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1.
Biochim Biophys Acta Rev Cancer ; 1872(2): 188315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31647985

RESUMO

BACKGROUND: Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy. OBJECTIVE: The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer. METHODS: A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors. RESULTS: The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%-31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28-26.62, P ≤.001). CONCLUSION: ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/genética , Mutação , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/genética , Feminino , Fulvestranto/uso terapêutico , Humanos , Ensaios Clínicos Controlados não Aleatórios como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/uso terapêutico
2.
Expert Opin Pharmacother ; 20(15): 1819-1829, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31486688

RESUMO

Introduction: Fulvestrant is currently the only selective estrogen receptor degrader (SERD) that is approved for clinical use in estrogen receptor (ER) positive advanced breast cancer (ABC). The drug is approved as single-agent therapy in the first and second-line setting of metastatic ER-positive breast cancer. Areas covered: In this review, the authors review the preclinical studies that were pivotal in the development of fulvestrant, the pharmacologic properties of the drug, and the key clinical trials that resulted in its approval for clinical use. The authors discuss mechanisms of endocrine resistance and potential targets for endocrine refractory disease while highlighting ongoing studies that assess fulvestrant use with novel agents. Expert opinion: While fulvestrant has limited use in the first-line setting in advanced breast cancer, it is most frequently used in the second line after progression with aromatase inhibitors. The combination of fulvestrant with CDK4/6 inhibitors has shown a clear benefit over monotherapy in patients who progress on prior endocrine therapy. Further study is necessary to assess if patient outcomes can be enhanced by optimizing the sequence of endocrine therapies, targeting resistance pathways with novel agents, and development of new agents in the SERD class.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/patologia , Feminino , Fulvestranto/farmacocinética , Fulvestranto/farmacologia , Humanos , Metástase Neoplásica
3.
Expert Opin Pharmacother ; 20(15): 1809-1818, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31500470

RESUMO

Introduction: Triptorelin is a luteinizing hormone-releasing hormone analog (LH-RHa) inducing ovarian function suppression (OFS). It is approved by FDA and EMA in association with tamoxifen or aromatase inhibitor (AI) and with fulvestrant and palbociclib in premenopausal women with hormone receptor (HR)-positive breast cancer. Its potential role to preserve ovarian function during chemotherapy has also been recently clarified. Areas covered: Several studies have investigated the role of adding OFS to tamoxifen and aromatase inhibitors as adjuvant treatment in early breast cancer. The addition of triptorelin is not free from adverse events as the combination with tamoxifen and exemestane resulted in an increase of endocrine-deprivation symptoms. Clinical trials have explored the combination of LH-RHa with chemotherapy in fertility preservation, demonstrating no detrimental effect on patients' oncological outcome. This is all discussed in this evaluation. Expert opinion: Triptorelin represents a standard-of-care in premenopausal women with HR-positive breast cancer and in some cases of male breast cancer. In the adjuvant setting, a personalized approach is required to combine LH-RHa with the right partner considering the risk of recurrence and the toxicity profile. LH-RHa may be offered to breast cancer patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Pamoato de Triptorrelina/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Pamoato de Triptorrelina/farmacologia
4.
Medicine (Baltimore) ; 98(29): e16599, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335742

