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1.
Aust Dent J ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31580483

RESUMO

Breast cancer is the most common cancer affecting women in Australia, and second overall for all Australians. Molecular targets have been developed in the management of breast cancer to allow directed therapy. Complications such as nausea and vomiting can be common as well as less common such as osteonecrosis of the jaw (ONJ). While previously thought to be attributable only to bisphosphonate medications, there has been an increase in recognition of other medications that may also cause this complication. This case report demonstrates a first instance of osteonecrosis of the jaw attributable to pertuzumab and trastuzumab, indicated in the management of HER2 positive metastatic breast cancer, in a patient naïve to ONJ associated anti-resorptive medications. Following sequestrectomy, the patient had an uncomplicated post-operative healing five months following intervention. With increasing medications being used for a number of malignant conditions such as this, an awareness of less common complications such as ONJ amongst dental and medical specialties is highlighted in this case report.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31507069

RESUMO

OBJECTIVES: The objective of this study was to evaluate patient compliance with management recommendations given by a breast cancer multidisciplinary team (MDT), assess for reasons for noncompliance, and perform an exploratory assessment on breast cancer outcomes in noncompliant patients. MATERIALS AND METHODS: A retrospective analysis of prospectively collected data was undertaken for patients selected by their primary clinician to be discussed at the MDT of Breast Cancer Research Centre-WA in Perth between 1st March 2011 and the 28th February 2016. The primary objective was the rate of compliance with MDT management recommendations. Secondary objectives included factors associated with noncompliance, rate of clinical trial uptake, and impact of treatment noncompliance on breast cancer events in a subgroup of early breast cancer (EBC) patients. RESULTS AND CONCLUSION: A total of 2614 MDT management recommendations were made for 925 patients. Overall, 92% were compliant with all recommendations given. Clinical trial recruitment was successful in 84.1%. The reasons given for treatment noncompliance were fear of toxicity, choosing an alternative treatment, and treatment inconvenience. In a subset of 337 EBC patients, there was a significantly higher rate of contralateral breast cancer, distant recurrence, and breast cancer-specific death, P = .0016, in those who were noncompliant. Our study demonstrates a high rate of MDT treatment recommendation compliance and clinical trial recruitment. In a subgroup of EBC patients, noncompliance was associated with significantly worse outcomes. Attention to educating patients to minimize their fear of treatment toxicity and ensuring their understanding of evidence-based treatment may lead to lower rates of noncompliance.

3.
Future Oncol ; 15(21): 2489-2501, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31140297

RESUMO

Aim: To evaluate the efficacy and safety of neratinib as extended adjuvant therapy in patients from Asia based on exploratory analyses of the Phase III ExteNET trial. Patients & methods: A total of 2840 women with early stage HER2-positive breast cancer were randomly assigned to neratinib 240 mg/day or placebo for 1 year after trastuzumab-based adjuvant therapy. Results: A total of 341 patients were from Asia (neratinib, n = 165; placebo, n = 176). 2-year invasive disease-free survival rates were 92.8 and 90.8% with neratinib and placebo, respectively (HR: 0.70; 95% CI: 0.31-1.55), and 5-year rates were 91.9 and 87.2%, respectively (HR: 0.57; 95% CI: 0.27-1.13). Diarrhea was the most common adverse event with neratinib. Conclusion: Extended adjuvant therapy with neratinib reduces disease recurrences in Asian women with HER2-positive breast cancer. Trial registration: Clinicaltrials.gov NCT00878709.

