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1.
PLoS One ; 15(2): e0227961, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023267

RESUMO

PURPOSE: Trastuzumab (TZM) improves survival and the risk of recurrence among patients with early-stage HER2+ breast cancer (BC). TZM treatment can be given intravenously (IV-TZM) or subcutaneously (SC-TZM). Although both methods have similar efficacy and safety, they differ in dosage and administration. Previous studies of cost minimization determined that SC-TZM is associated with lower costs than IV-TZM; however, those studies did not include the costs associated with body weight-based dosage and the treatment of adverse drug reactions (ADRs). METHODS/PATIENTS: We performed a model-based cost-minimization analysis. The analysis included direct and indirect medical costs associated with TZM preparation (adjusted by body weight) and administration and also costs due to severe ADRs and non-medical costs that occurred during the total treatment course (18 cycles). We performed a sensitivity analysis to test the robustness of the results across various TZM costs and patient body weights. RESULTS: The overall cost (in USD) of IV-TZM treatment was $83,309.1 per patient compared with $77,067.7 per patient for SC-TZM. Thus, one year of SC-TZM treatment cost $6,241.4 less per patient than one year of IV-TZM treatment. The sensitivity analysis revealed that the results were mainly driven by the price of each TZM vial and body weight. CONCLUSION: SC-TZM is a cost-saving therapy for Chilean patients with early-stage HER2+ BC. Given their similar efficacy and safety, we suggest the use of SC formulations rather than IV formulations. The use of SC-TZM instead of IV-TZM may have a significant economic impact on public/private healthcare systems.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/economia , Custos e Análise de Custo , Custos de Cuidados de Saúde , Receptor ErbB-2/metabolismo , Trastuzumab/economia , Trastuzumab/uso terapêutico , Administração Intravenosa , Relação Dose-Resposta a Droga , Feminino , Recursos em Saúde , Humanos , Incidência , Injeções Subcutâneas , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos
2.
Asia Pac J Clin Oncol ; 16(1): 34-38, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31657878

RESUMO

AIMS: We sought to describe survival outcomes and toxicities of trastuzumab in real-world patients with HER2-positive, metastatic breast cancer (MBC) and compare these to a recent systematic review of clinical trials. METHODS: We searched the medical records of three Sydney cancer centers for patients with HER2-positive, MBC starting trastuzumab from January 2001 to March 2017. We recorded patient, tumor, and treatment characteristics; survival times from start of palliative trastuzumab; and rates of cardiac toxicity. Survival distribution was summarized using the following percentiles (represented scenario): 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). Survival times were compared to recent review of HER2-positive MBC randomized trials. Factors associated with survival were assessed with Cox models. RESULTS: Characteristics of the 126 patients were: median age 53 years, ER positive cancer (50%), de-novo metastatic disease (23%), prior adjuvant trastuzumab (15%), liver metastases (37%), and brain metastases (23%). The median duration of first-line trastuzumab was 11 months (interquartile range, (IQR) 5-27). Survival times in months (vs the systematic review) were: 90th percentile 8 (9); 75th percentile 16 (19); and median 34 (33). Follow-up duration was insufficient to estimate the 25th and 10th percentiles, similar to the systematic review. Liver metastases were associated with shorter survival (HR = 1.74, 95% CI, 1.1-2.76, P = .02). Seventy percent of patients had a baseline cardiac assessment. Five patients (3.9%) developed symptomatic cardiac toxicity, similar to clinical trials. CONCLUSION: Survival and cardiac toxicity rates for women starting trastuzumab in routine practice were comparable to clinical trials. Oncologists can use clinical trial data as a reference point when explaining survival outcomes to women with HER2-positive MBC.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/mortalidade , Cardiotoxicidade/mortalidade , Padrões de Prática Médica/estatística & dados numéricos , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
3.
Cell Mol Life Sci ; 77(8): 1571-1589, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31650186

