients with the GSTM1 and GSTT1 null genotypes (odds ratio [OR] 2.06 and 1.45). Similar findings were noted in patients with either or both of the null genotypes (OR 2.67 and 1.16). Among the responders, patients with the GSTM1 and GSTT1 null genotypes had higher rates of complete response following chemotherapy than those with one or more active allele (OR 1.8 and 1.3), although the difference was not significant. CONCLUSIONS: There was an association between the polymorphism of glutathione S-transferases and responses to chemotherapy, but the differences were not significant. However, larger studies are needed to investigate the role and efficiency of GST polymorphism in predicting response to chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Glutationa Transferase/genética , Polimorfismo Genético , Adulto , Idoso , Neoplasias da Mama/enzimologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama Masculina/enzimologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Análise de Sobrevida , Resultado do TratamentoAssuntos
Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/uso terapêutico , Tamoxifeno/uso terapêutico , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Citocromo P-450 CYP2D6/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Adesão à Medicação , Recidiva Local de Neoplasia , Medição de Risco , Fatores de Risco , Tamoxifeno/metabolismo , Resultado do TratamentoRESUMO
Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-taxane adduct and possibly inhibit taxane toxicity. We suggest that CYP1B1 might affect taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/genética , Hipersensibilidade a Drogas/genética , Paclitaxel/efeitos adversos , Polimorfismo de Nucleotídeo Único , Taxoides/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Idoso , Antineoplásicos Fitogênicos/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/genética , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Citocromo P-450 CYP1B1 , Citocromo P-450 CYP2C8 , Sistema Enzimático do Citocromo P-450/metabolismo , Docetaxel , Hipersensibilidade a Drogas/enzimologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Itália , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Razão de Chances , Paclitaxel/farmacocinética , Fenótipo , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxoides/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: The use of cytochrome P450 2D6-inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in patients with breast cancer. The objectives of this study were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event-free time (EFT). PATIENTS AND METHODS: Data were from PHARMO and included a community pharmacy dispensing database; PALGA, a nationwide pathology database; and the Dutch Medical Register in the Netherlands. Patients with breast cancer treated with adjuvant tamoxifen between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for concomitant CYP2D6 inhibitor exposure was used. Adherence calculated over the first year after tamoxifen initiation was related to breast cancer events in the following period. RESULTS: In total, 1,962 patients with breast cancer using tamoxifen were included, among whom 150 (7.6%) frequently used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed (adjusted hazard ratio [HR], 0.87; 95% CI, 0.42 to 1.79; P = .69). Poor tamoxifen adherence was associated with lower EFT (adjusted HR, 0.987; 95% CI, 0.975 to 0.999; P = .029). CONCLUSION: This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen despite the strong biologic rationale. This study shows, to the best of our knowledge for the first time, that poor tamoxifen adherence is associated with an increased risk of breast cancer events.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/uso terapêutico , Adesão à Medicação , Recidiva Local de Neoplasia , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Citocromo P-450 CYP2D6/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco , Fatores de Risco , Tamoxifeno/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Despite good prognosis in most cases of lymph node (LN)-negative breast cancer, individual patients may have markedly different clinical outcomes. Here, we investigated the prognostic significance of HER2/neu overexpression in these tumors. MATERIALS AND METHODS: We employed a tissue microarray to examine HER2/neu overexpression by immunohistochemical staining in 359 consecutive patients diagnosed with LN-negative breast cancer, who underwent surgery from January 1993 to December 1998. RESULTS: HER2/neu overexpression was detected in 81 of 359 (23.1%) patients. The 10-year disease-free survival (DFS) values (81.2% versus 61.8%, P value 0.000) and overall survival (OS) rates (85.7% versus 63.9%, P value 0.000) were significantly different between cases with HER2/neu-negative or HER2/neu-positive tumors. After multivariate analysis, HER2/neu status and tumor size were identified as independent prognostic factors for 10-year OS. Moreover, HER2/neu overexpression was significantly associated with poorer clinical outcomes in an intermediate-risk group identified by the St Gallen classification (10-year DFS, 79.6% versus 61.8%, P value 0.000; 10-year OS, 84.7% versus 63.9%, P value 0.000). CONCLUSIONS: Our results show that HER2/neu overexpression is an important independent prognostic factor for LN-negative breast cancer cases and support the theory that more intensive adjuvant chemotherapy is required in the population with HER2/neu overexpression.