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1.
Cancer ; 129(12): 1821-1835, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37063057

RESUMO

BACKGROUND: Depression is common among breast cancer patients and can affect concordance with guideline-recommended treatment plans. Yet, the impact of depression on cancer treatment and survival is understudied, particularly in relation to the timing of the depression diagnosis. METHODS: The Kentucky Cancer Registry data was used to identify female patients diagnosed with primary invasive breast cancer who were 20 years of age or older in 2007-2011. Patients were classified as having no depression, depression pre-cancer diagnosis only, depression post- cancer diagnosis only, or persistent depression. The impact of depression on receiving guideline-recommended treatment and survival was examined using multivariable logistic regression and Cox regression, respectively. RESULTS: Of 6054 eligible patients, 4.1%, 3.7%, and 6.2% patients had persistent depression, depression pre-diagnosis only, and depression post-diagnosis only, respectively. A total of 1770 (29.2%) patients did not receive guideline-recommended cancer treatment. Compared to patients with no depression, the odds of receiving guideline-recommended treatment were decreased in patients with depression pre-diagnosis only (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.54-1.04) but not in patients with post-diagnosis only or persistent depression. Depression post-diagnosis only (hazard ratio, 1.51; 95% CI, 1.24-1.83) and depression pre-diagnosis only (hazard ratio, 1.26; 95% CI, 0.99-1.59) were associated with worse survival. No significant difference in survival was found between patients with persistent depression and patients with no depression (p > .05). CONCLUSIONS: Neglecting depression management after a breast cancer diagnosis may result in poorer cancer treatment concordance and worse survival. Early detection and consistent management of depression is critical in improving patient survival.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/complicações , Neoplasias da Mama/terapia , Neoplasias da Mama/diagnóstico , Kentucky/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros
2.
Blood ; 122(5): 648-57, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23777763

RESUMO

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.


Assuntos
Proteínas Recombinantes/farmacocinética , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/metabolismo , Fator de von Willebrand/farmacocinética , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Adulto Jovem , Fator de von Willebrand/efeitos adversos , Fator de von Willebrand/uso terapêutico
3.
Breast Cancer Res Treat ; 148(2): 437-44, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25257728

RESUMO

ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais , Pesquisa Biomédica , Neoplasias Ósseas/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Receptores de Progesterona/metabolismo
4.
Breast Cancer Res Treat ; 143(2): 325-32, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24327334

RESUMO

Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Sirolimo/análogos & derivados , Falha de Tratamento , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estradiol/efeitos adversos , Estradiol/uso terapêutico , Everolimo , Feminino , Fulvestranto , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
5.
Future Oncol ; 10(15): 2435-48, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24826798

RESUMO

BACKGROUND: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. MATERIALS & METHODS: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. RESULTS: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. CONCLUSION: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Niacinamida/uso terapêutico , Projetos Piloto , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Estrogênio/metabolismo , Sorafenibe , Tamoxifeno/uso terapêutico , Resultado do Tratamento
6.
Breast Cancer Res Treat ; 136(2): 565-72, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23053651

RESUMO

Breast cancer can metastasize at any time during its course, but timing of systemic relapse cannot be predicted by traditional TNM staging. Characteristics of distant recurrence within the first 3 years of diagnosis may identify a group of patients who could benefit from novel strategies to prevent systemic relapse. Of 1,089 patients with breast cancer treated at our institution between January 2007 and May 2011, we identified 76 with de novo metastases (on presentation) and 40 with systemic relapse after a median follow up of 2.2 years. Compared to relapse, de novo metastatic disease was more likely to be grade 1 or 2 (43.1 vs. 18.4 %, p = 0.032), estrogen receptor (ER) positive (69.7 vs. 47.5 %, p = 0.019), progesterone receptor (PgR) positive (56.6 vs. 32.5 %, p = 0.014), and HER2-positive (27.5 vs. 10.3 %, p = 0.035). In the 815 patients with stage I-III disease who were at risk of systemic relapse, univariate analyses were performed for age, tumor size, grade, ER, PgR, HER2, lymph nodes, and TNM stage. A multivariate Cox regression model was built using step-wise model selection and identified 4 covariates that were significantly associated with risk of early relapse: stage-III (p < 0.001), grade-III (p = 0.002), PgR-negative status (p = 0.014), and HER2-negative status (p = 0.033). A risk-score was developed based on the linear combination of these covariates and time-dependent predictive curves were used to evaluate the predictive accuracy of the proposed risk-score. The highest risk-score group had a 1, 2, and 3-year relapse probabilities of 11.5, 41.2, and 52.5 %, respectively. The corresponding 1, 2, and 3-year relapse probabilities for the overall population were 1.2, 4.4, and 6.3 %, respectively. Our proposed model can be used to select patients at high-risk of early relapse who could benefit from enrollment on clinical trials with novel therapies designed for this group.