RESUMO

Breast cancer is the most frequently occurring cancer among women worldwide. Human epidermal growth factor receptor 2 (HER2 or ErbB2) is overexpressed in between 20 and 25% of invasive breast cancers and is associated with poor prognosis. Trastuzumab, an anti-ErbB2 monoclonal antibody, reduces cancer recurrence and mortality in HER2-positive breast cancer patients, but unexpectedly induces cardiac dysfunction, especially when used in combination with anthracycline-based chemotherapy. Novel approved ErbB2-targeting drugs, including lapatinib, pertuzumab, and trastuzumab-emtansine, also potentially cause cardiotoxicity, although early clinical studies demonstrate their cardiac safety profile. Unfortunately, the mechanism involved in causing the cardiotoxicity is still not completely understood. In addition, the use of preventive interventions against trastuzumab-induced cardiac dysfunction, including angiotensin-converting enzyme inhibitors and beta-blockers, remain controversial. Thus, this review aims to summarize and discuss the evidence currently available from in vitro, in vivo, and clinical studies regarding the mechanism and potential interventions associated with the cardiotoxicity of ErbB2-targeted drugs.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/etiologia , Coração/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Feminino , Humanos , Lapatinib/efeitos adversos , Lapatinib/uso terapêutico , Terapia de Alvo Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêutico
4.
N Engl J Med ; 382(7): 597-609, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31825569

RESUMO

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/administração & dosagem , Oxazóis/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/administração & dosagem , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/secundário , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina/efeitos adversos , Quimioterapia de Consolidação , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Quinazolinas/efeitos adversos , Receptor ErbB-2/análise , Trastuzumab/efeitos adversos
5.
Jpn J Clin Oncol ; 50(1): 3-11, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31821506

RESUMO

BACKGROUND: The original aim of this study was to evaluate the treatment sequence and anthracycline requirement in docetaxel, cyclophosphamide and trastuzumab therapy. After one death in the anthracycline-containing arm, the protocol was amended to terminate the randomization. The single-docetaxel, cyclophosphamide and trastuzumab arm was continued to examine the efficacy and safety of the anthracycline-free regimen. METHODS: Women with human epidermal growth factor receptor-2-positive, operable and primary breast cancer were randomized to receive 5-fluorouracil, epirubicin and cyclophosphamide (four cycles) followed by docetaxel, cyclophosphamide and trastuzumab (four cycles), or docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide, or docetaxel, cyclophosphamide and trastuzumab (six cycles). After the protocol amendment, patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm alone. The primary endpoint was a pathological complete response. RESULTS: In total, 103 patients were enrolled between September 2009 and September 2011: 21, 22 and 24 patients in the 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel, cyclophosphamide and trastuzumab; docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide and docetaxel, cyclophosphamide and trastuzumab arms, respectively, and 36 patients in the docetaxel, cyclophosphamide and trastuzumab arm after the protocol amendment. In total, 60 patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm, in which the pathological complete response rate was 45.8%, and disease-free survival at 3 years was 96.6%. Patients with stage I or IIA in the docetaxel, cyclophosphamide and trastuzumab arm showed good disease-free survival (100% at 3 years). The comparison of efficacy among the three arms was statistically underpowered. Left ventricular ejection fraction decreased significantly after 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel-docetaxel, cyclophosphamide and trastuzumab (P = 0.017), but not after docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide or docetaxel, cyclophosphamide and trastuzumab. CONCLUSIONS: The pathological complete response rate for docetaxel, cyclophosphamide and trastuzumab was similar to previous reports of anthracycline-containing regimens. Docetaxel, cyclophosphamide and trastuzumab might be an option for primary systemic therapy in human epidermal growth factor receptor-2-positive early breast cancer. A larger confirmatory study is necessary.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Docetaxel/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Antraciclinas/uso terapêutico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Docetaxel/efeitos adversos , Epirubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Taxoides/uso terapêutico , Trastuzumab/efeitos adversos , Adulto Jovem
6.
Cancer ; 126(1): 181-188, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31454422

RESUMO

BACKGROUND: There is a controversy about late-onset congestive heart failure (CHF) among breast cancer survivors. This study investigated the incidence rate and risk factors of late-onset CHF more than 2 years after the breast cancer diagnosis. METHODS: A nationwide, retrospective study was conducted with the National Health Information Database. With 1:3 age- and sex-matched noncancer controls, Cox proportional hazard regression models were used to analyze the incidence and risk factors of late CHF. The cumulative incidence rate of late CHF was evaluated with a Kaplan-Meier analysis and a log-rank test. RESULTS: A total of 91,227 cases (286,480 person-years) and 273,681 controls (884,349 person-years) were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls (hazard ratio [HR], 1.396; 95% confidence interval [CI], 1.268-1.538). Younger survivors (age ≤ 50 years) showed a higher risk of late CHF than their younger counterparts (HR, 2.903; 95% CI, 2.425-3.474). Although older age was a risk factor for late CHF, older survivors (age ≥ 66 years) showed no difference in the risk of late CHF in comparison with their counterparts (HR, 0.906; 95% CI, 0.757-1.084). Anthracyclines and taxanes were risk factors for late CHF, although trastuzumab, radiation, and endocrine therapy were not. CONCLUSIONS: Young breast cancer survivors have a greater risk of late CHF than the young population without cancer. More attention should be paid to young breast cancer survivors who receive taxane- or anthracycline-based regimens over the long term.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/epidemiologia , Sobreviventes de Câncer , Insuficiência Cardíaca/epidemiologia , Adulto , Idoso , Antraciclinas/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Taxoides/efeitos adversos , Trastuzumab/efeitos adversos
7.
PLoS Med ; 16(12): e1002989, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31869400

