RESUMO
INTRODUCTION: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADPribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). RESULTS: Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. CONCLUSIONS: The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidadeRESUMO
Tumor vaccine after high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) aims at directing immune recovery toward tumor responses after optimizing minimal residual disease. We have characterized T-cell recovery and tumor response after a regimen devised as a platform for such immunotherapy. One hundred patients with high-risk or metastatic breast cancer received 3 to 7 cycles of paclitaxel and cyclophosphamide (overall response rate, 78%) and then HDC with melphalan and etoposide. Seventy-one patients received HDC and ASCT (no mortality at 100 days). At 24 months after transplantation, progression-free and overall survival probabilities for patients with stage IIIA, IIIB, and IV disease were 82%, 81%, and 42% and 100%, 94%, and 68%, respectively. The median progression-free and overall survivals from entry on study for stage IV patients were 15.3 and 38.1 months, respectively. CD3 + , CD8 + , and CD4 + cells were severely depleted after ASCT. Although total CD8 + T-cell numbers approached the normal range by 3 months, most of these cells were CD28 - . Naive CD45RA + CD4 + T cells approached the normal range only 18 months after ASCT and only in younger patients. The described observations provide the basis for devising a strategy for cancer vaccine administration after ASCT. Incorporating immune reconstitution enhancement after ASCT may be advantageous.
Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Recuperação de Função Fisiológica , Vacinação , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Vacinas Anticâncer/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/imunologia , Transplante AutólogoRESUMO
Earlier detection of invasive and noninvasive breast cancer and more effective treatments have led to both an improved prognosis for women with breast cancer and an increasing number of long-term survivors. However, such advances present various physical and emotional health challenges to patients facing breast cancer and its aftermath. Thus, understanding of the specific medical and psychosocial problems associated with survivorship is paramount in primary care.
Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Sobreviventes/psicologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/complicações , Feminino , Cardiopatias/induzido quimicamente , Humanos , Leucemia/induzido quimicamente , Menopausa/efeitos dos fármacos , Saúde Mental , Pessoa de Meia-Idade , Defeitos do Tubo Neural/induzido quimicamente , Osteoporose/complicações , Osteoporose/diagnóstico , Cuidados Pós-Operatórios/métodos , Gravidez , Insuficiência Ovariana Primária/induzido quimicamente , Prevenção Secundária , Taxa de Sobrevida , Tamoxifeno/efeitos adversos , Aumento de Peso/efeitos dos fármacosRESUMO
PURPOSE AND EXPERIMENTAL DESIGN: The purpose is to define intratumoral microvessel density (MVD) and potential biological markers that correlate with inflammatory breast cancer (IBC), we examined MVD, estrogen receptor a (ER) status, MIB-1 proliferation index, p53, and c-erbB-2 by immunohistochemistry in archival specimens from 67 women diagnosed with breast cancer with or without the inflammatory phenotype at the Institut Salah Azaiz (Tunis, Tunisia). RESULTS: The moderate (25-50/x400 field) to high microvessel count (>50/x400 field) was observed in 23 (51%) of 45 IBC tumors compared with 3 (14%) of 22 non-IBC tumors (P = 0.0031; chi(2) test). The presence of ER was found in 6 (14%) of 44 cases versus 7 (32%) of 22 cases in IBC and non-IBC, respectively (P = 0.10). In this series of 67 patient tumors, the median MVD count in ER-negative breast tumors was 21, whereas the median count was 4 in ER-positive breast tumors (P = 0.08; Wilcoxon rank-sum test). However, MIB-1, p53, and c-erbB-2 were not significantly different between IBC and non-IBC tumors. The intratumoral MVD between IBC and non-IBC was still statistically significant after adjustment for multiple comparisons (P = 0.02; Bonferroni test). CONCLUSIONS: These data suggest that there is an increased MVD in breast cancer with the inflammatory phenotype as compared with breast cancer without the inflammatory phenotype.