Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
1.
Breast Cancer Res Treat ; 176(3): 617-624, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31079282

RESUMO

PURPOSE: Aromatase inhibitors (AIs) are associated with musculoskeletal symptoms and risk of developing carpal tunnel syndrome (CTS), which can impair quality of life and prompt treatment discontinuation. The incidence of CTS and clinical utility of diagnostic tests such as 2-point discrimination (2-PD) have not been prospectively examined among women receiving AIs. METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were enrolled in a randomized clinical trial investigating adjuvant AIs (Exemestane and Letrozole Pharmacogenetics, ELPh) underwent prospective evaluation of 2-PD with the Disc-criminator™ (sliding aesthesiometer) and completed a CTS questionnaire at baseline, 3, 6, and 12 months, following initiation of AI. Changes in mean 2-PD were analyzed with multivariable mixed effects modelling. A p value < 0.05 was considered statistically significant. RESULTS: Of 100 women who underwent baseline 2-PD testing, CTS was identified by questionnaire in 11% at baseline prior to AI initiation. Prevalence of CTS at any time in the first year was 26%. A significant increase in worst 2-PD score was observed from baseline to 3 months (3.7 mm to 3.9 mm, respectively, p = 0.03) when adjusted for age, prior chemotherapy, randomized treatment assignment, and diabetes. There were no significant differences in treatment discontinuation due to CTS between the arms. CONCLUSION: For women receiving adjuvant AI, 2-PD scores were significantly worse at 3 months compared to baseline. Studies are required to assess whether change in 2-PD is an adequate objective assessment for CTS with AI therapy. Early diagnosis of CTS may expedite management, improve AI adherence, and enhance breast cancer outcomes.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/complicações , Síndrome do Túnel Carpal/diagnóstico , Síndrome do Túnel Carpal/etiologia , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/etiologia , Idoso , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Pós-Menopausa , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Avaliação de Sintomas
2.
Breast Cancer Res Treat ; 171(1): 121-129, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29752687

RESUMO

PURPOSE: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS. METHODS: In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively. RESULTS: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density. CONCLUSIONS: Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.


Assuntos
Antineoplásicos/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/prevenção & controle , Ácido Zoledrônico/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama/complicações , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Modelos de Riscos Proporcionais , Resultado do Tratamento
3.
Cancer ; 124(9): 1904-1911, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29381193

RESUMO

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer. METHODS: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses. RESULTS: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance). CONCLUSIONS: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/terapia , Cardiotoxicidade/etnologia , Disparidades nos Níveis de Saúde , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , População Negra/estatística & dados numéricos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Seguimentos , Humanos , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , População Branca/estatística & dados numéricos
4.
Clin Cancer Res ; 23(11): 2691-2701, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27979916

RESUMO

Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691-701. ©2016 AACR.


Assuntos
Azacitidina/administração & dosagem , Benzamidas/administração & dosagem , Epigênese Genética/genética , Piridinas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Azacitidina/efeitos adversos , Benzamidas/efeitos adversos , Biomarcadores Tumorais/sangue , Terapia Combinada , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Estadiamento de Neoplasias , Piridinas/efeitos adversos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Estados Unidos
5.
Clin Cancer Res ; 23(2): 379-386, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27489289

RESUMO

PURPOSE: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe. EXPERIMENTAL DESIGN: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumor DNA (ptDNA). RESULTS: We enrolled 26 women with metastatic TNBC who had received ≥1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples. CONCLUSIONS: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. Clin Cancer Res; 23(2); 379-86. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/sangue , DNA de Neoplasias/sangue , Proteínas de Neoplasias/genética , Neoplasias de Mama Triplo Negativas/sangue , Adulto , Idoso , Biópsia , Tratamento Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
J Clin Oncol ; 35(7): 751-758, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27870562