RESUMO

BACKGROUND: In patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease have been strongly correlated to the onset of cardiotoxicity. The influence of overweight and obesity as risk factors in the development of treatment-related cardiotoxicity in breast cancer (BC) was recently suggested. However, due to meta-analysis design, it was not possible to take into account associated cardiac risk factors or other classic risk factors for anthracycline (antineoplastic antibiotic) and trastuzumab (monoclonal antibody) cardiotoxicity. METHODS AND FINDINGS: Using prospective data collected from 2012-2014 in the French national multicenter prospective CANTO (CANcer TOxicities) study of 26 French cancer centers, we aimed to examine the association of body mass index (BMI) and cardiotoxicity (defined as a reduction in left ventricular ejection fraction [LVEF] > 10 percentage points from baseline to LVEF < 50%). In total, 929 patients with stage I-III BC (mean age 52 ± 11 years, mean BMI 25.6 ± 5.1 kg/m2, 42% with 1 or more cardiovascular risk factors) treated with anthracycline (86% epirubicin, 7% doxorubicin) and/or trastuzumab (36%), with LVEF measurement at baseline and at least 1 assessment post-chemotherapy were eligible in this interim analysis. We analyzed associations between BMI and cardiotoxicity using multivariate logistic regression. At baseline, nearly 50% of the study population was overweight or obese. During a mean follow-up of 22 ± 2 months following treatment completion, cardiotoxicity occurred in 29 patients (3.2%). The obese group was more prone to cardiotoxicity than the normal-weight group (9/171 versus 8/466; p = 0.01). In multivariate analysis, obesity (odds ratio [OR] 3.02; 95% CI 1.10-8.25; p = 0.03) and administration of trastuzumab (OR 12.12; 95% CI 3.6-40.4; p < 0.001) were independently associated with cardiotoxicity. Selection bias and relatively short follow-up are potential limitations of this national multicenter observational cohort. CONCLUSIONS: In BC patients, obesity appears to be associated with an important increase in risk-related cardiotoxicity (CANTO, ClinicalTrials.gov registry ID: NCT01993498). TRIAL REGISTRATION: ClinicalTrials.gov NCT01993498.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/tratamento farmacológico , Cardiopatias , Trastuzumab/efeitos adversos , Adulto , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Índice de Massa Corporal , Estudos de Coortes , Feminino , Cardiopatias/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Fatores de Risco
8.
Anticancer Res ; 39(11): 6355-6358, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704867

RESUMO

BACKGROUND/AIM: Pneumonitis is a serious complication after radiotherapy of breast cancer. This study aimed to identify its prevalence and potential risk factors. PATIENTS AND METHODS: A total of 606 patients irradiated following breast-conserving surgery or mastectomy were retrospectively analyzed. In patients developing pneumonitis, radiation and clinical parameters were investigated to identify potential risk factors. RESULTS: Eleven patients (1.8%) developed a pneumonitis grade ≥2. Mean doses to the ipsilateral lung were >7 Gy in 5 patients (45%). Of the other patients, 5 had a chronic inflammatory disease. Six patients (55%) had another malignancy (4 previous contralateral breast cancers, 1 previous ovarian and thyroid cancer, 1 synchronous carcinoma-in-situ (pTis) at the contralateral breast). Five patients (45%) received chemotherapy including taxanes and 4 patients (36%) received trastuzumab. CONCLUSION: The prevalence of pneumonitis was 1.8%. Potential risk factors included mean radiation dose to ipsilateral lung >7 Gy, systemic treatment with taxanes or trastuzumab, chronic inflammatory disease and history of another malignancy.


