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1.
N Engl J Med ; 385(5): 395-405, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34320285

RESUMO

BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).


Assuntos
Anastrozol/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Administração Oral , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Receptores de Estrogênio , Receptores de Progesterona , Tamoxifeno/uso terapêutico
4.
J Periodontal Res ; 56(4): 828-836, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33797064

RESUMO

BACKGROUND: Recent studies have shown that treatment with aromatase inhibitors contributes to an increased prevalence of periodontitis. OBJECTIVE: In this study, we assessed effects of the aromatase inhibitor anastrozole on cellular function of human gingival fibroblasts (HGFs) and endothelial cells. METHODS: Expression levels of collagen, extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were examined in HGFs exposed to anastrozole. Furthermore, inflammatory responses in HGFs cultured with anastrozole were evaluated in the presence of Porphyromonas gingivalis lipopolysaccharide. We also evaluated the vascular permeability and vascular endothelial (VE)-cadherin expression of endothelial cells exposed to anastrozole. RESULTS: Anastrozole enhanced expression levels of collagen, ECM proteins, TIMPs, and inflammatory cytokines in HGFs, as well as vascular permeability of endothelial cells. In addition, anastrozole reduced expression levels of MMPs in HGFs and VE-cadherin in endothelial cells. CONCLUSION: These results suggest that anastrozole modulates various cellular functions in HGFs and endothelial cells.


Assuntos
Inibidores da Aromatase , Células Endoteliais , Anastrozol/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Células Cultivadas , Fibroblastos , Gengiva , Humanos , Porphyromonas gingivalis
5.
Menopause ; 28(5): 589-600, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33857955

RESUMO

IMPORTANCE: Findings in this work might provide certain guidance for current clinical work. OBJECTIVE: This study aimed to evaluate the efficacy and safety of these drugs based on the Bayesian network meta-analysis. EVIDENCE REVIEW: Two researchers systematically and comprehensively searched PubMed, Embase, and the central databases of the Cochrane Library from inception to September 15, 2020. The number of specific events and sample size were extracted from each of the included studies. This Bayesian theory-based network meta-analysis included indirect comparisons and mixed treatment analysis. Indirect comparisons compare the efficacy of at least three interventions simultaneously and are mostly used when there are few direct comparison studies. In addition, indirect comparisons are conducted on the basis of direct comparisons through mixed treatment analysis, which can thus improve the accuracy of analysis. FINDINGS: A total of nine randomized controlled trials involving 60,732 participants were included. As a result, compared with placebo in high-risk pre- or postmenopausal women, endocrine therapy (ET) decreased the risks of total breast cancer (TBC, odds ratio [OR] 0.69, 95% confidence interval [CI] 0.56-0.85), invasive breast cancer (IBC, OR 0.69, 95% CI 0.53-0.89), estrogen receptor-positive breast cancer (ER+BC) (OR 0.49, 95% CI 0.38-0.64), and ductal carcinoma in situ (OR 0.74, 95% CI 0.56-0.98), but increased the risks of pulmonary embolism (OR 1.33, 95% CI 1.05-1.69), total venous thrombosis (OR 1.75, 95% CI 1.28-2.38), and endometrial carcinoma (EC, OR 1.84, 95% CI 1.17-2.88). In further network stratification analyses, anastrozole, exemestane, and tamoxifen were found to decrease the risks of TBC, IBC, and ER + BC relative to placebo. Similarly, raloxifene decreased the risk of IBC (OR 0.65, 95% CI 0.48-0.85), while tamoxifen increased the risk of EC (OR 2.42, 95% CI 1.10-7.35). CONCLUSIONS AND RELEVANCE: To sum up, ET decreased the risks of TBC, IBC, ER + BC, and ductal carcinoma in situ, while increasing the risks of pulmonary embolism, total venous thrombosis, and EC in high-risk pre- or postmenopausal women. Meanwhile, anastrozole, exemestane, and tamoxifen possibly exerted potential protective effects on TBC, IBC and ER + BC. Typically, raloxifene might be effective on IBC, while tamoxifen might increase the risk of EC. Therefore, clinicians should fully weigh the benefits and risks of ET to develop a rational individualized treatment.


Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Inibidores da Aromatase/efeitos adversos , Teorema de Bayes , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Metanálise em Rede , Pós-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/efeitos adversos
6.
J Med Case Rep ; 15(1): 207, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33910628

RESUMO

BACKGROUND: Adjuvant endocrine therapy is recommended for the treatment of hormone-receptor-positive breast cancer. Aromatase inhibitors are associated with significant musculoskeletal adverse effects, likely through growth hormone/insulin-like growth factor 1 modulation, while tamoxifen reduces insulin-like growth factor 1 production. We describe the case of a patient who was treated successfully with tamoxifen for her hormone-receptor-positive breast cancer and acromegaly. CASE PRESENTATION: A 57-year old White female with hormone-receptor-positive breast cancer was diagnosed with acromegaly. She received adjuvant endocrine therapy with anastrozole but could not tolerate this medication because of severe arthralgia, so she was switched to tamoxifen. Shortly after starting tamoxifen, the patient's musculoskeletal symptoms resolved and her insulin-like growth factor 1 levels normalized. She has remained in remission of her acromegaly and breast cancer since initiating tamoxifen. CONCLUSION: This case highlights the dual benefit of tamoxifen therapy in the treatment of hormone-receptor-positive breast cancer and acromegaly. Unlike anastrozole, tamoxifen has the benefit of lowering insulin-like growth factor 1 levels, which underscores its advantage in reducing adverse musculoskeletal symptoms during the treatment of hormone-receptor-positive breast cancer. We offer the first reported use of tamoxifen monotherapy for the successful treatment of acromegaly and hormone-receptor-positive breast cancer. While tamoxifen may offer an additional, oral option for acromegaly patients who do not respond to or tolerate conventional growth-hormone-lowering therapy, additional studies are necessary.


Assuntos
Acromegalia , Neoplasias da Mama , Acromegalia/tratamento farmacológico , Anastrozol/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Tamoxifeno/uso terapêutico
7.
Curr Oncol ; 28(2): 1067-1076, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652975

RESUMO

Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. This work aimed to assess bone loss, fracture incidence, and risk factors associated with these events, as well as the prognostic influence of fractures. We have conducted a retrospective cohort study of women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. Four-hundred-and-fifty-one eligible women were reviewed (median age 68 years). Median time under AI was 40 months. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in older women (mean 74 vs. 68 years, p = 0.006). Age (OR 1.01, 95% CI 1.01-1.07, p = 0.024) and time under AI (OR 1.02, 95% CI 1.00-1.04, p = 0.037) were independent predictors of fracture, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups, disfavoring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6-92.4 vs. 95.6%, 95% CI, 91.2-97.8, p = 0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted HR of 3.17, 95% CI 1.10-9.11; p = 0.032). Bone health is often forgotten, despite its great impact in survivorship. Our results validate the pathophysiologic link between EBC and bone metabolism, which translates into EBC recurrence. Further research in this area may help refine these findings. Moreover, early identification of women at higher risk for fractures is warranted.


Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Idoso , Inibidores da Aromatase/efeitos adversos , Densidade Óssea , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Recidiva Local de Neoplasia , Estudos Retrospectivos
8.
Cancer Sci ; 112(6): 2381-2392, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33686753

RESUMO

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2- advanced breast cancer.


Assuntos
Aminopiridinas/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Anastrozol/administração & dosagem , Anastrozol/efeitos adversos , Anastrozol/farmacocinética , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fulvestranto/efeitos adversos , Fulvestranto/farmacocinética , Humanos , Letrozol/administração & dosagem , Letrozol/efeitos adversos , Letrozol/farmacocinética , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Receptor ErbB-2/genética , Resultado do Tratamento
9.
Gynecol Oncol ; 161(1): 160-165, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33608144

RESUMO

BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.


Assuntos
Anastrozol/administração & dosagem , Neoplasias do Endométrio/tratamento farmacológico , Tumores do Estroma Endometrial/tratamento farmacológico , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Tumores do Estroma Endometrial/metabolismo , Tumores do Estroma Endometrial/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Intervalo Livre de Progressão , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
10.
Integr Cancer Ther ; 20: 1534735420980811, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33586504

RESUMO

BACKGROUND: Aromatase inhibitor-induced arthralgia (AIA) is the most common side effect of aromatase inhibitors (AIs) used in breast cancer patients and is related to the rate of adherence to AIs. The clinical effects of acupuncture on AIA have been assessed by some randomized controlled trials (RCTs). However, some studies reported that acupuncture was effective, while others claimed that it was ineffective. To clarify the clinical and placebo effects of acupuncture in treating AIA, we conducted this meta-analysis. METHODS: Two reviewers (XL and GW) independently searched for RCTs in 5 English databases (PubMed, Web of Science, Embase, Springer, Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure Database (CNKI), SinoMed, VIP and Wanfang Database) from their inception to 30 November 2019. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this meta-analysis was performed by fixed or random-effects models, and data were pooled with mean differences (MDs). RESULTS: Seven trials involving 603 patients were reviewed. The primary outcome, the Brief Pain Inventory (BPI) score, significantly differed between the acupuncture and control groups [pain-related interference: MD = -1.89, 95% confidence interval (CI) [-2.99, -0.79], Z = 3.36 (P = .008 < .05), pain severity: MD = -1.57, 95% CI [-2.46, -0.68], Z = 3.45 (P = .0006 < .05), worst pain: MD = -2.31, 95% CI [-3.15, -1.48], Z = 5.47 (P < .0001 < .05)]. No severe adverse events were reported in any study. CONCLUSION: This meta-analysis showed that acupuncture is a safe and effective treatment for breast cancer patients with AIA. Additional research with improved blinding methods is warranted to further explore the nature of non-specific and placebo effects in true and sham acupuncture.