RESUMO

Chylothorax after lobectomy is common, lacking reliable preventive measures. Octreotide is widely used for treatment of chyle leakage, but its role in preventing chylothorax has not been estimated. The aim of this study was to evaluate whether prophylactic octreotide could reduce the incidence of postoperative chylothorax.Patients who underwent lobectomy for lung cancer from January 2016 to September 2018 were retrospectively reviewed. The cases in prophylactic group received octreotide 1 day before the surgery until removal of chest tubes, while those in the control group did not use it unless the diagnosis of chylothorax.A total of 379 patients were enrolled, with 190 patients in control and 189 cases in prophylactic group. Octreotide was well tolerated in patients who received this agent. No 30-day mortality was indicated. Seven cases in control (3.7%, 7/190) and 3 cases in prophylactic group (1.6%, 3/189) with chylothorax were observed (P = .337). The patients in prophylactic group showed shorter duration of chest drainage ([3.6 ±â€Š1.6] days vs [4.1 ±â€Š2.0] days, P = .006) and reduced drainage volume ([441.8 ±â€Š271.1] mL vs [638.7 ±â€Š463.3] mL, P < .001). In addition, they showed similar stations and numbers of dissected lymph nodes, surgery-related complications, and postoperative hospital stay. Besides, 11 (5.8%, 11/190) patients in control and 6 (3.2%, 6/189) cases in the prophylactic group were readmitted for pleural effusion needing reinsertion of chest tubes (P = .321). Moreover, multivariable logistic analysis showed that induction therapy (odds ratio [OR] =12.03; 95% confidence interval [CI] 3.15-46.03, P < .001) was a risk factor, while high-volume experience of the surgeon (OR = 0.23; 95% CI 0.06-0.97, P = .045) was a preventive factor of surgery-related chylothorax. Additionally, prophylactic octreotide (OR = 0.18; 95% CI 0.11-0.28, P < .001) and perioperative low-fat diet (OR = 0.46; 95% CI 0.29-0.73, P = .001) were negatively associated with the drainage volume of pleural effusion. Furthermore, high-volume experience of the surgeon (OR = 6.03; 95% CI 1.30-27.85, P = .021) and induction therapy (OR = 8.87; 95% CI 2.97-26.48, P < .001) were risk factors of unplanned readmission.Prophylactic octreotide does not reduce the incidence of postoperative chylothorax or unplanned readmission following anatomic lobectomy. The routine application of octreotide should not be recommended. High-quality trials are required to validate these findings.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Quilotórax/prevenção & controle , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Octreotida/uso terapêutico , Pneumonectomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Tubos Torácicos , Quilotórax/etiologia , Dieta com Restrição de Gorduras , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Derrame Pleural , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
5.
Bull Cancer ; 106(11): 1000-1007, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31351573

RESUMO

INTRODUCTION: Microinvasive in situ ductal carcinomas of the breast are rare and of good prognosis. They are grouped with early stage invasive carcinomas in the TNM 2017 classification. This study assessed practitioners' treatment decisions and their justifications in comparison to the literature. MATERIALS AND METHODS: Three clinical cases were evaluated by anonymous forms regarding sentinel node decisions, tumour bed boost irradiation and hormone therapy. RESULTS: Sentinel lymph node was performed by 93.1%, 100% and 44.4% of the practitioners respectively. Radiation boost was a treatment option chosen by 62.1% and 61.1% of practitioners in both clinical cases. Hormone therapy was advocated for 65.5%, 94.7% and 50.0% patients depending on the clinical case. CONCLUSION: The therapeutic attitude proposed in microinvasive breast carcinomas was heterogeneous in this study, reflecting the absence of specific recommendations. In view of the existing literature, it is not currently possible to propose recommendations for these three therapeutic options. Prospective cohorts and meta-analyses of the microinvasive subgroup could provide answers.


Assuntos
Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Tomada de Decisão Clínica , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Adulto , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Invasividade Neoplásica , Oncologistas/estatística & dados numéricos , Prognóstico , Radiologistas/estatística & dados numéricos , Radioterapia Adjuvante/estatística & dados numéricos , Cirurgiões/estatística & dados numéricos
6.
J Zoo Wildl Med ; 50(2): 474-477, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260218

RESUMO

After a history of intermittent vomiting, endoscopic biopsies of stomach and duodenum were collected from a 13-yr-old male snow leopard (Uncia uncia). On microscopic examination, monomorphic small lymphocytes expanded the duodenal mucosa and occasionally formed intraepithelial nests. Immunohistochemistry of the infiltrating small lymphocytes in the mucosa and within the epithelium had strong, perimembranous labeling for CD3e, with few CD79a-positive lymphocytes located at the base of the villi. Polymerase chain reaction (PCR) for antigen receptor rearrangements (PARR) of feline T-cell receptor gamma (TCRG) detected a monoclonal cell population. The sequence of the PCR product was 100% homologous with the feline TCRG gene. By histology, immunophenotyping, and PARR testing, a final diagnosis of enteropathy-associated T-cell lymphoma, small cell type, was made. Homology in the nucleotide sequence between U. uncia and the domestic cat (Felis catus) indicates that feline PARR testing for TCRG may be diagnostic in snow leopards.


