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1.
J Natl Cancer Inst ; 115(8): 981-988, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37042724

RESUMEN

BACKGROUND: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints. METHODS: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks). RESULTS: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02). CONCLUSIONS: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.


Asunto(s)
Neoplasias de la Mama , Hematopoyesis Clonal , Humanos , Femenino , Anciano , Hematopoyesis Clonal/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Estudios Retrospectivos , Hematopoyesis/genética , Mutación
2.
J Geriatr Oncol ; 14(1): 101377, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36163163

RESUMEN

INTRODUCTION: Older adults with breast cancer receiving neo/adjuvant chemotherapy are at high risk for poor outcomes and are underrepresented in clinical trials. The ADVANCE (ADjuVANt Chemotherapy in the Elderly) trial evaluated the feasibility of two neo/adjuvant chemotherapy regimens in parallel-enrolling cohorts of older patients with human epidermal growth factor receptor 2-negative breast cancer: cohort 1-triple-negative; cohort 2-hormone receptor-positive. MATERIALS AND METHODS: Adults age ≥ 70 years with stage I-III breast cancer warranting neo/adjuvant chemotherapy were enrolled. Cohort 1 received weekly carboplatin (area under the curve 2) and weekly paclitaxel 80 mg/m2 for twelve weeks; cohort 2 received weekly paclitaxel 80 mg/m2 plus every-three-weekly cyclophosphamide 600 mg/m2 over twelve weeks. The primary study endpoint was feasibility, defined as ≥80% of patients receiving ≥80% of intended weeks/doses of therapy. All dose modifications were applied per clinician discretion. RESULTS: Forty women (n = 20 per cohort) were enrolled from March 25, 2019 through August 3, 2020 from three centers; 45% and 35% of patients in cohorts 1 and 2 were age > 75, respectively. Neither cohort achieved targeted thresholds for feasibility. In cohort 1, eight (40.0%) met feasibility (95% confidence interval [CI] = 19.1-63.9%), while ten (50.0%) met feasibility in cohort 2 (95% CI = 27.2-72.8). Neutropenia was the most common grade 3-4 toxicity (cohort 1-65%, cohort 2-55%). In cohort 1, 80% and 85% required ≥1 dose holds of carboplatin and/or paclitaxel, respectively. In cohort 2, 10% required dose hold(s) for cyclophosphamide and/or 65% for paclitaxel. DISCUSSION: In this pragmatic pilot examining chemotherapy regimens in older adults with breast cancer, neither regimen met target goals for feasibility. Developing efficacious and tolerable regimens for older patients with breast cancer who need chemotherapy remains an important goal. CLINICALTRIALS: gov Identifier: NCT03858322.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Carboplatino , Proyectos Piloto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Paclitaxel , Quimioterapia Adyuvante , Ciclofosfamida
3.
Breast Cancer Res Treat ; 195(2): 141-152, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35908120

RESUMEN

PURPOSE: To support shared decision-making, patient-facing resources are needed to complement recently published guidelines on approaches for surveillance mammography in breast cancer survivors aged ≥ 75 or with < 10-year life expectancy. We created a patient guide to facilitate discussions about surveillance mammography in older breast cancer survivors. METHODS: The "Are Mammograms Still Right for Me?" guide estimates future ipsilateral and contralateral breast (in-breast) cancer risks, general health, and the potential benefits/harms of mammography, with prompts for discussion. We conducted in-clinic acceptability testing of the guide by survivors and their clinicians at a National Cancer Institute-designated comprehensive cancer center, including two community practices. Patients and clinicians received the guide ahead of a clinic visit and surveyed patients (pre-/post-visit) and clinicians (post-visit). Acceptability was defined as ≥ 75% of patients and clinicians reporting that the guide (a) should be recommended to others, (b) is clear, (c) is helpful, and (d) contains a suitable amount of information. We also elicited feedback on usability and mammography intentions. RESULTS: We enrolled 45 patients and their 21 clinicians. Among those responding in post-visit surveys, 33/37 (89%) patients and 15/16 (94%) clinicians would recommend the guide to others; 33/37 (89%) patients and 15/16 (94%) clinicians felt everything/most things were clear. All other pre-specified acceptability criteria were met. Most patients reported strong intentions for mammography (100% pre-visit, 98% post-visit). CONCLUSION: Oncology clinicians and older breast cancer survivors found a guide to inform mammography decision-making acceptable and clear. A multisite clinical trial is needed to assess the guide's impact mammography utilization. TRIAL REGISTRATION: ClinicalTrials.gov-NCT03865654, posted March 7, 2019.


Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Femenino , Humanos , Esperanza de Vida , Mamografía , Sobrevivientes
4.
JAMA Oncol ; 7(4): 609-615, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33507222

RESUMEN

IMPORTANCE: There is currently no guidance on how to approach surveillance mammography for older breast cancer survivors, particularly when life expectancy is limited. OBJECTIVE: To develop expert consensus guidelines that facilitate tailored decision-making for routine surveillance mammography for breast cancer survivors 75 years or older. EVIDENCE: After a literature review of the risk of ipsilateral and contralateral breast cancer events among breast cancer survivors and the harms and benefits associated with mammography, a multidisciplinary expert panel was convened to develop consensus guidelines on surveillance mammography for breast cancer survivors 75 years or older. Using an iterative consensus-based approach, input from clinician focus groups, and critical review by the International Society for Geriatric Oncology, the guidelines were refined and finalized. FINDINGS: The literature review established a low risk for ipsilateral and contralateral breast cancer events in most older breast cancer survivors and summarized the benefits and harms associated with mammography. Draft mammography guidelines were iteratively evaluated by the expert panel and clinician focus groups, emphasizing a patient's risk for in-breast cancer events, age, life expectancy, and personal preferences. The final consensus guidelines recommend discontinuation of routine mammography for all breast cancer survivors when life expectancy is less than 5 years, including those with a history of high-risk cancers; consideration to discontinue mammography when life expectancy is 5 to 10 years; and continuation of mammography when life expectancy is more than 10 years. Individualized, shared decision-making is encouraged to optimally tailor recommendations after weighing the benefits and harms associated with surveillance mammography and patient preferences. The panel also recommends ongoing clinical breast examinations and diagnostic mammography to evaluate clinical findings and symptoms, with reassurance for patients that these practices will continue. CONCLUSIONS AND RELEVANCE: It is anticipated that these expert guidelines will enhance clinical practice by providing a framework for individualized discussions, facilitating shared decision-making regarding surveillance mammography for breast cancer survivors 75 years or older.


Asunto(s)
Neoplasias de la Mama , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Detección Precoz del Cáncer , Femenino , Humanos , Esperanza de Vida , Mamografía , Tamizaje Masivo , Sobrevivientes
5.
PLoS One ; 13(10): e0204589, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30286096

RESUMEN

Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs' specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease.


Asunto(s)
MicroARNs/sangre , Macroglobulinemia de Waldenström/sangre , Adulto , Anciano , Biomarcadores/sangre , Línea Celular , Progresión de la Enfermedad , Exosomas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Macroglobulinemia de Waldenström/genética
7.
Cell Rep ; 19(1): 218-224, 2017 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-28380360

RESUMEN

The development of sensitive and non-invasive "liquid biopsies" presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Médula Ósea/genética , Pruebas Genéticas/métodos , Mieloma Múltiple/genética , Células Neoplásicas Circulantes , Biomarcadores de Tumor/sangre , Neoplasias de la Médula Ósea/sangre , Neoplasias de la Médula Ósea/patología , Recuento de Células , ADN/sangre , Análisis Mutacional de ADN , GTP Fosfohidrolasas/sangre , GTP Fosfohidrolasas/genética , Humanos , Estudios Longitudinales , Proteínas de la Membrana/sangre , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/patología , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/sangre , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , Secuenciación del Exoma
8.
Blood ; 127(21): 2598-606, 2016 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-26903547

RESUMEN

Familial aggregation of Waldenström macroglobulinemia (WM) cases, and the clustering of B-cell lymphoproliferative disorders among first-degree relatives of WM patients, has been reported. Nevertheless, the possible contribution of inherited susceptibility to familial WM remains unrevealed. We performed whole exome sequencing on germ line DNA obtained from 4 family members in which coinheritance for WM was documented in 3 of them, and screened additional independent 246 cases by using gene-specific mutation sequencing. Among the shared germ line variants, LAPTM5(c403t) and HCLS1(g496a) were the most recurrent, being present in 3/3 affected members of the index family, detected in 8% of the unrelated familial cases, and present in 0.5% of the nonfamilial cases and in <0.05 of a control population. LAPTM5 and HCLS1 appeared as relevant WM candidate genes that characterized familial WM individuals and were also functionally relevant to the tumor clone. These findings highlight potentially novel contributors for the genetic predisposition to familial WM and indicate that LAPTM5(c403t) and HCLS1(g496a) may represent predisposition alleles in patients with familial WM.


Asunto(s)
Proteínas Sanguíneas/genética , Exoma , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Proteínas de la Membrana/genética , Macroglobulinemia de Waldenström/genética , Proteínas Adaptadoras Transductoras de Señales , Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino
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