RESUMO

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Metilação de DNA , DNA de Neoplasias/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , DNA de Neoplasias/genética , Intervalo Livre de Doença , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Metástase Neoplásica , Modelos de Riscos Proporcionais , Estudos Prospectivos , Taxa de Sobrevida
7.
J Clin Oncol ; 34(36): 4390-4397, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27998227

RESUMO

Purpose Gene expression profiling assays are frequently used to guide adjuvant chemotherapy decisions in hormone receptor-positive, lymph node-negative breast cancer. We hypothesized that the clinical value of these new tools would be more fully realized when appropriately integrated with high-quality clinicopathologic data. Hence, we developed a model that uses routine pathologic parameters to estimate Oncotype DX recurrence score (ODX RS) and independently tested its ability to predict ODX RS in clinical samples. Patients and Methods We retrospectively reviewed ordered ODX RS and pathology reports from five institutions (n = 1,113) between 2006 and 2013. We used locally performed histopathologic markers (estrogen receptor, progesterone receptor, Ki-67, human epidermal growth factor receptor 2, and Elston grade) to develop models that predict RS-based risk categories. Ordering patterns at one site were evaluated under an integrated decision-making model incorporating clinical treatment guidelines, immunohistochemistry markers, and ODX. Final locked models were independently tested (n = 472). Results Distribution of RS was similar across sites and to reported clinical practice experience and stable over time. Histopathologic markers alone determined risk category with > 95% confidence in > 55% (616 of 1,113) of cases. Application of the integrated decision model to one site indicated that the frequency of testing would not have changed overall, although ordering patterns would have changed substantially with less testing of estimated clinical risk-high or clinical risk-low cases and more testing of clinical risk-intermediate cases. In the validation set, the model correctly predicted risk category in 52.5% (248 of 472). Conclusion The proposed model accurately predicts high- and low-risk RS categories (> 25 or ≤ 25) in a majority of cases. Integrating histopathologic and molecular information into the decision-making process allows refocusing the use of new molecular tools to cases with uncertain risk.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Perfilação da Expressão Gênica/estatística & dados numéricos , Adulto , Idoso , Neoplasias da Mama/terapia , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Modelos Lineares , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Receptores de Progesterona/genética , Estudos Retrospectivos
8.
Breast Cancer Res Treat ; 160(2): 291-296, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27699555

RESUMO

PURPOSE: In 2004, The National Comprehensive Cancer Network (NCCN) Guidelines incorporated omission of radiation therapy after breast-conservation surgery in women ≥70 years old with stage I, estrogen receptor-positive breast cancer who plan to receive endocrine therapy. One study demonstrated wide variation in implementing this change across 13 NCCN institutions. We evaluated the practice pattern at our institution. METHODS: We identified women ≥70 years old treated at our institution from 2009 to 2014. We calculated radiation therapy omission rate in those meeting the guidelines. We explored associations between radiation therapy omission, year of diagnosis, and patient characteristics with Wilcoxon rank sum tests and Fisher's exact tests. RESULTS: A total of 667 women met the inclusion criteria, and 117 (18 %) were candidates for radiation therapy omission. Mean age among the 117 was 76.3 years (Range: 70-95). Overall radiation therapy omission rate was 36.8 %, but varied greatly by year of diagnosis (Range: 7.7-54.5 %). This variation persisted after excluding women who did not receive endocrine therapy (Mean: 39.0 %, Range: 0.0-75.0 %). Factors associated with higher radiation therapy omission rates included older age and not having pathological nodal evaluation. The radiation therapy omission rate did not vary by race, tumor type, grade, or size. CONCLUSIONS: The implementation of the NCCN guideline has not been consistent at our institution. Our data suggest that other tools should be considered to apply the guidelines more consistently. We have implemented a quality improvement protocol that incorporates life expectancy estimate and geriatric assessment in women meeting the NCCN guideline at our institution.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Radioterapia Adjuvante , Resultado do Tratamento
9.
Cancer Prev Res (Phila) ; 9(8): 673-682, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27261491

