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BACKGROUND: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. METHODS: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. RESULTS: 132 pts were included. Median age was 56 years (28-91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5-6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. CONCLUSION: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience.
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Anticorpos Monoclonais Humanizados , Camptotecina , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Pessoa de Meia-Idade , Feminino , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Adulto , Reino Unido/epidemiologia , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Camptotecina/administração & dosagem , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Metástase Neoplásica , ImunoconjugadosRESUMO
BACKGROUND: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. METHODS: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. RESULTS: Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. CONCLUSION: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT01618136.
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Biomarcadores Tumorais/genética , Isoquinolinas/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Quinazolinonas/administração & dosagem , Administração Oral , Adulto , Idoso , Compostos Azo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/genética , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Mature cystic teratomas are common in women of all ages; however, malignant transformation within them is rare and difficult to diagnosis preoperatively. Primary melanoma of the ovary is exceptionally rare and only occurs in relation to a teratoma where it can originate from sporadic somatic mutagenesis within epidermal junctional melanocytes, through malignant transformation of a benign nevus formed within the mature cystic teratoma or from other well differentiated pigment-containing structures such as the uvea. We present a case of primary malignant melanoma arising within a mature cystic teratoma in a young patient, who ultimately developed widespread metastasis necessitating systemic therapy. Our case highlights the role of molecular medicine not only in forming an understanding the origin of the melanoma, but also guiding targeted systemic therapies. Alongside the case we present a review of the literature describing the incidence of molecular aberrations within melanoma as well as the established and emerging techniques and cytotoxic agents for malignant melanoma.
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Biomarcadores Tumorais/genética , Melanoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , PTEN Fosfo-Hidrolase/genética , Teratoma/diagnóstico , Neoplasias Uveais/diagnóstico , Adulto , Feminino , Perfil Genético , Humanos , Imuno-Histoquímica , Melanoma/genética , Melanoma/patologia , Melanoma/cirurgia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Ovário/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Teratoma/genética , Teratoma/patologia , Teratoma/cirurgia , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Neoplasias Uveais/cirurgiaRESUMO
BACKGROUND: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). METHODS: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. RESULTS: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. CONCLUSION: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. TRIAL REGISTRATION: EudraCT Number: 2013-003894-87; registered 09-September-2013.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Capecitabina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Resultado do Tratamento , Vinorelbina/administração & dosagem , Vinorelbina/efeitos adversos , Vinorelbina/uso terapêuticoRESUMO
BACKGROUND: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. METHODS: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. RESULTS: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. CONCLUSIONS: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Capecitabina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Furanos/farmacocinética , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Cetonas/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Intervalo Livre de ProgressãoAssuntos
Anticorpos Monoclonais Humanizados , Glucocorticoides/administração & dosagem , Hepatite , Melanoma , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Colagogos e Coleréticos/administração & dosagem , Colangite Esclerosante/imunologia , Colangite Esclerosante/terapia , Feminino , Hepatite/etiologia , Hepatite/imunologia , Hepatite/terapia , Humanos , Testes de Função Hepática/métodos , Melanoma/patologia , Melanoma/fisiopatologia , Melanoma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Neoplasias Cutâneas/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Ácido Ursodesoxicólico/administração & dosagemRESUMO
AIMS: Calpain-1 is a ubiquitously expressed calcium-activated intracellular cysteine protease. Altered expression of calpain system proteins has been implicated in cancer progression and response to chemotherapy. METHODS AND RESULTS: The aim of the current study was to confirm previous data that suggested that calpain-1 expression is associated with relapse-free survival in trastuzumab-treated breast cancer patients (n = 93). An expanded patient cohort from Nottingham (n = 194; including 72 of the previous cohort) and an independent patient cohort from Newcastle (n = 87) were used. All patients received trastuzumab following adjuvant therapy according to local guidelines with expression of calpain-1 investigated using standard immunohistochemistry. Results show that calpain-1 expression is associated with relapse-free survival in both the Nottingham (P = 0.01) and Newcastle (P = 0.019) cohorts, with high expression associated with adverse relapse-free survival. Expression was also associated with poor relapse-free survival when patient cohorts were combined (n = 281, P = 0.01). Calpain-1 remained, from multivariate analysis, an independent marker for relapse-free survival in the Newcastle cohort [hazard ratio (HR) = 5.169; 95% confidence interval (CI) 1.468-18.200; P = 0.011]. CONCLUSIONS: Calpain-1 expression is associated with poor relapse-free survival in breast cancer patients treated with trastuzumab. Further work is warranted to standardize and develop methodology with a view to potentially introducing assessment of this important biomarker into clinical practice.