4.
Breast Cancer Res ; 21(1): 39, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30867034

RESUMO

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. METHODS: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1-3c (modified to stage 2-3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. RESULTS: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72-2.50; P = 0.357). Neratinib's effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17-0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36-1.41; P = 0.34). The interaction test was non-significant (P = 0.309). CONCLUSIONS: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Quinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Prognóstico , Quinolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo
5.
BMC Health Serv Res ; 18(1): 513, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970087

RESUMO

BACKGROUND: Gay, bisexual and other men who have sex with men (gbMSM) in Canada continue to experience high rates of incident HIV. Pre-exposure prophylaxis (PrEP, the regular use of anti-HIV medication) reduces HIV acquisition and could reduce incidence. However, there are too few physicians with expertise in HIV care to meet the projected demand for PrEP. To meet demand and achieve greater public health impact, PrEP delivery could be 'decentralized' by incorporating it into front-line prevention services provided by family physicians (FPs) and sexual health clinic nurses. METHODS: This PrEP decentralization project will use two strategies. The first is an innovative knowledge dissemination approach called 'Patient-Initiated CME' (PICME), which aims to empower individuals to connect their family doctors with online, evidence-based, continuing medical education (CME) on PrEP. After learning about the project through community agencies or social/sexual networking applications, gbMSM interested in PrEP will use a uniquely coded card to access an online information module that includes coaching on how to discuss their HIV risk with their FP. They can provide their physician a link to the accredited CME module using the same card. The second strategy involves a pilot implementation program, in which gbMSM who do not have a FP may bring the card to designated sexual health clinics where trained nurses can deliver PrEP under a medical directive. These approaches will be evaluated through quantitative and qualitative methods, including: questionnaires administered to patients and physicians at baseline and at six months; focus groups with patients, FPs, and sexual health clinic staff; and review of sexual health clinic charts. The primary objective is to quantify the uptake of PrEP achieved using each decentralization strategy. Secondary objectives include a) characterizing barriers and facilitators to PrEP uptake for each strategy, b) assessing fidelity to core components of PrEP delivery within each strategy, c) measuring patient-reported outcomes including satisfaction with clinician-patient relationships, and d) conducting a preliminary costing analysis. DISCUSSION: This study will assess the feasibility of a novel strategy for disseminating knowledge about evidence-based clinical interventions, and inform future strategies for scale-up of an underutilized HIV prevention tool.

6.
Breast ; 41: 127-132, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30048865

RESUMO

INTRODUCTION: Hair loss as a result of chemotherapy for early breast cancer (EBC) is a frequent and distressing side effect. Minimising hair loss may improve mood and body image. Our aim was to determine scalp cooling (SC) efficacy in EBC patients receiving contemporary chemotherapy regimen, to inform future patients choice to use SC or not. METHODS AND RESULTS: Prospective cohort study of 60 stage 1-3 EBC patients recommended to receive taxane or anthracycline-taxane chemotherapy regimens. The primary outcome was incidence of minimal hair-loss (MHL - defined as 60% Dean grade 1 or 2). Patients were categorised by chemotherapy (3 groups) and randomised 1:1 within each group to two scalp cooling temperature settings using the Dignitana Dignicap machine (secondary endpoint). Patients reported degree of hair loss using the Dean score on day 1 of each cycle and following the last chemotherapy. RESULTS: On an intention-to-treat basis, 33% of patients reported MHL, thus our primary endpoint was not achieved. Patients receiving taxane-only chemotherapy had the highest rate of MHL (45%). No other factors (including hair type, age, body weight, temperature setting) predicted for MHL. Patient-reported anxiety reduced significantly in all patients, but no difference was observed for depression or body image irrespective of degree of hair loss. SC-related adverse events were uniformly of low grade and all resolved. We would recommend the use of SC for all patients receiving taxane-based chemotherapy, with its use for those patients recommended for anthracycline-taxane regimens being made on an individual basis. Trial Registration anztr.org.au ACTRN12615001106527.

