RESUMO
OBJECTIVES: Women with a BRCA1 or BRCA2 mutation are recommended to undergo prophylactic (or risk reducing) bilateral salpingo-oophorectomy (BSO) before age 40, resulting in surgical menopause. Given the concerns of estrogen deprivation on overall health, hormone therapy (HT) is often discussed, yet safety concerns persist. MATERIALS AND METHODS: We performed a systematic literature review of the safety of HT in women with a BRCA mutation undergoing prophylactic BSO. RESULTS: Although there remains a paucity of data on this topic, as evidenced by this systematic review of the contemporary literature, these patients do benefit from treatment, especially as it relates to menopausal symptoms without an apparently increased risk of breast cancer. CONCLUSIONS: Decisions regarding the use of HT in women who undergo BSO after detection of a BRCA mutation must be individualized based on careful consideration of the risks and benefits. However, the risks of a subsequent cancer diagnosis appear small, particularly in regards to the benefits of treatment afforded by HT.
Assuntos
Terapia de Reposição Hormonal , Menopausa Precoce , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Neoplasias Ovarianas/prevenção & controle , Procedimentos Cirúrgicos Profiláticos , Salpingo-Ooforectomia/efeitos adversosRESUMO
Multiple myeloma (MM) remains an incurable disease, with a treatment-refractory state eventually developing in all patients. Constant clonal evolution and genetic heterogeneity of MM are a likely explanation for the emergence of drug-resistant disease. Monitoring of MM genomic evolution on therapy by serial bone marrow biopsy is unfortunately impractical because it involves an invasive and painful procedure. We describe how noninvasive and highly sensitive isolation and characterization of circulating tumor cells (CTCs) from peripheral blood at single-cell resolution recapitulate MM in the bone marrow. We demonstrate that CTCs provide the same genetic information as bone marrow MM cells and even reveal mutations with greater sensitivity than bone marrow biopsies in some cases. Single CTC RNA sequencing enables classification of MM and quantitative assessment of genes that are relevant for prognosis. We propose that the genomic characterization of CTCs should be included in clinical trials to follow the emergence of resistant subclones after MM therapy.
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Medula Óssea/patologia , Heterogeneidade Genética , Mieloma Múltiplo/genética , Células Neoplásicas Circulantes/patologia , Análise Mutacional de DNA , Estudos de Viabilidade , Perfilação da Expressão Gênica , Genótipo , Humanos , Perda de Heterozigosidade , Mieloma Múltiplo/sangue , Mutação , Plasmócitos/metabolismo , Prognóstico , Estudo de Prova de Conceito , Análise de Sequência de RNA , Análise de Célula Única , Transcrição Gênica , Carga TumoralRESUMO
BACKGROUND: Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. METHODS: In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40-240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3â+â3 design according to three different regimens on days 1-21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, number NCT01583283. FINDINGS: Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1-21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1-2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhoea (grade 1-2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% [95% CI 38-71]) of 38 patients had an overall response. INTERPRETATION: The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma. FUNDING: Acetylon Pharmaceuticals.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivadosRESUMO
INTRODUCTION: Cancer clinical trial (CT) participation rates are low and financial barriers likely play a role. We implemented a cancer care equity program (CCEP) to address financial burden associated with trial participation. We sought to examine the impact of the CCEP on CT enrollment and to assess barriers to participation. METHODS: We used an interrupted time series design to determine trends in CT enrollment before and after CCEP implementation. Linear regression models compared trial enrollment before and after the CCEP. We also compared patient characteristics before and after the CCEP and between CCEP and non-CCEP participants. We surveyed CCEP and non-CCEP participants to compare pre-enrollment financial barriers. RESULTS: After accounting for increased trial availability and the trends in accrual for prior years, we found that enrollment increased after CCEP implementation (18.97 participants per month greater than expected; p < .001). A greater proportion of CCEP participants were younger, female, in phase I trials, lived farther away, had lower incomes, and had metastatic disease. Of 87 participants who completed the financial barriers survey, 49 CCEP and 38 matched, non-CCEP participants responded (63% response rate). CCEP participants were more likely to report concerns regarding finances (56% vs. 11%), medical costs (47% vs. 14%), travel (69% vs. 11%), lodging (60% vs. 9%), and insurance coverage (43% vs. 14%) related to trial participation (all p < .01). CONCLUSION: CT participation increased following implementation of the CCEP and the program enrolled patients experiencing greater financial burden. These findings highlight the need to address the financial burden associated with CT participation. IMPLICATIONS FOR PRACTICE: Financial barriers likely discourage patients from participating in clinical trials. Implementation of a cancer care equity program (CCEP) seeking to reduce financial barriers by assisting with travel and lodging costs was associated with increased trial accrual. The CCEP provided assistance to patients particularly in need, including those living farther away, those with lower incomes, and those reporting financial barriers related to trial participation. These findings suggest that financial concerns represent a major barrier to patient participation in clinical trials and underscore the importance of efforts to address these concerns.
Assuntos
Acessibilidade aos Serviços de Saúde/economia , Neoplasias/economia , Neoplasias/epidemiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Participação do Paciente/economia , Seleção de Pacientes , Pobreza/economia , Inquéritos e QuestionáriosRESUMO
Whole genome sequencing studies have identified several oncogenic mutations in multiple myeloma (MM). As MM progresses, it evolves genetically underscoring the need to have tools for rapid detection of targetable mutations to optimize individualized treatment. Massachusetts General Hospital (MGH) has developed a Clinical Laboratory Improvement Amendments (CLIA)-approved, high-throughput, genotyping platform to determine the mutation status of a panel of known oncogenes. Sequence analysis using SNaPshot on DNA extracted from bone marrow and extramedullary plasmacytomas is feasible and leads to the detection of potentially druggable mutations. Screening MM patients for somatic mutations in oncogenes may provide novel targets leading to additional therapies for this patient population.
Assuntos
Mieloma Múltiplo/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Humanos , Pessoa de Meia-IdadeRESUMO
To evaluate the effect of an educational intervention on four domains of health care utilization and cervical cancer prevention and screening in a Hispanic population. Data collected from a survey were used to design education strategies focused on four domains of interest. A second survey was conducted to measure the impact of the intervention. Following the intervention, respondents were more likely to have any knowledge of human papillomavirus (HPV). Respondents living in the United States (US) for <5 years were more likely to have had a Papanicolaou smear in the preceding 3 years (p = 0.0314), to report knowledge of HPV vaccination (p = 0.0258), and to be willing to vaccinate themselves (p = 0.0124) and their children (p = 0.0341) after the intervention. Educational interventions designed to meet the needs identified by the sample group led to an increase in HPV awareness throughout the entire population surveyed and an increase in health care service utilization and HPV vaccine acceptance for women living in the US for <5 years. These tools should be promoted to reduce the cervical cancer burden on vulnerable populations.