Assuntos
Antineoplásicos/farmacocinética , Tumores do Estroma Gastrointestinal/metabolismo , Indóis/farmacocinética , Obesidade/metabolismo , Pirróis/farmacocinética , Adulto , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Indóis/uso terapêutico , Masculino , Obesidade/complicações , Pirróis/uso terapêutico , SunitinibeRESUMO
Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II alpha (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.
Assuntos
Antígenos de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Amplificação de Genes , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/terapia , Adulto , Antraciclinas/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/enzimologia , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização In Situ , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Países Baixos , Transplante de Células-Tronco de Sangue Periférico , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico , Receptor ErbB-2/genética , Tiotepa/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. PATIENTS AND METHODS: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation. RESULTS: At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02). CONCLUSIONS: The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Genes erbB-2 , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imuno-Histoquímica , Segunda Neoplasia Primária/induzido quimicamente , Estudos Prospectivos , Análise de SobrevidaRESUMO
Gemcitabine (2'-deoxy-2'-difluorocytidine monohydrochloride) at a dose of 1250 mg/m(2) was given as a 30-min intravenous (i.v.) infusion on days 1 and 8 in a 3-weekly schedule to 32 patients with advanced soft-tissue sarcoma (STS) failing first-line chemotherapy. One patient was ineligible due to a delay between the previous chemotherapy and the start of treatment. Of the eligible patients, median age was 53 years (range 23-73 years). The predominant histological subtype was leiomyosarcoma in 12 patients (38%). The median number of cycles was three (range 1-8 cycles) with a median total dose of gemcitabine of 6.25 g/m(2) (range 1.25-19.97 g/m(2)). The relative dose intensity of gemcitabine was 96% (range 50-103%). Treatment was tolerated very well with non-complicated haematological toxicity as the most frequently observed side-effect. Only one partial tumour response was documented, giving a response rate of 3.23% (95% Confidence Interval (CI): 0.08-16.2%). The median overall survival was 268 days (95% CI: 129-377) and the median time to progression was 45 days (95% CI: 41-79). These results indicate that gemcitabine given at this dose and schedule is not active as second-line therapy in advanced STS.