8.
Cancer Med ; 7(5): 1660-1669, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29573207

RESUMO

This randomized, open-label, active-controlled study investigated the safety and efficacy of three doses of Rolontis (eflapegrastim), a novel, long-acting myeloid growth factor, versus pegfilgrastim in breast cancer patients being treated with docetaxel and cyclophosphamide (TC). The primary efficacy endpoint was duration of severe neutropenia (DSN) during the first cycle of treatment. Patients who were candidates for adjuvant/neoadjuvant TC chemotherapy were eligible for participation. TC was administered on Day 1, followed by 45, 135, or 270 µg/kg Rolontis or 6 mg pegfilgrastim on Day 2. Complete blood counts were monitored daily when the absolute neutrophil count (ANC) fell to <1.5 × 109 /L. Up to four cycles of TC were investigated. The difference in DSN (time from ANC <0.5 × 109 /L to ANC recovery ≥2.0 × 109 /L) between the Rolontis and pegfilgrastim groups was -0.28 days (confidence interval [CI]: -0.56, -0.06) at 270 µg/kg, 0.14 days (CI: -0.28, 0.64) at 135 µg/kg, and 0.72 days (CI: 0.19, 1.27) at 45 µg/kg. Noninferiority to pegfilgrastim was demonstrated at 135 µg/kg (P = 0.002) and 270 µg/kg (P < .001), with superiority demonstrated at 270 µg/kg (0.03 days; P = 0.023). The most common treatment-related adverse events (AEs) were bone pain, myalgia, arthralgia, back pain, and elevated white blood cell counts, with similar incidences across groups. All doses of Rolontis were well tolerated, and no new or significant treatment-related toxicities were observed. In Cycle 1, Rolontis demonstrated noninferiority at the 135 µg/kg dose and statistical superiority in DSN at the 270 µg/kg dose when compared to pegfilgrastim.

9.
Int J Biochem Cell Biol ; 96: 63-78, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29309917

RESUMO

Breast cancer is the most common cancer affecting women worldwide, with bone metastases presenting as the most common site of disease recurrence. Bone metastases secondary to breast cancer negatively impacts patient survival, mobility, and quality of life. Furthermore, the clinical complications of breast cancer bone metastases are associated with significant financial burden to the individual and society. The molecular mechanisms involved in the metastasis, colonisation, and proliferation of breast cancer cells in bone are complex and involve crosstalk between breast cancer cells and the bone microenvironment. The ability of metastatic breast cancer cells to hijack normal biological processes involved in bone remodelling is a key driver of osteolytic and osteoblastic bone lesions. As such, our understanding of how breast cancer cells manipulate normal bone remodelling pathways is essential for the development of new therapeutic agents to improve patient outcomes. In this review, we discuss bone remodelling under normal physiological conditions and explore key pathways dysregulated in breast cancer metastasis to bone. We provide an overview of systemic therapies currently recommended for the treatment of breast cancer bone metastases and highlight emerging therapeutic targets.

10.
JAMA Oncol ; 4(3): 302-308, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29327055

RESUMO

Importance: Studies of neoadjuvant chemotherapy regimens using anthracyclines followed by taxanes have reported a doubling of pathological complete remission (pCR) rates compared with anthracycline-based regimens alone. A reverse sequence did not reduce activity. Nab-paclitaxel is an albumin-bound nanoparticle of paclitaxel that allows for safe infusion without premedication, and its use led to a significantly higher rate of pCR in the GeparSepto trial. Objective: To determine whether nab-paclitaxel improves the outcomes of early and locally advanced human epidermal growth factor receptor 2 (ERBB2/HER2)-negative breast cancer compared with paclitaxel when delivered in a neoadjuvant setting. Design, Setting, and Participants: In this multicenter, open-label study, in collaboration with Grupo Español de Investigación en Cáncer de Mama (GEICAM) and Breast Cancer Research Center-Western Australia (BCRC-WA), patients with newly diagnosed and centrally confirmed ERBB2/HER2-negative breast cancer were recruited. Participants were randomly allocated to paclitaxel, 90 mg/m2 (349 patients), or nab-paclitaxel, 125 mg/m2 (346 patients). The 2 drugs were given on weeks 1, 2, and 3 followed by 1 week of rest for 4 cycles before 4 cycles of an anthracycline regimen per investigator choice. Main Outcomes and Measures: The primary end point was the rate of pCR, defined as absence of invasive cells in the breast and axillary nodes (ie, ypT0/is ypN0) at the time of surgery. A secondary end point was to assess tolerability and safety of the 2 regimens. Results: From May 2013 to March 2015, 814 patients were registered to the study; 695 patients met central confirmation eligibility and were randomly allocated to receive either paclitaxel (349), or nab-paclitaxel (346) (median age, 50 years; range, 25-79 years). The intention-to-treat analysis of the primary end point pCR revealed that the improved pCR rate after nab-paclitaxel (22.5%) was not statistically significant compared with paclitaxel (18.6%; odds ratio [OR], 0.77; 95% CI, 0.52-1.13; P = .19). Overall, 38 of 335 patients (11.3%) 11.3% of patients had at least 1 serious adverse event in the paclitaxel arm and 54 of 337 patient (16.0%) in the nab-paclitaxel arm. Peripheral neuropathy of grade 3 or higher occurred in 6 of 335 patients (1.8%) and in 15 of 337 (4.5%), respectively. Conclusions and Relevance: The improved rate of pCR after nab-paclitaxel was not statistically significant. The multivariate analysis revealed that tumor subtype (triple-negative vs luminal B-like) was the most significant factor (OR, 4.85; 95% CI, 3.28-7.18) influencing treatment outcome. Trial Registration: clinicaltrials.gov Identifier: NCT01822314.