Assuntos
Terapia por Acupuntura , Neoplasias da Mama , Inibidores da Aromatase/efeitos adversos , Artralgia/induzido quimicamente , Artralgia/terapia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Resultado do Tratamento
11.
Br J Cancer ; 124(8): 1373-1378, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33495601

RESUMO

BACKGROUND: Anastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment. METHODS: One thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate. RESULTS: Five- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (-0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (-1.35% (-1.70 to -0.98)). CONCLUSIONS: These are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.


Assuntos
Anastrozol/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/prevenção & controle , Colo do Fêmur/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Absorciometria de Fóton , Idoso , Anastrozol/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Estudos de Casos e Controles , Método Duplo-Cego , Feminino , Colo do Fêmur/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Coluna Vertebral/efeitos dos fármacos
12.
Eur J Cancer ; 145: 19-28, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33418233

RESUMO

BACKGROUND: Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression-free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8% and 55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. METHODS: Anonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FINDINGS: The OR for clinical benefit rate was 1.56, in favour of AIs (p < 0.001). The duration of clinical benefit was not significantly increased by AIs (HzR 0·88; p = 0.08). For PFS the HzR (0.82) was in favour of AIs (p = 0·007). However, for OS the HzR (1.05) was not significantly different between AIs and tamoxifen (p = 0.42). INTERPRETATION: Although third generation AIs put significantly more patients into 'clinical benefit', their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Pós-Menopausa , Receptores de Estrogênio/análise , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Idoso , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos , Fatores de Tempo
14.
Lancet Oncol ; 22(1): 74-84, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387497

RESUMO

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tegafur/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Ácido Oxônico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tegafur/efeitos adversos , Fatores de Tempo , Adulto Jovem
15.
Lancet Oncol ; 22(2): 212-222, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33460574

RESUMO

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Modelos de Riscos Proporcionais , Piridinas/efeitos adversos , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Tamoxifeno/administração & dosagem
16.
Oncology ; 99(2): 84-95, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32992318

RESUMO

BACKGROUND: Aromatase inhibitors (AIs) as adjuvant therapy after breast cancer (BC) surgery have demonstrated to reduce the risk of disease recurrence, to lower the risk of contralateral BC, and to improve survival when compared to tamoxifen in patients with limited-stage hormone receptor-positive (HR+) BC. However, AIs are associated with adverse events that can have a significant impact on patient quality of life (QoL). AIM: This study aimed to identify profiles of psychological symptoms and QoL in HR+ BC patients undergoing AI therapy. METHOD: Data were collected with questionnaires administered at three time points: AI initiation (t0); 3 months after AI initiation (t1); and 6 months after AI initiation (t2). The FACT-G, FACT-B, and FACT-ES questionnaires were used to assess QoL; psychological symptoms were assessed using the SCL-90-R. RESULTS: 43 women were enrolled in the study (t0), and 37 completed the t1 evaluation and 29 the t2 evaluation. We found (1) a progressive decrease over time in FACT-G and FACT-ES scores, in particular in the Physical, Emotional, and Endocrine subscales, and an increase in the SOM (somatization) subscale of the SCL-90-R; (2) the presence of 4 clusters related to different psychological symptoms and QoL evolution over time; (3) that patients belonging to the cluster characterized by worsening symptoms and QoL during time differed from the others in the Emotional subscale of the FACT-B and in the GSI (Global Score), OCD (obsessive-compulsive), DEP (depression), ANX (anxiety), and SLP (sleep disorders) dimensions of the SCL-90-R and had significantly higher BMI levels; and (4) that 3 items from the SCL-90-R and 2 items from FACT Emotional Well-Being subscale were predictive of the "worst" cluster. CONCLUSIONS: Although larger studies are needed to confirm these results, our data open up new ways of investigation into the effects of AIs on QoL in HR+ BC patients.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Pós-Menopausa/psicologia , Qualidade de Vida/psicologia , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inquéritos e Questionários , Resultado do Tratamento
17.
Spec Care Dentist ; 41(1): 41-48, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33156573