Assuntos
Neoplasias da Mama/diagnóstico , Modelos Estatísticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Recidiva , Sistema de Registros , Medição de Risco , Padrão de Cuidado , Adulto Jovem
8.
AAPS PharmSciTech ; 10(2): 410-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19381833

RESUMO

In the current study, novel paclitaxel-loaded cross-linked hyaluronan nanoparticles were engineered for the local delivery of paclitaxel as a prototype drug for cancer therapy. The nanoparticles were prepared using a desolvation method with polymer cross-linking. In vitro cytotoxicity studies demonstrated that less than 75% of the MDA-MB-231 and ZR-75-1 breast cancer cells were viable after 2-day exposure to paclitaxel-loaded hyaluronan nanoparticles or free paclitaxel, regardless of the dose. These results suggest that hyaluronan nanoparticles maintain the pharmacological activity of paclitaxel and efficiently deliver it to the cells. Furthermore, in vivo administration of the drug-loaded nanoparticles via direct intratumoral injection to 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor in female rats was studied. The paclitaxel-loaded nanoparticles treated group showed effective inhibition of tumor growth in all treated rats. Interestingly, there was one case of complete remission of tumor nodule and two cases of persistent reduction of tumor size that was observed on subsequent days. In the case of free paclitaxel-treated group, the mean tumor volume increased almost linearly (R(2) = 0.93) with time to a size that was 4.9-fold larger than the baseline volume at 57 days post-drug administration. Intratumoral administration of paclitaxel-loaded hyaluronan nanoparticles could be a promising treatment modality for solid mammary tumors.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , 9,10-Dimetil-1,2-benzantraceno , Animais , Química Farmacêutica , Feminino , Paclitaxel/química , Paclitaxel/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade
9.
N Engl J Med ; 353(16): 1673-84, 2005 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-16236738

RESUMO

BACKGROUND: We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. METHODS: The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. RESULTS: By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831. CONCLUSIONS: Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2 , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Cardiopatias/induzido quimicamente , Humanos , Mastectomia , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Modelos de Riscos Proporcionais , Receptor ErbB-2/análise , Recidiva , Análise de Sobrevida , Trastuzumab
10.
J Clin Oncol ; 35(35): 3942-3948, 2017 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-29072977

RESUMO

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Receptor ErbB-2/biossíntese , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Sobreviventes de Câncer , Quimioterapia Adjuvante , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Qualidade de Vida , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Disfunção Ventricular Esquerda/fisiopatologia
11.
J Clin Oncol ; 23(31): 7811-9, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16258083

RESUMO

PURPOSE: Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines. PATIENTS AND METHODS: National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms. RESULTS: Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity. CONCLUSION: Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Disfunção Ventricular Esquerda/induzido quimicamente , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Incidência , Linfonodos , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Trastuzumab , Disfunção Ventricular Esquerda/tratamento farmacológico
12.
Clin Adv Hematol Oncol ; 4(3 Suppl 7): suppl 1, 4-9; discussion suppl 10; quiz 2 p following suppl 10, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16736568

RESUMO

The development of adjuvant therapy has made a significant positive impact on clinical outcomes for patients with breast cancer. Over the past 30 years the field of adjuvant therapy has evolved from its cyclophosphamide/methotrexate/5-fluorouracil beginnings by adding new agents and modifying treatment schedules and dosing. More recently, the application of targeted therapies based on hormone receptor status and HER2 expression is providing a new level of efficacy for these patients. The biologic agent trastuzumab, a monoclonal antibody directed against HER2, first demonstrated significant activity in patients with metastatic breast cancer, reducing the risk of death by 30%. The agent was then evaluated in an adjuvant setting in several large trials. In a recently published joint efficacy analysis, the addition of trastuzumab to standard adjuvant chemotherapy regimens led to a 52% reduction in events (ie, recurrent cancer, second primary cancer, or death before recurrence) and a significant improvement in overall survival. These dramatic findings highlight the need for accurate HER2 testing to best identify the HER2(+) patients who would benefit from the treatment. Currently there is some debate about how to best approach HER2 testing: with the protein-based immunohistochemistry or the genetic-based fluorescence in situ hybridization. Current research evaluating the different techniques may help to settle this question. Finally, new targeted agents are being investigated and ongoing research aims to identify additional potential therapeutic targets to further improve outcomes for these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Inibidores da Angiogênese/uso terapêutico , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/mortalidade , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , Taxa de Sobrevida
13.
J Natl Cancer Inst ; 94(11): 852-4, 2002 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-12048273

RESUMO

Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC) results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Seleção de Pacientes , Receptor ErbB-2/análise , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto/métodos , Contraindicações , Erros de Diagnóstico , Amplificação de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Garantia da Qualidade dos Cuidados de Saúde , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Reprodutibilidade dos Testes , Trastuzumab
14.
Curr Probl Cancer ; 40(2-4): 106-116, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27816189