Assuntos
Neoplasias da Mama/radioterapia , Pneumonite por Radiação/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma in Situ/radioterapia , Feminino , Humanos , Pulmão/efeitos da radiação , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas , Prednisolona/uso terapêutico , Prevalência , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/etiologia , Estudos Retrospectivos , Fatores de Risco , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos
9.
BMC Cancer ; 19(1): 973, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638935

RESUMO

BACKGROUND: Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients. METHODS: A comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0. RESULTS: Twenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08-1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68-0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64-1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82-1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81-1.95; P = 0.309). CONCLUSIONS: Our study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia). TRIAL REGISTRATION: A systematic review protocol was registered with PROSPERO (identification number: CRD42018110415 ).


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/farmacologia , Antineoplásicos Imunológicos/farmacologia , Diarreia/etiologia , Docetaxel/uso terapêutico , Epistaxe/etiologia , Exantema/etiologia , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Terapia Neoadjuvante , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/efeitos adversos , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
10.
Biol Pharm Bull ; 42(12): 2045-2053, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31597885

RESUMO

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Trastuzumab/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes erbB-2 , Loci Gênicos/genética , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Trastuzumab/farmacologia
11.
Cardiol Clin ; 37(4): 407-418, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31587782

RESUMO

Trastuzumab targets the human epidermal growth factor receptor 2 (HER2). Its overexpression occurs in 25% of breast cancers and is associated with aggressive tumor characteristics and poor prognosis in absence of targeted therapy. Trastuzumab dramatically improves HER2-positive breast cancer outcomes; however, its clinical use is associated with left ventricular dysfunction and heart failure. Patients receiving trastuzumab or other HER2-targeted therapies undergo routine cardiac function assessment. Holding and/or stopping trastuzumab treatment in the setting of left ventricular dysfunction is recommended. This article summarizes the role of trastuzumab in cancer treatment, the mechanisms of trastuzumab-induced cardiotoxicity, recent clinical investigations, and current controversies.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cardiomiopatias/induzido quimicamente , Trastuzumab/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Cardiomiopatias/epidemiologia , Cardiotoxicidade , Feminino , Saúde Global , Humanos , Incidência
12.
Anticancer Res ; 39(10): 5741-5745, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570476

RESUMO

BACKGROUND/AIM: Cardiovascular risk factors (CVRFs) predict cardiotoxicity in cancer patients but their role in late cardiac toxicity is less clear. PATIENTS AND METHODS: This was a retrospective analysis of patients treated with anthracyclines (A) and/or trastuzumab (T) and a correlation with early (≤5 years) or late (>5 years) cardiac toxicity, and baseline CVRFs and CVRFs at toxicity time. RESULTS: A total of 610 patients were included, 422 with (Group A) and 188 without (Group B) baseline CVRFs. In group A toxicity incidence was 4.7% with all events during treatment or immediately after [mean onset time 0.7 years (range=0.2-1.6)]. Events rate was 3.2% in group B with all events after five years [mean time onset 6.9 years (range=5.2-7.5)]. All group B patients who developed late cardiac toxicity presented with CVRFs at the time of toxicity not reported before. CONCLUSION: CVRFs could predict late cardiac toxicity and their control should be part of the survivorship program.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiopatias/induzido quimicamente , Adulto , Idoso , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos
13.
Curr Oncol ; 26(4): 240-246, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548803

RESUMO

Background: The major limitation in the use of trastuzumab therapy is cardiotoxicity. We evaluated the safety of a strategy of continuing trastuzumab in patients with breast cancer despite mild, asymptomatic left ventricular impairment. Methods: Charts of consecutive patients referred to a cardio-oncology clinic from January 2015 to March 2017 for decline in left ventricular ejection fraction (lvef), defined as a fall of 10 percentage points or more, or a value of less than 50% during trastuzumab therapy, were reviewed. The primary outcome of interest was change in lvef, measured before and during trastuzumab exposure and up to 3 times after initiation of cardiac medications during a median of 9 months. Results: All 18 patients referred for decline in lvef chose to remain on trastuzumab and were included. All patients were treated with angiotensin converting-enzyme inhibitors or beta-blockers, or both. After initiation of cardiac medications, lvef increased over time by 4.6 percentage points (95% confidence interval: 1.9 percentage points to 7.4 percentage points), approaching baseline values. Of the 18 patients, 17 (94%) were asymptomatic at all future visits. No deaths occurred in the group. Conclusions: Many patients with mildly reduced lvef and minimal heart failure symptoms might be able to continue trastuzumab without further decline in lvef, adverse cardiac events, or death when treated under the supervision of a cardiologist with close follow-up.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Trastuzumab/efeitos adversos , Disfunção Ventricular Esquerda/tratamento farmacológico , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos
14.
BMC Cancer ; 19(1): 909, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31510955