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Calpaína/metabolismo , Trastuzumab/uso terapêutico , Adulto , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Análise Serial de TecidosRESUMO
BACKGROUND: Socio-demographic disparities in traditional breast cancer treatment receipt in non-publicly funded healthcare systems are well documented. This study investigated trastuzumab receipt by socio-demographic factors within a female, HER2+ breast cancer population in England's publicly funded National Health Service. METHODS: The English national population-based cancer registry and linked Systemic Anti-Cancer Therapy (SACT) database identified 36,985 women with HER2+ invasive breast cancer diagnosed 01/01/2012-31/12/2017. Multivariable logistic regression determined likelihood of trastuzumab receipt in (i) early and (ii) metastatic disease by deprivation category of area of residence and other socio-demographic characteristics. RESULTS: Early-stage trastuzumab receipt followed a socio-economic gradient. Women residing in the most deprived areas were 10% less likely to receive trastuzumab (multivariable OR 0.90, (95% CI) 0.83, 0.98) compared to women residing in the least deprived areas. In both early and metastatic disease, trastuzumab receipt was less likely in older women with more comorbidities, ER positive disease, and who were not discussed at a multidisciplinary team meeting. CONCLUSIONS: Despite provision of free at the point of delivery care in England, socio-demographic disparities in early-stage HER2+ trastuzumab receipt occur. Further research determining how inequities contribute to disparities in outcomes is warranted to ensure optimized trastuzumab use for all. IMPACT: Fair access to novel cancer treatments regardless of place of residence, socio-demographic characteristics, and/or cancer stage requires prioritization in future cancer improvement policies.
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PURPOSE: To systematically review and meta-analyse the efficacy of exercise interventions delivered before and/or during taxane-containing chemotherapy regimens on chemotherapy-induced peripheral neuropathy (CIPN), fatigue, and health-related quality of life (HR-QoL), in women with breast cancer. METHODS: Seven electronic databases were systematically searched for randomised controlled trials (RCTs) reporting on the effects of exercise interventions in women with breast cancer receiving taxane-containing chemotherapeutic treatment. Meta-analyses evaluated the effects of exercise on CIPN symptoms, fatigue, and HR-QoL. RESULTS: Ten trials involving exercise interventions ranging between 2 and 12 months were included. The combined results of four RCTs consisting of 171 participants showed a reduction in CIPN symptoms following exercise compared with usual care (standardised mean difference - 0.71, 95% CI - 1.24 to - 0.17, p = 0.012; moderate-quality evidence, I2 = 76.9%). Pooled results from six RCTs with 609 participants showed that exercise interventions before and/or during taxane-containing chemotherapy regimens improved HR-QoL (SMD 0.42, 95% CI 0.07 to 0.76, p = 0.03; moderate-quality evidence, I2 = 49.6%). There was no evidence of an effect of exercise on fatigue (- 0.39, 95% CI - 0.95 to 0.18, p = 0.15; very low-quality evidence, I2 = 90.1%). CONCLUSIONS: This systematic review found reduced levels of CIPN symptoms and an improvement in HR-QoL in women with breast cancer who exercised before and/or during taxane-based chemotherapy versus usual care controls. IMPLICATIONS FOR CANCER SURVIVORS: This evidence supports the role of exercise as an adjunctive treatment for attenuating the adverse effects of taxane-containing chemotherapy on CIPN symptoms and HR-QoL.