RESUMO

The advent of the targeted monoclonal antbody trastuzumab for treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer marked a revolution in the understanding and management of mammary carcinoma and, in practice, separated this subtype from other kinds of primary breast malignancy. Long term follow-up from the initial large adjuvant trials continue to show remarkably positive results. Currently, at least four additional agents targeting this receptor, using different and complementary mechanisms of action compared with trastuzumab, have been incorporated into clinical trials. The small molecule tyrosine kinase inhibitors lapatinib and neratinib, in addition to the antibody pertuzumab and the antibody-drug conjugate trastuzumab-ematansine, have shown efficacy in metastatic breast cancer and are being evaluated both in neoadjuvant and adjuvant trials for early stage disease. The cytotoxic chemotherapy regimens used in combination with these agents also are evolving and different therapeutic approaches are emerging for patients depending on their relative level of risk from their cancers, thus moving clinical management toward individualized therapy. Much has been learned about managing the toxicities of treatment and pre-operative approaches have provided a means of assessing the sensitivity of individual patients' cancers to specific treatment regimens. This review traces the development of these studies and focuses on improvements in adjuvant and neoadjuvant therapy for patients with HER2-positive disease whose prognosis has changed in the last decade from dire to favorable. A path forward has been set by which the goal of cure is attainable for almost all patients faced with this aggressive form of breast cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Genes erbB-2 , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiorradioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Feminino , Testes Genéticos/normas , Coração/efeitos dos fármacos , Humanos , Lapatinib , Medicina de Precisão , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia
15.
J Natl Cancer Inst ; 108(1)2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26518884

RESUMO

BACKGROUND: The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database. METHODS: The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect. RESULTS: Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow-up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident. CONCLUSIONS: Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/prevenção & controle , Recidiva Local de Neoplasia/prevenção & controle , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária/métodos , Fatores de Tempo , Resultado do Tratamento
16.
Cancer Epidemiol Biomarkers Prev ; 25(1): 51-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26545405

RESUMO

BACKGROUND: Body mass index (BMI) has been associated with breast cancer outcomes. However, few studies used clinical trial settings where treatments and outcomes are consistently evaluated and documented. There are also limited data assessing how patient/disease characteristics and treatment may alter the BMI-breast cancer association. METHODS: We evaluated 15,538 breast cancer participants from four NSABP protocols. B-34 studied early-stage breast cancer patients (N = 3,311); B-30 and B-38 included node-positive breast cancer patients (N = 5,265 and 4,860); and B-31 studied node-positive and HER2-positive breast cancer patients (N = 2,102). We used Cox proportional hazards regression to calculate adjusted hazards ratios (HR) for risk of death and recurrence, and conducted separate analyses by estrogen receptor (ER) status and treatment group. RESULTS: In B-30, increased BMI was significantly related to survival. Compared with BMI < 25, HRs were 1.04 for BMI 25 to 29.9 and 1.18 for BMI ≥ 30 (P = 0.02). Separate analyses indicated the significant relationship was only in ER-positive disease (P = 0.002) and the subgroup treated with doxorubicin/cyclophosphamide (P = 0.005). There were no significant trends across BMI for the other three trials. Similar results were found for recurrence. Increased BMI was significantly related to recurrence in B-30 (P = 0.03); and the significant relationship was only in ER-positive breast cancers (P = 0.001). Recurrence was also significant among ER-positive disease in B-38 (P = 0.03). CONCLUSIONS: In our investigation, we did not find a consistent relationship between BMI at diagnosis and breast cancer recurrence or death. IMPACT: This work demonstrates that the heterogeneity of breast cancer between different breast cancer populations and the different therapies used to treat them may modify any association that exists between BMI and breast cancer outcome.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/mortalidade , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Taxa de Sobrevida
17.
Clin Breast Cancer ; 15(1): 48-53, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25199576

RESUMO

BACKGROUND: Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists. PATIENTS AND METHODS: We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests. RESULTS: Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils. CONCLUSION: In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Doenças Hematológicas/induzido quimicamente , Sirolimo/análogos & derivados , Anemia/induzido quimicamente , Anemia/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Contagem de Eritrócitos , Índices de Eritrócitos , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Everolimo , Feminino , Fulvestranto , Doenças Hematológicas/epidemiologia , Humanos , Contagem de Leucócitos , Leucopenia/induzido quimicamente , Leucopenia/epidemiologia , Metástase Neoplásica , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia
18.
Rare Tumors ; 6(2): 5366, 2014 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-25002952

RESUMO

Angiosarcomas are exceedingly rare tumors that are often difficult to diagnose. Exceptionally unusual is the presentation of these tumors with Kasabach-Merritt Syndrome, a curious form of intratumoral coagulation that can be impossible to distinguish from intravascular coagulation, which is more common. Instant recognition of this clinical association can help making a prompt diagnosis and timely initiation of therapy.

20.
J Clin Oncol ; 32(33): 3744-52, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25332249

RESUMO

PURPOSE: Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. METHODS: In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. RESULTS: Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. CONCLUSION: The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Adolescente , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Trastuzumab
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