Assuntos
Linfoma de Células T Associado a Enteropatia/veterinária , Felidae , Doenças Inflamatórias Intestinais/veterinária , Animais , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Clorambucila/uso terapêutico , Linfoma de Células T Associado a Enteropatia/diagnóstico , Linfoma de Células T Associado a Enteropatia/tratamento farmacológico , Linfoma de Células T Associado a Enteropatia/patologia , Doenças Inflamatórias Intestinais/diagnóstico , Masculino , Prednisolona/uso terapêutico , Vitamina B 12/administração & dosagem , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico
7.
Nat Commun ; 10(1): 2399, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160585

RESUMO

Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD's stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression.


Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Resistencia a Medicamentos Antineoplásicos/genética , Superóxido Dismutase/genética , Acetilação , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Técnicas In Vitro , Lisina/metabolismo , Células MCF-7 , Camundongos , Mutação , Transplante de Neoplasias , Peroxidase/metabolismo , Estrutura Quaternária de Proteína/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Tamoxifeno/uso terapêutico , Proteínas Supressoras de Tumor
8.
J Cancer Res Ther ; 15(3): 722-724, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169251

RESUMO

Tamoxifen-induced ocular complications including cataracts, keratopathies, retinopathy, impaired visual acuity, ocular irritation, optical neuritis, and retinal vein occlusion are uncommonly reported in the literature. Herein, we report on a premenopausal patient with right-side breast carcinoma who received adjuvant tamoxifen therapy (20 mg/day) for 1.5 years and developed sudden visual loss. Fundal examination revealed an obstruction in the branch of the retinal vein. The diagnosis was confirmed by fluorescein angiography and optical coherence tomography. Thus, tamoxifen was switched to an aromatase inhibitor. Tamoxifen-induced ocular complications should be kept in mind when visual symptoms are seen in patients undergoing tamoxifen therapy. In such cases, a complete ocular examination should be performed.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/etiologia , Tamoxifeno/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Feminino , Angiofluoresceinografia , Humanos , Pessoa de Meia-Idade , Tamoxifeno/uso terapêutico , Tomografia de Coerência Óptica
9.
Gynecol Oncol ; 154(3): 531-538, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31227223

RESUMO

OBJECTIVE: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. METHODS: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6 months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. CONCLUSIONS: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.


Assuntos
Anastrozol/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Pós-Menopausa , Intervalo Livre de Progressão , Estudos Prospectivos , Qualidade de Vida , Receptores de Progesterona/metabolismo , Adulto Jovem
10.
N Engl J Med ; 380(25): 2395-2405, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31157962

RESUMO

BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Tamoxifeno/uso terapêutico , Adulto , Fatores Etários , Idoso , Algoritmos , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Pré-Menopausa , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptor ErbB-2 , Fatores de Risco
11.
Anticancer Res ; 39(6): 2941-2950, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177133

RESUMO

BACKGROUND: Several studies have established a positive relationship between quality of life (QOL) and prognosis in patients with various cancer types. This study investigated QOL of elderly patients with primary hormone receptor-positive breast cancer who chose endocrine therapy as their first-line treatment. PATIENTS AND METHODS: QOL-ACD-B scores were evaluated before and after endocrine therapy for 75 patients. The results of the interviews were used to determine the Charlson Comorbidity Index. RESULTS: In a univariate analysis, baseline objective response rate (p=0.009), and increase in QOL (p=0.037) significantly correlated with longer progression-free survival time. There was a correlation between 3-month QOL score and longer overall survival in the multivariate analysis (p=0.035). CONCLUSION: In elderly patients with breast cancer who underwent first-line endocrine therapy, improved QOL at 3 months after treatment initiation correlated with prolonged progression-free survival. High QOL scores were associated with prolonged overall survival.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Prognóstico , Intervalo Livre de Progressão , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
12.
J Manag Care Spec Pharm ; 25(6): 714-718, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31134859