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INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.
Assuntos
Neoplasias da Mama , Linfoma não Hodgkin , Linfoma , Adulto , Humanos , Feminino , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Estudos Prospectivos , Enalapril/uso terapêutico , Antibióticos Antineoplásicos/efeitos adversos , Antraciclinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
OBJECTIVE: A SNP in the NQO1 gene has been implicated in the response of patients with breast cancer to anthracycline containing regimens. NQO1, and its homologue NQO2, share many substrates yet retain distinct functional differences, with NQO2 being a more permissive molecule for electron accepting substrates. We aimed to determine whether functional NQO2 variants are associated with altered response to adjuvant doxorubicin and cyclophosphamide therapy, with or without tamoxifen, in the treatment of breast cancer. METHODS: Genomic DNA samples from 227 women with early breast cancer were genotyped for NQO1 and NQO2 polymorphisms. All participants were treated with an AC adjuvant therapy regimen. The functional implications of NQO2 polymorphisms were validated in in-vitro ectopic expression models. RESULTS: The NQO1 SNP (rs1800566) was associated with a poorer outcome and a lower likelihood of having a treatment delay. Patients who had ER and PR negative disease and were wild type for both the NQO1 and an NQO2 SNP (rs1143684) had 100% 5-year overall survival compared with 88% for carriers of one minor allele and 70% for carriers of two or more minor alleles (P=0.018, log rank). Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank). MCF-7 cells were sensitized to growth inhibition by doxorubicin and 4OH tamoxifen, but not cyclophosphamide, by ectopic expression of NQO2. CONCLUSION: This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , NAD(P)H Desidrogenase (Quinona)/genética , Quinona Redutases/genética , Alelos , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Genótipo , Humanos , Polimorfismo Genético , Tamoxifeno/administração & dosagemRESUMO
CONTEXT: Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available. OBJECTIVE: To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. DESIGN, SETTING, AND PATIENTS: The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data. INTERVENTIONS: Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy. MAIN OUTCOME MEASURE: Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy). RESULTS: The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001). CONCLUSION: The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00311636.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Infertilidade Feminina/prevenção & controle , Luteolíticos/uso terapêutico , Menopausa/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/prevenção & controle , Pamoato de Triptorrelina/uso terapêutico , Adulto , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/efeitos adversos , Cisplatino/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Gosserrelina/uso terapêutico , Humanos , Injeções Intramusculares , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Pré-Menopausa , Tamoxifeno/uso terapêuticoRESUMO
Life-threatening infection as an adverse reaction to cytotoxic therapy of cancer remains a major problem, potentially limiting efficacy. Administration of colony-stimulation factors benefits only a minority of patients, and improved stratification guidelines are needed to identify those patients likely to benefit. We investigated single nucleotide polymorphisms (SNPs) in two genes related to immune function to identify associations with severe infection following treatment of breast cancer with doxorubicin and cyclophosphamide. CD95 mediates the extrinsic apoptosis pathway in haematopoietic cells and a CD95 promoter SNP (rs2234767) has been shown to result in reduced expression of the receptor. MBL2 activates the classical complement pathway in the presence of pathogens and independently of antibodies. Numerous SNPs have been described including a promoter SNP (rs7096206) which results in decreased expression of the protein. Homozygotes for the CD95 minor allele were more likely to experience a grade 3 infection than heterozygote and homozygote wild-type patients (29%, 3% and 5%, respectively p=0.048). CD95 minor allele homozygotes also had higher basal white blood cell and neutrophil counts compared with wild-type allele carriers, which was sustained throughout therapy. There was an allele-dose association between the MBL2 SNP and grade 3 infection, with 2, 8 and 17% of wild-type homozygotes, heterozygotes and minor allele homozygotes, respectively, experiencing grade 3 infection (p=0.02). These associations demonstrate the utility of a pharmacogenetic approach to identify individuals more likely to acquire a life-threatening infection during chemotherapy. The apparent association with a CD95 SNP and a mild neutrophilia merits further investigation.