11.
Cancer Discov ; 8(3): 336-353, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29242214

RESUMO

We sought to uncover genetic drivers of hormone receptor-positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Liu et al., p. 354This article is highlighted in the In This Issue feature, p. 253.

13.
Lancet Oncol ; 18(12): 1688-1700, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29146401

RESUMO

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quinolinas/administração & dosagem , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Administração Oral , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Japão , Estimativa de Kaplan-Meier , Mastectomia/métodos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Quinolinas/efeitos adversos , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Trastuzumab/efeitos adversos , Resultado do Tratamento
14.
Clin Breast Cancer ; 17(8): 585-594.e4, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28830796

RESUMO

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Administração Oral , Idoso , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Síndrome Mão-Pé/epidemiologia , Síndrome Mão-Pé/etiologia , Humanos , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Niacinamida/uso terapêutico , Placebos , Receptor ErbB-2/metabolismo , Sorafenibe , Taxoides/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento
15.
Support Care Cancer ; 25(12): 3785-3791, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28691132

RESUMO

PURPOSE: Aromatase inhibitors are standard of care in women with hormone receptor-positive early breast cancer. Published evidence demonstrates that adverse effects may have an impact on drug compliance, with arthralgias being one of the most commonly reported adverse effects. METHODS: Eligible patients were postmenopausal women who had experienced arthralgia following initiation of an aromatase inhibitor. Patients who experienced arthralgias following a minimum of a 3-month treatment on the aromatase inhibitor were randomized to emu oil or placebo oil. The primary endpoint was to assess for a reduction in pain as measured by a visual analogue score after 8 weeks of treatment. RESULTS: Seventy-three patients comprised the intent-to-treat population, and there was no statistically significant benefit with use of EO. However, there was a statistically significant improvement in pain (visual analogue score was -1.28; p < 0.001) and Brief Pain Inventory severity score -0.88 (p < 0.001), as well as functional interference (Brief Pain Inventory interference -1.10 (p < 0.001) for the entire population following an 8-week administration of EO or placebo oil. CONCLUSIONS: Arthralgias, as a result of aromatase inhibitor use, may be ameliorated by the use of topical oil massaged onto the joint. Further research into interventions for this common side effect is needed.