RESUMO

BACKGROUND: Despite the well-documented association of medication refill synchronization with medication adherence, little is known about how best to measure synchronization at pharmacy visits or about its relationship to number of medications. OBJECTIVE: To examine the relationship of a commonly cited synchronization measure with the number of prescription medications. METHODS: Using a cohort of women aged 66-90 years with stage 0-3 hormone receptor-positive breast cancer from the Surveillance, Epidemiology and End Result (SEER)-Medicare data, we identified women with pharmacy claims for at least 1 endocrine therapy prescription and at least 1 other medication fill. Twelve-month medication refill synchronization was calculated as the quotient of the number of pharmacy visits and the number of filled medications subtracted from 1. Multiple linear regression (including polynomials) was then used to assess the relationship between refill synchronization, number of medications, and other potentially influential factors. RESULTS: Over 47% of cohort subjects took more than 10 unique medications. Subjects made an average (SD) of 29.9 (18.0) pharmacy visits, resulting in a mean (SD) synchronization of 0.28 (0.18, range = 0.0-0.92). The number of medications, including powers through to the fourth, was strongly associated with refill synchronization, with a rapid initial rise followed by a gradual increase after 10 medications. Although patient age and race/ethnicity were not associated with synchronization, there was a significant positive association of receipt of a low-income subsidy and residence in rural areas with synchronization. CONCLUSIONS: There is a complex relationship between refill synchronization and number of prescribed medications, and future research into synchronization should account for this. DISCLOSURES: This study was supported by the National Institute on Minority Health and Health Disparities under grant R01 MD010728. The authors have nothing to disclose. This study was presented as an oral abstract at the Society of General Internal Medicine Meeting; April 13, 2018; Denver, CO.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Assistência Farmacêutica/organização & administração , Polimedicação , Medicamentos sob Prescrição/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Adesão à Medicação/estatística & dados numéricos , Modelos Estatísticos , Assistência Farmacêutica/estatística & dados numéricos , Programa de SEER/estatística & dados numéricos , Fatores de Tempo , Estados Unidos
13.
N Engl J Med ; 380(20): 1929-1940, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31091374

RESUMO

BACKGROUND: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODS: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. RESULTS: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONS: Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Fulvestranto/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/genética , Diarreia/induzido quimicamente , Feminino , Fulvestranto/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona , Tiazóis/efeitos adversos
14.
Rev Med Suisse ; 15(651): 1027-1031, 2019 May 15.
Artigo em Francês | MEDLINE | ID: mdl-31091037

RESUMO

New targeted therapies modify therapeutic strategies for advanced stage breast and tubo-ovarian cancers. Chemotherapy and endocrine therapy remain the cornerstones of breast cancer treatment. Inhibitors of CDK4/6, mTOR and PI3K are associated with endocrine therapy to increase its effectiveness. PARP inhibitors outperform chemotherapy in BRCA1/2 mutation carriers. Immunotherapy integrates into the treatment of triple-negative cancers with very promising results. For tubo-ovarian cancers, the concept of « platinum-sensitive ¼ has been tempered since the arrival of antiangiogenic treatment and PARP inhibitors that prolong the disease control not only in patients with BRCA1/2 mutation, but also in others.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
15.
Nat Commun ; 10(1): 2115, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073170

RESUMO

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/patologia , Citoesqueleto/patologia , Queratinas Tipo II/genética , Recidiva Local de Neoplasia/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Citoesqueleto/genética , Resistencia a Medicamentos Antineoplásicos/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Queratinas Tipo II/metabolismo , Células MCF-7 , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Domínios Proteicos/genética , Regulação para Cima
16.
Asian Pac J Cancer Prev ; 20(5): 1475-1479, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31127911