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Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Infecções/induzido quimicamente , Lectina de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Receptor fas/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Genótipo , Humanos , Infecções/genética , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Farmacogenética , Análise de Sobrevida , Receptor fas/sangueRESUMO
Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Perda de Heterozigosidade , Polimorfismo de Nucleotídeo Único , Receptor ErbB-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias da Mama/enzimologia , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Homozigoto , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Fenótipo , Receptor ErbB-2/análise , Regulação para CimaRESUMO
PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. EXPERIMENTAL DESIGN: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. RESULTS: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. CONCLUSIONS: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Dor Abdominal/induzido quimicamente , Administração Oral , Adulto , Idoso , Regulação Alostérica , Anorexia/induzido quimicamente , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Diarreia/induzido quimicamente , Toxidermias/etiologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Fadiga/induzido quimicamente , Feminino , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Masculino , Dose Máxima Tolerável , Mesotelioma/tratamento farmacológico , Mesotelioma/metabolismo , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Náusea/induzido quimicamente , Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Fosfoproteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Espectrometria de Massas em TandemRESUMO
PURPOSE: Most adjuvant breast cancer treatment regimens include the combination of an anthracycline (epirubicin or doxorubicin) and the alkylating agent cyclophosphamide. This study sought to investigate the influence of pharmacogenetics on the pharmacokinetics and metabolism of these agents. METHODS: Blood samples were taken from patients treated with cyclophosphamide (n = 51) and epirubicin (n = 35), with or without 5-fluorouracil (5-FU). The pharmacokinetics and metabolism of the three drugs were investigated, together with pharmacogenetic investigations for cyclophosphamide and epirubicin. Cyclophosphamide and its metabolites and also epirubicin and epirubicinol were measured in plasma. DNA was extracted from whole blood and genotyping performed using RT-PCR. RESULTS: Patients with at least one variant CYP2C19*17 allele had a longer CP half-life (p = 0.007), as did homozygous variants for the CYP2B6*6 allele. There was no significant effect of GSTP1, CYP2B6*2, CYP2B6*5 or CYP2C19*2 on any pharmacokinetic parameter of CP. An NQO2 exonic SNP was associated with a higher exposure to epirubicinol relative to epirubicin (p = 0.011). Other polymorphic variants of NQO1, carbonyl reductase, UGT enzymes and transporters had no influence on epirubicin or its metabolite. CONCLUSION: Overall, pharmacogenetic factors had only a minor influence on cyclophosphamide or anthracycline-based adjuvant therapy of breast cancer.
Assuntos
Neoplasias da Mama , Ciclofosfamida , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C19/genética , Epirubicina , Fluoruracila , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Biotransformação/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quimioterapia Adjuvante/métodos , Ciclofosfamida/metabolismo , Ciclofosfamida/farmacocinética , Ensaios de Seleção de Medicamentos Antitumorais , Epirubicina/metabolismo , Epirubicina/farmacocinética , Feminino , Fluoruracila/metabolismo , Fluoruracila/farmacocinética , Meia-Vida , Humanos , Pessoa de Meia-IdadeRESUMO
Trastuzumab is a therapeutic monoclonal antibody against the Her2 oncoprotein, which is over-expressed in approximately 30% of breast cancers, and is now used routinely in the management of early and metastatic Her2+ disease. However, not all Her2+ breast cancer patients respond to trastuzumab and the pharmacodynamic and pharmacokinetic parameters behind this variation in response are unknown. Pharmacological investigations into variable response to trastuzumab have been hampered by the lack of a published feasible method to determine trastuzumab concentration in plasma. Here we describe the development and validation of a cell-based ELISA to measure trastuzumab in human plasma. The assay specifically measures the interaction between trastuzumab and Her2 and has a dynamic range of between 10 and 120 microg/ml. The mean intra-assay and inter-assay variability of the ELISA was 9%. Trastuzumab in plasma was stable for at least 10 weeks at -20 degrees C and 72 h at 4 degrees C, and was unaffected by 5 freeze/thaw cycles. Having validated the assay, the trough plasma trastuzumab concentrations of 30 patients being treated for metastatic or early disease were measured. The median trough concentration was 62 (range 21 to 441) microg/ml. This cell-based ELISA method has undergone appropriate validation and is suitable for quantification of trastuzumab in the plasma of patients treated with Herceptin.