RESUMO

Methods to determine individualized breast cancer risk lack sufficient sensitivity to select women most likely to benefit from preventive strategies. Alterations in DNA methylation occur early in breast cancer. We hypothesized that cancer-specific methylation markers could enhance breast cancer risk assessment. We evaluated 380 women without a history of breast cancer. We determined their menopausal status or menstrual cycle phase, risk of developing breast cancer (Gail model), and breast density and obtained random fine-needle aspiration (rFNA) samples for assessment of cytopathology and cumulative methylation index (CMI). Eight methylated gene markers were identified through whole-genome methylation analysis and included novel and previously established breast cancer detection genes. We performed correlative and multivariate linear regression analyses to evaluate DNA methylation of a gene panel as a function of clinical factors associated with breast cancer risk. CMI and individual gene methylation were independent of age, menopausal status or menstrual phase, lifetime Gail risk score, and breast density. CMI and individual gene methylation for the eight genes increased significantly (P < 0.001) with increasing cytological atypia. The findings were verified with multivariate analyses correcting for age, log (Gail), log (percent density), rFNA cell number, and body mass index. Our results demonstrate a significant association between cytological atypia and high CMI, which does not vary with menstrual phase or menopause and is independent of Gail risk and mammographic density. Thus, CMI is an excellent candidate breast cancer risk biomarker, warranting larger prospective studies to establish its utility for cancer risk assessment. Cancer Prev Res; 9(8); 673-82. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação de DNA , Adulto , Fatores Etários , Biópsia por Agulha Fina , Índice de Massa Corporal , Mama/metabolismo , Mama/patologia , Densidade da Mama , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Mamografia , Pessoa de Meia-Idade , Análise Multivariada , Progesterona/sangue , Estudos Prospectivos , Distribuição Aleatória , Análise de Regressão , Fatores de Risco , Fatores de Tempo
10.
Am J Clin Pathol ; 145(3): 365-72, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27124919

RESUMO

OBJECTIVES: Metaplastic breast carcinomas (MBCs) are rare, aggressive cancers lacking targeted therapy. Here, we review the clinicopathologic features, treatment, and outcomes of patients with MBC treated at our institution. METHODS: We searched clinical and pathology databases for patients with histologically confirmed MBC from 1999 to 2012. We estimated survival probabilities using the Kaplan-Meier method and evaluated prognostic factors using Cox regression. RESULTS: Forty-five cases were identified, including chondroid (24%), spindled (20%), sarcomatoid (16%), squamous (11%), and mixed (29%) histologic subtypes. Median tumor size was 3 cm, with 86% grade III and 69% triple-negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Most had negative lymph nodes, and two patients had metastases at diagnosis. Six patients received neoadjuvant therapy, with one pathologic complete response. All patients underwent surgery, 60% received adjuvant radiation, and 58% had adjuvant chemotherapy. Five-year recurrence-free survival was 64%; 5-year overall survival was 69%. Tumor size, history of breast cancer, and mixed histology were associated with inferior outcomes. CONCLUSIONS: We report one of the largest single-institution series of patients with MBC. MBC is associated with a poor prognosis, despite low nodal involvement. Most patients in this series had high-grade, triple-negative tumors and were treated with optimal therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Metaplasia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
11.
Breast Cancer Res Treat ; 150(3): 589-95, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25788225

RESUMO

Preoperative sentinel node localization (SNL) using a subareolar injection of radiotracer technetium-99m-sulfur colloid (Tc(99m)SC) is associated with significant pain. Lidocaine use during SNL is not widely adopted partly due to a concern that it can obscure sentinel node identification and reduce its diagnostic accuracy. We prospectively identified women with a biopsy-proven infiltrating breast cancer who were awaiting a SNL. The women completed the McGill pain questionnaire, Visual Analog Scale, and Wong-Baker FACES Pain Rating Scale prior to and following SNL. We identified a retrospective cohort of women with similar demographic and tumor characteristics who did not receive lidocaine before SNL. We compared sentinel lymph node identification rates in the two cohorts. We used Wilcoxon rank sum tests to compare continuous measures and Fisher's exact test for categorical measures. Between January 2011 to July 2012, 110 women consented, and 105 were eligible for and received lidocaine prior to Tc(99m)SC injection. The post-lidocaine identification rate of SNL was 95 % with Tc(99m)SC, and 100 % with the addition of intraoperative methylene blue dye/saline. Pain range prior to and following the SNL was unchanged (P = 0.703). We identified 187 women from 2005 to 2009 who did not receive lidocaine during preoperative SNL. There was no significant difference in the success rate of SNL, with or without lidocaine (P = 0.194). The administration of lidocaine during SNL prevents pain related to isotope injection while maintaining the success rate. We have changed our practice at our center to incorporate the use of lidocaine during all SNL.