RESUMO

BACKGROUND: Older patients with HER2-positive metastatic breast (HER2 + MBC) cancer are underrepresented in clinical trials. We aim to describe the treatment patterns and overall survival (OS) for older women receiving trastuzumab for HER2 + MBC. METHODS: Retrospective, whole-of-population cohort study using demographic, dispensing, and medical services data for Australian women ≥ 65 years initiating trastuzumab for HER2 + MBC between 2003 and 2015. We describe time-on-trastuzumab; type and timing of other cancer treatments; rates of cardiac monitoring; and OS from trastuzumab initiation for HER2 + MBC. RESULTS: Of 5404 women initiating trastuzumab for HER2 + MBC, 1583 (29%) were ≥ 65 years old, and the proportion of older patients increased from 20% in 2003 to 38% in 2015. The median age for older women was 73 years and 516 (33%) were ≥ 75 years. Most older patients (92%) received ≥3medicines for comorbidities other than cancer. Median (IQR) time on trastuzumab was 14.1 months (5.9-32.1) and on all chemotherapy was 5.6 months (3.3-10.8). 74% received ≥1 chemotherapy agent and 56% received endocrine therapy. Half (49%) of patients had a cardiac assessment prior to initiating trastuzumab and overall 1228 (76%) had ≥1 cardiac assessment during the study period. At a median follow-up of 6 years, 73% of patients had died and the median OS was 25.6 months (IQR 10.7-58.7). CONCLUSIONS: Older patients comprise a growing proportion of patients treated with HER2-targeted therapies in the real-world but they remain underrepresented in trials of these agents. Few trials report duration or OS estimates for older patients but our estimates are similar to those from trials that have. Although cardiac monitoring was a requirement of accessing trastuzumab during our study period, many patients did not undergo a cardiac assessment.


Assuntos
Neoplasias da Mama/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Vigilância da População , Receptor ErbB-2/genética , Estudos Retrospectivos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Trastuzumab/efeitos dos fármacos , Resultado do Tratamento
15.
Cancer Chemother Pharmacol ; 84(4): 839-847, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31428820

RESUMO

PURPOSE: Neoadjuvant CT-P6, a trastuzumab biosimilar, demonstrated equivalent efficacy to reference trastuzumab in a phase 3 trial of HER2-positive early-stage breast cancer (EBC) (NCT02162667). We report post hoc analyses evaluating pathological complete response (pCR) and breast pCR alongside additional efficacy and safety measures. METHODS: Following neoadjuvant treatment and surgery, patients received adjuvant CT-P6 or trastuzumab (6 mg/kg) every 3 weeks for ≤ 1 year. RESULTS: In total, 271 and 278 patients received CT-P6 and trastuzumab, respectively. pCR and breast pCR rates were comparable between treatment groups regardless of age, region, or clinical stage. Overall, 47.6% (CT-P6) and 52.2% (trastuzumab) of patients experienced study drug-related treatment-emergent adverse events (TEAEs), including 17 patients reporting heart failure (CT-P6: 10; trastuzumab: 7). Two CT-P6 and three trastuzumab patients discontinued adjuvant treatment due to TEAEs. CONCLUSION: Adjuvant CT-P6 demonstrated comparable efficacy and safety to trastuzumab at 1 year in patients with HER2-positive EBC, supporting CT-P6 and trastuzumab comparability.


Assuntos
Medicamentos Biossimilares , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca , Trastuzumab , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Monitoramento de Medicamentos/métodos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Trastuzumab/farmacocinética , Resultado do Tratamento
16.
Curr Oncol ; 26(3): e314-e321, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31285674

