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1.
Breast Cancer Res Treat ; 177(3): 659-667, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31297647

RESUMO

PURPOSE: The identification of biomarkers of hormonal therapy (HT) failure would allow tailored monitoring in metastatic breast cancer (mBC) patients. PIK3CA gene mutation is one of the most frequent events in mBC and is associated with HT resistance. We evaluated the early prognostic value of cell-free DNA (cfDNA) PIK3CA detection in first-line HT-treated mBC patients. METHODS: Between June 2012 and January 2014, 39 patients were prospectively included in a dedicated clinical trial (NCT01612871). Blood sampling was performed before (M0) and 4 weeks (M1), 3 months (M3) and 6 months (M6) after HT initiation, and at tumor progression. Patients were followed until progression or until the end of the study (2 years). Mutation detection was performed using droplet-based digital PCR (ddPCR). Progression-free survival (PFS) was used as primary endpoint. RESULTS: Median age at inclusion was 63 years (range 40-86). Most patients (34/39) received an aromatase inhibitor and presented a non-measurable disease (71.8%). PIK3CA mutations were reported in 10 (27.8%) and 5 (14.3%) cases at M0 and M1, respectively. The persistence of a detectable circulating mutation at M1 was highly correlated with a worse progression-free survival (PFS), rate at 1 year: 40% versus 76.7%; p = 0.0053). CONCLUSIONS: Four-week persistence of cfDNA PIK3CA mutation appears highly correlated with PFS. TRIAL REGISTRATION: NCT01612871, registered on June 6th, 2012; https://clinicaltrials.gov/ct2/show/NCT01612871 .


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , DNA Tumoral Circulante , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
2.
Br J Cancer ; 118(5): 679-697, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29438365

RESUMO

BACKGROUND: Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined. METHODS: We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results. RESULTS: In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD. CONCLUSIONS: The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Tomada de Decisão Clínica , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Projetos de Pesquisa
3.
BMC Cancer ; 15: 659, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26449988

RESUMO

BACKGROUND: Our retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting. METHODS: Patients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data. RESULTS: Two hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1-9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1-19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20-31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25-4.3) and 11.2 (95 %CI: 9.3-12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3-4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia. CONCLUSION: EM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Furanos/uso terapêutico , Cetonas/uso terapêutico , Taxoides/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Feminino , Furanos/farmacologia , Humanos , Cetonas/farmacologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
4.
Clin Chem Lab Med ; 51(9): 1833-41, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23787470

RESUMO

BACKGROUND: Anemia, a frequent and deleterious condition in patients with cancer, is mainly caused by chemotherapy toxicity, iron deficiency, or inflammation. We evaluated the baseline iron metabolism biomarkers and their association with anemia occurrence during chemotherapy in patients with early breast cancer (EBC). METHODS: In this monocentric retrospective study, classical iron metabolism markers and new biomarkers as well as sTfR and hepcidin were assessed at baseline in 347 patients with EBC who received a sequential taxane and anthracycline-based regimen between April 2007 and October 2009. Hemoglobin level was measured every 21 days. RESULTS: Thirty-five patients had baseline iron deficiency and 13 inflammatory iron sequestration. In multivariate analysis, only high sTfR (OR=27.6, p<0.001, 95% CI 8.74-87) and pre-menopausal status (OR=7.3, 95% CI 0.04-0.43, p=0.001) remained statistically associated with iron deficiency. High hepcidin values and inflammatory iron sequestration were significantly associated (p=0.032). In total 6.1% patients had baseline anemia and 86.2% patients developed anemia during chemotherapy (41 had grade ≥2 anemia). Baseline hemoglobin below 13 g/dL and low hepcidin levels were the two independent predictive factors of severe anemia. CONCLUSIONS: In early breast cancer treated by chemotherapy, only baseline hemoglobin and hepcidin levels are independent predictive factors of anemic syndrome occurrence.


Assuntos
Anemia Ferropriva/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Hemoglobinas/metabolismo , Hepcidinas/sangue , Receptores da Transferrina/sangue , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
BMJ Case Rep ; 16(12)2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38114295

RESUMO

Chemotherapy-induced hypertriglyceridaemia (HTG) is a potential serious adverse event. Severe HTG with triglycerides (TG) >11.3 mmol/L (1000 mg/dL) can cause acute pancreatitis in addition to cardiovascular diseases such as coronary artery disease. While the association of capecitabine (5-fluorouracil (5-FU) prodrug) with clinically relevant HTG is a well-known adverse reaction, 5-FU is not typically associated with HTG. We here report the case of a patient who developed 5-FU-associated grade 4 HTG with TG level raising up to 37.1 mmol/L (3286 mg/dL) occurring after the ninth cycle of adjuvant FOLFOX (Fluorouracil and Oxaliplatin) chemotherapy. Fenofibrate treatment and diet were started. Chemotherapy was postponed and then resumed for two additional cycles. However, severe HTG recurred shortly after. Chemotherapy was therefore permanently stopped. Approximately 8 weeks after chemotherapy discontinuation, TG fell back to range at 2.1 mmol/L (189 mg/dL) allowing interruption of fenofibrate without HTG recurrence at 3 months.


Assuntos
Fluoruracila , Hipertrigliceridemia , Humanos , Fenofibrato/uso terapêutico , Fluoruracila/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/tratamento farmacológico , Pancreatite/etiologia
6.
J Clin Oncol ; 33(19): 2158-65, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26014300

RESUMO

PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Dose Máxima Tolerável
7.
Clin Chim Acta ; 434: 34-40, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24768787

RESUMO

Iron plays a fundamental role in cell life and its concentration in living organisms is precisely regulated. Different molecules for iron storage and transport are used to maintain its intracellular homeostasis which is often altered in cancer cells. Specifically, recent studies have demonstrated that in breast cancer cells, the expression/activity of several iron-related proteins, such as ferritin, hepcidin and ferroportin, is deregulated and that these alterations may have a prognostic impact in patients with breast cancer. Moreover, molecules that regulate iron metabolism could become therapeutic targets. This review focuses on recent findings on iron metabolism particularly in breast cancer and on the development of new biomarkers that may be used in the clinical routine for the diagnosis, prognosis and management of cancer-associated anemia as well as for monitoring personalized treatments.


Assuntos
Anemia Ferropriva/sangue , Neoplasias da Mama/metabolismo , Homeostase/fisiologia , Ferro/metabolismo , Anemia Ferropriva/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos
8.
Ann Biol Clin (Paris) ; 70(4): 387-96, 2012.
Artigo em Francês | MEDLINE | ID: mdl-22796610

RESUMO

Iron plays a fundamental role in biology and its concentration in living organisms is regulated very precisely. Many molecules of storage and transportation are used to maintain the intracellular homeostasis. Cancer cells have alterations in this balance. Recent studies have shown that breast cancer cells present abnormal expression of several proteins such as hepcidin and ferroportin. A prognostic impact of these alterations has been reported in patients with breast cancer. Regulatory molecules of iron metabolism could become therapeutic targets. This is an innovative approach that has emerged for treating a cancer which, despite advances in treatment and the emergence of targeted therapies, remains the leading cause of cancer death in women.


Assuntos
Neoplasias da Mama/metabolismo , Ferro/metabolismo , Anemia/diagnóstico , Anemia/etiologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Biomarcadores , Citocinas/metabolismo , Dano ao DNA , Estradiol/fisiologia , Feminino , Hepcidinas , Humanos , Inflamação/metabolismo , Estresse Oxidativo
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