Assuntos
Anestésicos Locais/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Lidocaína/administração & dosagem , Dor/prevenção & controle , Biópsia de Linfonodo Sentinela/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Dor/etiologia , Cintilografia , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Coloide de Enxofre Marcado com Tecnécio Tc 99m/administração & dosagem , Coloide de Enxofre Marcado com Tecnécio Tc 99m/efeitos adversos , Resultado do Tratamento
12.
J Nucl Med ; 56(1): 31-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25476537

RESUMO

UNLABELLED: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SUL(max)) on (18)F-FDG PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes. METHODS: Participants were randomly assigned to 12 wk of preoperative carboplatin (area under the curve of 2, weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg orally daily, days 1-3 of every 7-d period) or placebo. All patients underwent (18)F-FDG PET and research biopsy at baseline and on cycle 1 day 15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SUL(max) on (18)F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR. RESULTS: In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat, 25.8%; placebo, 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SUL(max) 15 d after initiating preoperative therapy between those achieving pCR versus not (percentage reduction, 63.0% vs. 32.9%; P = 0.003). Patients with 50% or greater reduction in SUL(max) were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (odds ratio, 5.1; 95% confidence interval, 1.3-22.7; P = 0.023). Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not. CONCLUSION: Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SUL(max) on (18)F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test (18)F-FDG PET as a potential treatment-selection biomarker.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons , Receptor ErbB-2/metabolismo , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Transporte Biológico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Período Pré-Operatório , Segurança , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
13.
Cancer Res ; 74(8): 2160-70, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24737128

RESUMO

The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 µL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , DNA de Neoplasias/sangue , Adulto , Idoso , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Metilação de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Prospectivos , Reprodutibilidade dos Testes
14.
Clin Cancer Res ; 20(10): 2643-2650, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24504125

RESUMO

PURPOSE: Detecting circulating plasma tumor DNA (ptDNA) in patients with early-stage cancer has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection. EXPERIMENTAL DESIGN: In this prospective study, primary breast tumors and matched pre- and postsurgery blood samples were collected from patients with early-stage breast cancer (n = 29). Tumors (n = 30) were analyzed by Sanger sequencing for common PIK3CA mutations, and DNA from these tumors and matched plasma were then analyzed for PIK3CA mutations using ddPCR. RESULTS: Sequencing of tumors identified seven PIK3CA exon 20 mutations (H1047R) and three exon 9 mutations (E545K). Analysis of tumors by ddPCR confirmed these mutations and identified five additional mutations. Presurgery plasma samples (n = 29) were then analyzed for PIK3CA mutations using ddPCR. Of the 15 PIK3CA mutations detected in tumors by ddPCR, 14 of the corresponding mutations were detected in presurgical ptDNA, whereas no mutations were found in plasma from patients with PIK3CA wild-type tumors (sensitivity 93.3%, specificity 100%). Ten patients with mutation-positive ptDNA presurgery had ddPCR analysis of postsurgery plasma, with five patients having detectable ptDNA postsurgery. CONCLUSIONS: This prospective study demonstrates accurate mutation detection in tumor tissues using ddPCR, and that ptDNA can be detected in blood before and after surgery in patients with early-stage breast cancer. Future studies can now address whether ptDNA detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Adulto , Idoso , Neoplasias da Mama/cirurgia , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA/métodos , DNA de Neoplasias/química , Éxons/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/genética , Reação em Cadeia da Polimerase/métodos , Período Pós-Operatório , Período Pré-Operatório , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Hum Pathol ; 45(4): 880-3, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24444464