RESUMO

Leuprorelin is a synthetic analogue of naturally occurring gonadotropin-releasing hormone. It is currently approved in the United States, Europe and Asia and has indications in advanced prostate cancer, endometriosis, breast cancer and precocious puberty. This review examined clinical trials of leuprorelin in women with breast cancer in Asia. Methods: Four studies were identified, involving 999 premenopausal females with breast cancer. Leuprorelin was administered subcutaneously at doses of 3.75 mg every 4 weeks, 11.25 mg every 12 weeks or 22.5 mg every 24 weeks in addition to either adjuvant chemotherapy or hormonal therapy. Results: Leuprorelin was shown to preserve ovarian function, reduce symptoms of ovarian failure, the occurrence of early menopause, and the time to resumption of menses. Leuprorelin-related adverse events included hot flush, mood swings and urogenital symptoms. Conclusion: Clinical studies in breast cancer patients from Asia have primarily investigated the effect of leuprorelin on the protection of ovarian function in patients who receive chemotherapy, assessed the ability of leuprorelin to suppress serum estradiol to menopausal levels, or to determine the efficacy and safety of leuprorelin in daily medical practice.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Leuprolida/uso terapêutico , Ásia , Humanos , Menopausa/efeitos dos fármacos , Pré-Menopausa/efeitos dos fármacos
17.
Breast Cancer Res Treat ; 176(2): 377-386, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041683

RESUMO

PURPOSE: EndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C). METHODS: A total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses. RESULTS: EPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49-3.13), P < 0.0001) as well as in those who received ET + C (HR 2.27 (1.99-2.59), P < 0.0001). Women who received ET + C had significantly smaller increases in 10-year DR rates with the increasing EPclin score than those receiving ET alone (EPclin = 5; 12% ET + C vs. 20% ET alone). We observed a significant positive interaction between EPclin and treatment groups (P-interaction = 0.022). CONCLUSIONS: In this comparative non-randomised analysis, the rate of increase in DR with EPclin score was significantly reduced in women who received ET + C versus ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Idoso , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento
18.
J Urol ; 202(3): 533-538, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31042111

RESUMO

PURPOSE: The purpose of this amendment is to incorporate newly-published literature into the original ASTRO/AUA Adjuvant and Salvage Radiotherapy after Prostatectomy Guideline and to provide an updated clinical framework for clinicians. MATERIALS AND METHODS: The original systematic review yielded 294 studies published between January 1990 and December 2012. In April 2018, the guideline underwent an amendment and incorporated 155 references that were published from January 1990 through December 2017. Two new key questions were added. One on the use of genomic classifiers and the other on the treatment of oligo-metastases with radiation post-radical prostatectomy. RESULTS: A new statement on the use of hormone therapy with salvage radiotherapy after radical prostatectomy was added and long-term data was used to update an existing statement on adjuvant radiotherapy. The balance of the guideline statements were re-affirmed and references were added to the existing literature base. A discussion on the use of genomic classifiers as a risk stratification tool was added to the future research discussion. No relevant data on oligo-metastases was found. CONCLUSIONS: Hormone therapy should be offered to patients who have had radical prostatectomy and who are candidates for salvage radiotherapy. The clinician should discuss possible short- and long-term side effects with the patient as well as the potential benefits of preventing recurrence. The decision to use hormone therapy should be made by the patient and a multi-disciplinary team of providers with full consideration of the patient's history, values, preferences, quality of life, and functional status.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Quimiorradioterapia Adjuvante/normas , Neoplasias da Próstata/terapia , Terapia de Salvação/normas , Sociedades Médicas/normas , Quimiorradioterapia Adjuvante/métodos , Tomada de Decisão Clínica/métodos , Humanos , Masculino , Recidiva Local de Neoplasia/prevenção & controle , Equipe de Assistência ao Paciente/normas , Participação do Paciente , Prostatectomia , Qualidade de Vida , Radioterapia (Especialidade)/normas , Terapia de Salvação/métodos , Urologia/normas
19.
J Manag Care Spec Pharm ; 25(5): 578-586, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31039059