RESUMO

Background: Clinical trials have demonstrated an increased risk of cardiotoxicity in patients with breast cancer (bca) receiving trastuzumab-based therapy. Diabetes, dyslipidemia, and obesity are known risk factors for cardiovascular disease. Studies have yielded conflicting results about whether those factors increase the risk of cardiotoxicity in patients with bca receiving trastuzumab. Methods: In this retrospective cohort study, data were collected for 243 patients with bca positive for her2 (the human epidermal growth factor receptor 2) who were receiving trastuzumab and who were referred to The Ottawa Hospital Cardio-oncology Referral Clinic between 2008 and 2013. The data collected included patient demographics, reason for referral, cardiac function, chemotherapy regimen (including anthracycline use), and 3 comorbidities (diabetes, dyslipidemia, obesity). Rates of symptomatic cancer treatment-related cardiac dysfunction (sctcd) and asymptomatic decline in left ventricular ejection fraction (adlvef) were calculated for patients with and without the comorbidities of interest. Results: Of the 243 identified patients, 104 had either diabetes, dyslipidemia, or obesity. In that population, the most likely reason for referral to the cardio-oncology clinic was adlvef. The combination of 2 or 3 comorbidities significantly increased the incidence of sctcd in our population, reaching a rate of 67% for patients with obesity and dyslipidemia [relative risk (rr): 2.2; p = 0.04], 69% for patients with obesity and diabetes (rr: 2.3; p = 0.02), and 72% for patients with all 3 risk factors (rr: 2.4; p = 0.08). Conclusions: The combination of 2 or 3 comorbidities significantly increases the incidence of symptomatic cancer treatment-related cardiotoxicity. Patients with bca experiencing cancer treatment-related cardiotoxicity who have a history of diabetes, dyslipidemia, and obesity might require more proactive strategies for prevention, detection, and treatment of cardiotoxicity while receiving trastuzumab-based treatment.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/epidemiologia , Cardiotoxicidade/epidemiologia , Diabetes Mellitus/epidemiologia , Dislipidemias/epidemiologia , Obesidade/epidemiologia , Trastuzumab/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco
18.
Expert Rev Clin Pharmacol ; 12(8): 815-824, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31287333

RESUMO

Objective: Breast cancer remains to be the globally leading female cancer. About 15% to 20% of breast cancers have human epidermal growth factor receptor 2 (HER2)-positive tumors - a more aggressive breast cancer subtype with shortened survival. In the light of new and updated trial data on trastuzumab therapy for HER2-positive early-stage breast cancer (EBC), we conducted a systematic review and meta-analysis to update the pooling of its relative treatment effects. Methods: Systematic search was performed through Pubmed and Scopus to identify studies comparing survival outcomes and risks of heart toxicity effects of adjuvant trastuzumab with chemotherapy versus chemotherapy alone for HER2-positive EBC patients. Results: Based on the eight included studies in the review, combining trastuzumab with chemotherapy continues to show lowered death and relapse risks by one-third. The decision to initiate trastuzumab, however, needs to be prudently deliberated as two to three times more cardiotoxicity risk was shown to be associated with its use. Conclusion: Administering adjuvant trastuzumab in a weekly cycle concurrently with anthracycline-taxane chemotherapy regimen appears to be a preferable option to optimize its favorable effect in improving DFS and to prevent significantly higher risk for cardiotoxic effects.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos
19.
Breast J ; 25(6): 1097-1103, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31254304

RESUMO

The purpose of this study was to report rates and severities of radiation-related toxicities and analyze disease-control outcomes in patients who have received hypofractionated whole breast radiation (HF) with concurrent trastuzumab with or without pertuzumab. We conducted a retrospective cohort study including women with stage I-III HER2-positive breast cancer who received HF at the University of Pennsylvania between 1/2005 and 5/2018 with concurrent trastuzumab with or without pertuzumab. Fractionation was 266 cGy daily to a total dose of 4256 cGy with or without a sequential tumor bed boost. Eighty patients were included in the cohort with a median follow-up time of 21.44 months. There was one grade 3 acute toxicity (fatigue) and no grade 3 late toxicities. 91% and 25% of patients experienced grade 1-2 acute and late skin reactions, respectively. An excellent-good cosmetic outcome was reported by 74% and 95% of patients and physicians, respectively. No patients experienced tumor recurrences, and the only death was due to a secondary cause. These results suggest that hypofractionated whole breast radiation administered concurrently with anti-HER-2 therapies is efficacious and has acceptable toxicity in early-stage breast cancer patients treated with lumpectomy. Continued follow-up is warranted to evaluate long-term outcomes.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Hipofracionamento da Dose de Radiação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Feminino , Humanos , Mastectomia Segmentar/métodos , Pessoa de Meia-Idade , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/métodos , Receptor ErbB-2 , Estudos Retrospectivos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos
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