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1.
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
2.
Breast Cancer Res Treat ; 131(3): 915-24, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22076478

RESUMO

Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Sinvastatina/administração & dosagem , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Proteína C-Reativa/metabolismo , Estrogênios/sangue , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Lipídeos/sangue , Pessoa de Meia-Idade , Qualidade de Vida , Sinvastatina/efeitos adversos
3.
JCO Precis Oncol ; 20172017.
Artigo em Inglês | MEDLINE | ID: mdl-30003184

RESUMO

PURPOSE: Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. METHODS: A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. RESULTS: One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. CONCLUSION: The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

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.
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
7.
Clin Cancer Res ; 18(12): 3462-9, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22421194

RESUMO

PURPOSE: We sought to evaluate the feasibility of detecting PIK3CA mutations in circulating tumor DNA (ctDNA) from plasma of patients with metastatic breast cancer using a novel technique called BEAMing. EXPERIMENTAL DESIGN: In a retrospective analysis, 49 tumor and temporally matched plasma samples from patients with breast cancer were screened for PIK3CA mutations by BEAMing. We then prospectively screened the ctDNA of 60 patients with metastatic breast cancer for PIK3CA mutations by BEAMing and compared the findings with results obtained by screening corresponding archival tumor tissue DNA using both sequencing and BEAMing. RESULTS: The overall frequency of PIK3CA mutations by BEAMing was similar in both patient cohorts (29% and 28.3%, respectively). In the retrospective cohort, the concordance of PIK3CA mutation status by BEAMing between formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from temporally matched plasma was 100% (34 of 34). In the prospective cohort, the concordance rate among 51 evaluable cases was 72.5% between BEAMing of ctDNA and sequencing of archival tumor tissue DNA. When the same archival tissue DNA was screened by both sequencing and BEAMing for PIK3CA mutations (n = 41 tissue samples), there was 100% concordance in the obtained results. CONCLUSIONS: Analysis of plasma-derived ctDNA for the detection of PIK3CA mutations in patients with metastatic breast cancer is feasible. Our results suggest that PIK3CA mutational status can change upon disease recurrence, emphasizing the importance of reassessing PIK3CA status on contemporary (not archival) biospecimens. These results have implications for the development of predictive biomarkers of response to targeted therapies.


Assuntos
Neoplasias da Mama/genética , DNA de Neoplasias/sangue , Fosfatidilinositol 3-Quinases/sangue , Fosfatidilinositol 3-Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Estudos de Coortes , Feminino , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estudos Retrospectivos
8.
J Clin Oncol ; 27(22): e35-7; author reply e38-9, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19564528
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