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/enzimologia , Receptor ErbB-2/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/patologia , Neoplasias da Mama Masculina/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Novel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects. PATIENTS AND METHODS: Thirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-beta overexpression and none showed c-kit expression. RESULTS: No objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-gamma production by TCR-activated CD4(+) T cells. CONCLUSION: Imatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/biossíntese , Pirimidinas/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/biossíntese , Adulto , Antineoplásicos/uso terapêutico , Benzamidas , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama Masculina/imunologia , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/enzimologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Mesilato de Imatinib , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Estrogênios , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Nitrilas/uso terapêutico , Progesterona , Triazóis/uso terapêutico , Neoplasias da Mama Masculina/sangue , Neoplasias da Mama Masculina/induzido quimicamente , Neoplasias da Mama Masculina/enzimologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/induzido quimicamente , Carcinoma Ductal de Mama/enzimologia , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/secundário , Terapia Combinada , Acetato de Ciproterona/efeitos adversos , Acetato de Ciproterona/uso terapêutico , Estradiol/sangue , Estrogênios Conjugados (USP)/efeitos adversos , Estrogênios Conjugados (USP)/uso terapêutico , Humanos , Letrozol , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/sangue , Neoplasias Hormônio-Dependentes/induzido quimicamente , Neoplasias Hormônio-Dependentes/enzimologia , Transtornos Fóbicos/tratamento farmacológico , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/secundário , Testosterona/sangue , Resultado do TratamentoRESUMO
The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels (AU)
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama Masculina/sangue , Neoplasias da Mama Masculina/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Estrogênios/uso terapêutico , Acetonitrilas/uso terapêutico , Triazóis/uso terapêutico , Progesterona/uso terapêutico , Neoplasias da Mama Masculina/induzido quimicamente , Neoplasias da Mama Masculina/enzimologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/induzido quimicamente , Acetato de Ciproterona/uso terapêutico , Estrogênios Conjugados (USP)/efeitos adversos , Estrogênios Conjugados (USP)/uso terapêutico , Neoplasias da Medula Espinal/radioterapia , Neoplasias da Medula Espinal/secundárioRESUMO
BACKGROUND: Male breast cancer (MBC) commonly expresses hormone receptors and there is anecdotal evidence of disease responsivity to aromatase inhibitors in the metastatic setting. Our objectives were to: (i) assess clinical-pathologic characteristics in a consecutive cohort of MBC (ii) evaluate intratumoral aromatase (ITA) expression via tissue microarray (TMA) and (iii) assess the prognostic impact of ITA METHODS: A retrospective review was conducted to identify all cases of MBC seen at the Nova Scotia Cancer Center between 1985 and 2005. Specimens were reviewed for standard pathologic characteristics and tumor blocks were incorporated into three TMA's (four 1 mm cores per tumor). Immunohistochemistry (IHC) for ER, PR, Her2-neu and ITA was performed blinded to clinical outcomes. ITA staining intensity was compared to control, benign hepatic tissue and if greater than or equal to liver was scored positive and if less than liver was scored negative. The log-rank test was used for survival comparisons and Kaplan-Meyer curves were used to estimate 3- and 5-year progression-free and overall survival probabilities. RESULTS: Fifty-four cases were identified with a median age of 64 (31-85 years). Median tumor size was 2.6 cm (0.3-8.0 cm) and 22(41%) had nodal metastases. Forty-five cases had tissue available for IHC. Of these, 40 (89%) were ER and 33 (73%) were PR positive. Her2-neu was overexpressed in four cases (10%) and 12 (27%) were positive for ITA expression. ITA positive tumors were less likely to be grade 3, have lymphovascular invasion or nodal metastases and were more likely to be of favorable histology compared to ITA negative tumors. In univariate analysis strong (versus weak) ITA expression was associated with improved 5 year overall (92% vs. 49%, P = 0.038) but not progression-free (82% vs. 76% P = 0.44) survival rates. CONCLUSIONS: Tumors with strong ITA expression may have a less aggressive phenotype compared to those with negative/weak ITA expression. Further investigation of ITA as a relevant prognostic factor as well as a potential therapeutic target in MBC is warranted.
Assuntos
Aromatase/metabolismo , Neoplasias da Mama Masculina/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/patologia , Progressão da Doença , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Análise Serial de TecidosRESUMO
BACKGROUND: Spleen tyrosine kinase (Syk) kinase has recently been considered as a tumor suppressor gene in breast cancer. MATERIALS AND METHODS: Syk expression in patients with invasive breast cancer was immunohistochemically assessed. RESULTS: Decreased expression was found in 26% of the specimens examined. In cases with vascular invasion, expression of Syk was lost in the intravascular emboli. A significant relationship between increased proliferation levels (as estimated by the proliferative index, Ki67) and decreased Syk expression (p <0.05) was found. CONCLUSION: Our data suggest that Syk protein expression inversely correlates with the proliferation and invasive capacity of breast cancer.
Assuntos
Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama/enzimologia , Proteínas Tirosina Quinases/biossíntese , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/patologia , Processos de Crescimento Celular/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptores de Interleucina-8A/biossíntese , Receptores de Interleucina-8B/biossíntese , Quinase SykRESUMO
Serine/threonine protein phosphatase 5 (PP5) appears to play an underappreciated role in the regulation of cellular proliferation. In estrogen-responsive cells, PP5 expression is stimulated by 17 beta-estradiol, and in a variety of p53 wild-type tumor cells the suppression of PP5 expression with ISIS 15534 inhibits growth. To further explore the relationship between PP5 and the development of human cancer, here we tested the effect of elevated PP5 expression on tumor growth using a mouse xenograph model and a stable MCF-7 cell line in which the expression of wild-type PP5 was placed under the control of tetracycline-off regulated transactivator and operator plasmids. In the xenograph model a modest two fold increase in PP5 protein levels significantly enhanced the growth rate of estrogen-dependent tumors, suggesting PP5 plays a positive role in tumor development.