RESUMO

Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood. Using this technique, we identified mutant PIK3CA DNA in circulating ptDNA (plasma tumor DNA) from a patient with concurrent early stage breast cancer and non-small cell lung cancer. The patient underwent successful resection of both her breast and lung cancers, and using standard Sanger sequencing the breast cancer was shown to harbor the identical PIK3CA mutation identified in peripheral blood. This case report highlights potential applications and concerns that can arise with the use of ptDNA in clinical oncology practice.


Assuntos
Neoplasias da Mama/genética , DNA de Neoplasias/sangue , Neoplasias Pulmonares/genética , Mutação , Neoplasias Primárias Múltiplas/genética , Fosfatidilinositol 3-Quinases/genética , Reação em Cadeia da Polimerase/métodos , Idoso , Sequência de Bases , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Classe I de Fosfatidilinositol 3-Quinases , DNA de Neoplasias/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Primárias Múltiplas/sangue , Neoplasias Primárias Múltiplas/patologia , Fosfatidilinositol 3-Quinases/sangue
16.
Cancer ; 120(3): 381-9, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24375332

RESUMO

BACKGROUND: Aromatase inhibitors (AIs) have been associated with decrements in patient-reported outcomes (PROs). The objective of this study was to assess whether real acupuncture (RA), compared with sham acupuncture (SA), improves PROs in patients with breast cancer who are receiving an adjuvant AI. METHODS: Postmenopausal women with a stage 0 through III breast cancer who received an AI and had treatment-associated musculoskeletal symptoms were randomized to receive 8 weekly RA versus SA in a dual-center, randomized controlled trial. The National Surgical Adjuvant Breast and Bowel Project (NSABP) menopausal symptoms questionnaire, the Center for Epidemiological Studies Depression (CESD) scale, the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), the hot flash daily diary, the Hot Flash-Related Daily Interference Scale (HFRDI), and the European quality-of-life survey (EuroQol) were used to assess PROs at baseline and at 4weeks, 8 weeks, and 12 weeks. RESULTS: The intention-to-treat analysis included 23 patients in the RA arm and 24 patients in the SA arm. There were no significant differences in baseline characteristics between the 2 groups. Compared with baseline, scores in the RA arm improved significantly at week 8 on the CESD (P = .022), hot flash severity (P = .006), hot flash frequency (P = .011), the HFRDI (P = .014), and NSABP menopausal symptoms (P = .022); scores in the SA arm improved significantly on the EuroQol (P = .022),the HFRDI (P = .043), and NSABP menopausal symptoms (P = .005). Post-hoc analysis indicated that African American patients (n = 9) benefited more from RA than SA compared with non-African American patients (n = 38) in reducing hot flash severity (P < .001) and frequency (P < .001) scores. CONCLUSIONS: Both RA and SA were associated with improvement in PROs among patients with breast cancer who were receiving AIs, and no significant difference was detected between arms. Racial differences in response to acupuncture warrant further study.


Assuntos
Terapia por Acupuntura , Inibidores da Aromatase/efeitos adversos , Doenças Ósseas/prevenção & controle , Neoplasias da Mama/terapia , Doenças Musculares/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Ósseas/induzido quimicamente , Neoplasias da Mama/psicologia , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Qualidade de Vida
17.
Microsurgery ; 33(6): 421-31, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23836495