Assuntos
Inibidores da Aromatase/efeitos adversos , Artralgia/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Óleos/administração & dosagem , Adjuvantes Farmacêuticos/administração & dosagem , Administração Tópica , Adulto , Inibidores da Aromatase/administração & dosagem , Artralgia/induzido quimicamente , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pós-Menopausa
16.
Oncoimmunology ; 6(3): e1282590, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28405507

RESUMO

Historically, the immune environment was not considered an important target for breast cancer treatment. However, the association of lymphocytic infiltrates in triple negative and HER-2 over-amplified breast cancer subtypes with better outcomes, has provoked interest in evaluating the role of the immune system in the luminal B subtype that accounts for 39% of breast cancers and has a poor patient prognosis. It is unknown which immunosuppressive cell types or molecules (e.g., checkpoint molecules) are relevant, or where measurement is most informative. We hypothesize that a profound immunosuppressive tumor and/or lymph node milieu is prognostic and impacts on responses to therapies.

17.
Clin Breast Cancer ; 17(2): 91-99.e1, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27756583

RESUMO

BACKGROUND: The purpose of this study was to evaluate the efficacy of 3 first-line chemotherapy combination regimens for HER2-negative metastatic breast cancer (mBC). PATIENTS AND METHODS: In this open-label, 3-arm, randomized phase II trial, patients were randomized to all-oral NORCAP (vinorelbine/capecitabine), GEMPAC (gemcitabine/paclitaxel), or GEMDOC (gemcitabine/docetaxel) as first-line chemotherapy for HER2-negative mBC. Stratification factors were center, previous (neo)adjuvant anthracycline, and age. The primary end point was disease control rate (DCR; complete or partial response, or stable disease for ≥3 months). RESULTS: The DCR was 73% (95% confidence interval [CI], 59-85) with NORCAP (36 of 49 patients), 78% (95% CI, 64-88) with GEMPAC (39 of 50 patients), and 80% (95% CI, 66-90) with GEMDOC (40 of 50 patients). Objective response rates were 33% (16 of 49 patients), 24% (12 of 50 patients), and 50% (25 of 50 patients), respectively; median progression-free survival was 7.6, 9.0, and 11.4 months, respectively. Median overall survival was 30 to 31 months with all regimens. The most common Grade ≥3 adverse event with each regimen was neutropenia (24 patients [50%], 23 patients [46%], and 43 patients [86%], respectively). The most common nonhematological Grade ≥3 adverse event was fatigue. Grade 2 alopecia occurred in 36 patients (72%) who received GEMPAC and 38 patients (76%) who received GEMDOC, but only 4 patients (8%) who received NORCAP. There was no evidence of a detrimental effect of NORCAP on quality of life. CONCLUSION: All-oral NORCAP is an active first-line chemotherapy regimen and might be offered as an alternative to first-line taxane-based therapy for HER2-negative mBC, particularly if patients wish to avoid alopecia or frequent intravenous administrations.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Receptor ErbB-2/metabolismo , Vimblastina/análogos & derivados , Administração Intravenosa , Administração Oral , Adulto , Idoso , Alopecia/induzido quimicamente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Fadiga/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Qualidade de Vida , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/uso terapêutico , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Vinorelbina
19.
N Engl J Med ; 375(18): 1738-1748, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27717303

RESUMO

BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).


Assuntos
Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilos/administração & dosagem , Purinas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Letrozol , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona
20.
Ther Adv Med Oncol ; 8(5): 339-50, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27583026

RESUMO

The management of HER-2-positive breast cancer has improved significantly with the use of targeted agents to the HER-2 signaling pathway. Despite the improved survival achieved with the use of trastuzumab and chemotherapy in both the adjuvant and metastatic setting, patients may still recur or progress; whilst preclinical data demonstrate that these cancer cells remain addicted to the HER-2 oncogene. Neratinib, an oral small molecule tyrosine-kinase inhibitor has efficacy in the metastatic and adjuvant setting of patients who have previously received trastuzumab-based treatment. Diarrhea, being a class effect of tyrosine-kinase inhibitor, is the most common side effect seen following neratinib administration, but recent data suggests that a prophylactic loperamide regimen can reduce the incidence of grade 3 diarrhea. Phase I through to III clinical trials of neratinib will be reviewed, with discussion of the postulated mechanism underlying diarrheal events and its management.

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