Assuntos
Anticorpos Monoclonais/sangue , Antineoplásicos/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos , Receptor ErbB-2/metabolismo , Sensibilidade e Especificidade , TrastuzumabRESUMO
PURPOSE: To evaluate the in vivo effect of adding gefitinib to preoperative chemotherapy on the EGFR-dependent p42/44 MAPK in operable breast cancer (BC) patients. Secondary aims: to evaluate EGFR, (p)-EGFR, Ki67, apoptotic index (TUNEL test) and VEGFR2 expression from baseline to surgery, percentage of pathologic complete response (pCR), and toxicity. PATIENTS AND METHODS: 90 patients with stage II-IIIA BC have been randomized to receive epirubicin 90 mg/sqm and paclitaxel 175 mg/sqm on day 1 plus: gefitinib 250 mg daily from day 5 to 16 (Arm A, intermittent), gefitinib 250 mg daily from day 1 to 21 (Arm B, continuous), or placebo (Arm C). Treatment plan: 4 courses every 3 weeks, followed by surgery. RESULTS: After preoperative therapy, 86/90 patients underwent surgery; 46 patients (51%) received breast conservative surgery. A pCR was observed in 4 patients. No significant differences in the expression of p42/44 MAPK, EGFR, (p)-EGFR, VEGFR2, proliferation index and apoptosis were observed comparing the combined Arms A + B vs C, and comparing Arm A vs B. Hematologic toxicities were not significantly different comparing Arms A + B vs Arm C, and comparing Arm A vs B. Significantly higher skin and mucosal toxicities were observed when comparing the two gefitinib Arms (A + B) vs Arm C (32% vs 9.6%, P = 0.018; 57% vs 29%, P = 0.009 respectively), while no significant differences were observed comparing Arm A vs B. CONCLUSION: Adding gefitinib to chemotherapy did not result in different effects on the EGFR-dependent pathway, proliferation, apoptosis and VEGFR2 expression as compared to placebo, while enhancing skin and mucosal toxicity. The two schedules of gefitinib (intermittent vs continuous) did not result in different biologic effects.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Epirubicina/administração & dosagem , Receptores ErbB/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Gefitinibe , Humanos , Antígeno Ki-67/análise , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Cooperação do Paciente , Quinazolinas/administração & dosagem , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/análiseRESUMO
OBJECTIVES: The aromatase inhibitors Anastrozole, Letrozole (type 2 nonsteroidal aromatase inhibitors: n-SAI) and Exemestane (type 1 steroidal aromatase inactivator) are used respectively as first- and second-line hormonal therapy in postmenopausal metastatic breast cancer women. Few clinical data are published on the sequential use of different classes of aromatase inhibitors. METHODS: We report an analysis on 30 postmenopausal metastatic breast cancer women treated between January 2000 and May 2002 in 2 Italian Oncology Institutions with the hormonal sequence n-SAI (Anastrozole, Letrozole) --> Exemestane. RESULTS: When receiving n-SAI (Anastrozole 8 patients and Letrozole 22 patients), 1 out of 30 women achieved a partial response, 20 of 30 patients no change (NC) > or =6 months. The analysis of the entire population treated with Exemestane showed an overall clinical benefit (CB) of 46.6 percent (14/30) with a median duration of 12 months (95%CI 6-25) and a median time to progression (TTP) of 4 months (95%CI 1-25). CONCLUSIONS: These data confirm a partial lack of cross-resistance between n-SAI --> Exemestane given in sequence.