RESUMO

BACKGROUND: Some sensation to the breast returns after breast reconstruction, but recovery is variable and unpredictable. We primarily sought to assess the impact of different types of breast reconstruction [deep inferior epigastric artery perforator (DIEP) flaps versus implants] and radiation therapy on the return of sensation. METHODS: Thirty-seven patients who had unilateral or bilateral breast reconstruction via a DIEP flap or implant-based reconstruction, with or without radiation therapy (minimum follow-up, 18 months; range, 18-61 months) were studied. Of the 74 breasts, 27 had DIEP flaps, 29 had implants, and 18 were nonreconstructed. Eleven breasts with implants and 10 with DIEP flaps had had prereconstruction radiation therapy. The primary outcome was mean patient-perceived static and moving cutaneous pressure threshold in nine areas. We used univariate and multivariate analyses to assess what independent factors affected the return of sensation (significance, P < 0.05). RESULTS: Implants provided better static (P = 0.071) and moving sensation (P = 0.041) than did DIEP flaps. However, among irradiated breasts, skin over DIEP flaps had significantly better sensation than did that over implants (static, P = 0.019; moving, P = 0.028). Implant reconstructions with irradiated skin had significantly worse static (P = 0.002) and moving sensation (P = 0.014) than did nonirradiated implant reconstructions. CONCLUSIONS: Without irradiation, skin overlying implants is associated with better sensation recovery than DIEP flap skin. However, with irradiation, DIEP flap skin had better sensation recovery than did skin over implants. Neurotization trended toward improvement in sensation in DIEP flaps.


Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia , Retalhos Cirúrgicos/inervação , Adulto , Idoso , Implante Mamário , Neoplasias da Mama/radioterapia , Feminino , Humanos , Mamoplastia/métodos , Pessoa de Meia-Idade , Transferência de Nervo , Mamilos/inervação , Mamilos/cirurgia , Projetos Piloto , Período Pós-Operatório , Sensação
18.
Clin Cancer Res ; 19(14): 4008-16, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23719261

RESUMO

PURPOSE: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not. EXPERIMENTAL DESIGN: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. RESULTS: Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. CONCLUSIONS: Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Ácidos Hidroxâmicos/uso terapêutico , Antígeno Ki-67/metabolismo , Adulto , Idoso , Antineoplásicos/farmacocinética , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/cirurgia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Terapia Combinada , Ciclina B1/genética , Ciclina B1/metabolismo , Feminino , Humanos , Ácidos Hidroxâmicos/farmacocinética , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Estudos Prospectivos , Survivina , Transativadores/genética , Transativadores/metabolismo , Transcriptoma , Vorinostat
19.
Breast Cancer Res Treat ; 139(1): 135-43, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23588952

RESUMO

The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m(2) BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Adenocarcinoma/patologia , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Farmacogenética
20.
Breast Cancer Res Treat ; 138(1): 167-74, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23393007

RESUMO

Up to 50 % of women receiving aromatase inhibitor (AI) complain of AI-associated musculoskeletal symptoms (AIMSS) and 15 % discontinue treatment. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture improves AIMSS and to explore potential mechanisms. Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to eight weekly real or sham acupuncture sessions. We evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS) following the intervention compared to baseline. Serum estradiol, ß-endorphin, and proinflammatory cytokine concentrations were measured pre and post-intervention. We enrolled 51 women of whom 47 were evaluable, including 23 randomized to real and 24 to sham acupuncture. Baseline characteristics were balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group (p = 0.047). We did not observe a statistically significant difference in reduction of HAQ-DI (p = 0.30) or VAS (p = 0.31) between the two groups. Following eight weekly treatments, we observed a statistically significant reduction of IL-17 (p ≤ 0.009) in both groups. No significant modulation was seen in estradiol, ß-endorphin, or other proinflammatory cytokine concentrations in either group. We did not observe a significant difference in AIMSS changes between real and sham acupuncture. As sham acupuncture used in this study may not be equivalent to placebo, further studies with a non-acupuncture arm may be required to establish whether acupuncture is beneficial for the treatment of AIMSS.


Assuntos
Terapia por Acupuntura , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/reabilitação , Dor Musculoesquelética/induzido quimicamente , Dor Musculoesquelética/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Mediadores da Inflamação/sangue , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , beta-Endorfina/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...