RESUMO

BACKGROUND: Adjuvant endocrine therapy (AET) is a critical therapy in that it improves survival in women with hormone receptor-positive (HR+) breast cancer (BC), but adherence to AET is suboptimal. The purpose of this study was to fill scientific gaps about predictors of adherence to AET among black and white women diagnosed with BC. OBJECTIVE: To assess AET adherence in black and white insured women using multiple measures, including one that uses an innovative statistical approach. METHODS: Black and white women newly diagnosed with HR+ BC were identified from 2 health maintenance organizations. Pharmacy records captured the type of oral AET prescriptions and all fill dates. Multivariable logistic regression was used to identify predictors of adherence defined in terms of proportion of days covered (PDC; ≥ 80%) and medication gap of ≤ 10 days. A zero-inflated negative binomial (ZINB) regression model was used to identify variables associated with the total number of days of medication gaps. RESULTS: 1,925 women met inclusion criteria. 80% were PDC adherent (> 80%); 44% had a medication gap of ≤ 10 days; and 24% had no medication gap days. Race and age were significant in all multivariable models. Black women were less likely to be adherent based on PDC than white women (OR = 0.72, 95% CI = 0.57-0.90, P < 0.01), and they were less likely to have a medication gap of ≤ 10 days (OR = 0.65, 95% CI = 0.54-0.79, P < 0.001). Women aged 25-49 years were less likely to be PDC adherent than women aged 65-93 years (OR = 0.65, 95% CI = 0.48-0.87, P < 0.001). In the ZINB model, women were without their medication for an average of 37 days (SD = 50.5). CONCLUSIONS: Racial disparities in adherence to AET in the study highlight a need for interventions among insured women. Using various measures of adherence may help better understand this multidimensional concept. There might be benefits from using both more common dichotomous measures (e.g., PDC) and integrating novel statistical approaches to allow tailoring adherence to patterns within a specific sample. DISCLOSURES: This research was funded by the National Institutes of Health (R01CA154848). It was also supported in part by the NIH-NCI Cancer Center Support Grant P30 CA016059, the Laboratory of Telomere Health P30 CA51008, and the TSA Award No. UL1TR002649 from the National Center for Advancing Translational Sciences. The contents of this study are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Bosworth reports grants from Sanofi, Otsuka, Johnson & Johnson, and Blue Cross/Blue Shield of NC and consulting fees from Sanofi and Otsuka. The other authors have nothing to disclose. The datasets generated during and/or analyzed during the current study are not publicly available due to privacy reasons but are available from the corresponding author on reasonable request. The author does not own these data. Data use was granted to the author as part of a data use agreement between specific agencies and organizations.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/terapia , Sobreviventes de Câncer/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Adesão à Medicação/estatística & dados numéricos , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Estados Unidos
20.
Pancreas ; 48(4): 496-503, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946246

RESUMO

OBJECTIVES: The objective of this study was to describe the periprocedural management of patients with well-differentiated neuroendocrine tumors with hepatic metastases who underwent liver-directed procedures. METHODS: We performed a retrospective review of patients with metastatic neuroendocrine tumors who underwent liver resection, ablation, or embolotherapy at a single center from 2012 to 2016. The primary outcome was occurrence of documented carcinoid crisis (CC) or hemodynamic instability (HDI), defined as 10 minutes or more of systolic blood pressure less than 80 or greater than 180 mm Hg, or pulse greater than 120 beats per minute. RESULTS: We identified 75 patients who underwent liver resection/ablation (n = 38) or embolotherapy (n = 37). Twenty-four patients (32%) experienced CC or HDI (CC/HDI); CC occurred in 3 patients. No clinicopathologic or procedural factors, including procedure type, octreotide or long-acting somatostatin analog use, and history of carcinoid syndrome, were associated with CC/HDI. Grades 2 to 4 complications were reported in 42% of patients who experienced CC/HDI versus in 16% of patients who did not experience CC/HDI (P < 0.05). CONCLUSIONS: A significant portion of patients developed CC/HDI, and these patients were more likely to develop severe postprocedural complications. Periprocedural octreotide use was not associated with lower CC/HDI occurrence, but continued use is advised given its safety profile until additional studies definitively demonstrate lack of benefit.


Assuntos
Embolização Terapêutica/métodos , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Tumores Neuroendócrinos/cirurgia , Assistência Perioperatória/métodos , Adulto , Idoso , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/etiologia , Embolização Terapêutica/efeitos adversos , Feminino , Hemodinâmica/efeitos dos fármacos , Hepatectomia/efeitos adversos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Avaliação de Resultados (Cuidados de Saúde)/métodos , Avaliação de Resultados (Cuidados de Saúde)/estatística & dados numéricos , Assistência Perioperatória/efeitos adversos , Estudos Retrospectivos
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