RESUMO

AIM: To study the dental and periodontal status of women with breast cancer (BCa) having tamoxifen or aromatase inhibitors (AIs) treatment in comparison with control healthy women. METHODS: Fifty-one women on tamoxifen therapy, 52 women on AIs therapy and 52 systemically healthy controls were included in the study. The total number of teeth, the number of teeth indicated for extraction, the number of decayed teeth, and the duration of medication were recorded. Periodontal status was evaluated with gingival index (GI); plaque index (PI); bleeding on probing (BOP); probing depth (PD) and clinical attachment loss (CAL). RESULTS: The lowest number of teeth and decayed teeth was found in AIs users (P < .001 and P = .003 respectively). The highest CAL value was seen in AIs users (P = .042) whereas no significant difference was found between the groups in terms of PI, GI, and PD (P = .102, P = .233, and P = .306, respectively). Lower PI was observed in patients using AIs for less than 2 years (P = .048). CONCLUSIONS: While tamoxifen did not affect the dental and periodontal condition, AIs medication adversely affected the dental and periodontal condition by more tooth loss and higher CAL.


Assuntos
Neoplasias da Mama , Preparações Farmacêuticas , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Estudos Transversais , Índice de Placa Dentária , Feminino , Humanos , Perda da Inserção Periodontal , Tamoxifeno/efeitos adversos
18.
J Womens Health (Larchmt) ; 30(1): 131-136, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33103945

RESUMO

Background: Women on aromatase inhibitors (AIs) as part of their breast cancer treatment often experience difficult to control side effects. Although there are several medications to manage the side effects of AI therapy, many of them are associated with their own risk, particularly sedation. The objective of this study was to describe the prescribing practices for side effect managing (SE) medications among women with breast cancer on AI therapy and to assess for combinations of medications that may present a clinical risk to patients. Methods: Retrospective data analysis using Surveillance, Epidemiology and End Results (SEER)-Medicare data of all women aged 66-90 years with stage I-III hormone positive breast cancer diagnosed between 2008 and 2014 who initiated AI therapy within 12 months of their diagnosis. We determined the percentage of patients prescribed an SE medication in the 12 months prior and in the 24 months after the initiation of AI therapy. We calculated the number of prescriptions and the number of days of overlapping (i.e., >1 SE) prescriptions, and examined predictors of overlapping prescriptions. Results: The use of SE medications was pervasive and increased after initiation of AI therapy. The most commonly prescribed medications were opiates (55.1%), selective serotonin reuptake inhibitors (22.6%), benzodiazepines (18.4%), tramadol (17.7%) and gabapentin (14.6%). In total 15.5% of patients had overlapping prescriptions; among those, 36.2% had three overlapping prescriptions. Prior use was the strongest predictor of overlapping prescriptions with an odds ratio of 7.9 (95% confidence interval: 7.17-8.77). Conclusion: Among women on AI therapy, the use of SE medications is common and many have overlapping prescriptions raising concern for potential harm from polypharmacy.


Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Idoso , Analgésicos Opioides/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Medicare , Estudos Retrospectivos , Estados Unidos
19.
Osteoporos Int ; 32(1): 1-6, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33146750

RESUMO

The COVID-19 pandemic has resulted in huge disruption to healthcare provision, including to dual-energy X-ray absorptiometry (DXA) imaging. Increased waiting lists for DXA from the pandemic mean potential long and uncertain delays in treatment for osteoporosis. To address these increased waiting lists, we propose a rapid, simple, one-stop algorithm incorporating medication use (aromatase inhibitor, corticosteroid) and clinical risk stratification supplementing a standard FRAX assessment. Our pragmatic algorithm produces a recommendation to treat empirically, image with DXA, or observe. If applied, we model a significant reduction in DXA scan requirements with a corresponding reduction in treatment delays for those awaiting DXA. We estimate this will reduce DXA scan numbers by about 50%, whilst pragmatically ensuring those with the highest clinical need correctly receive treatment without delay. This algorithm will help many clinicians including general practitioners/family physicians prioritise DXA when they may not always have the expertise to make this judgement based on clinical information alone. Although we have used UK guidelines as an example, this approach is flexible enough for adaptation by other countries based on their local guidelines, licensing, prescribing requirements, and DXA waiting list times. There are some limitations to our proposal. However, it represents one way of managing the uncertainty of the current COVID-19 pandemic.


Assuntos
Absorciometria de Fóton , COVID-19 , Tomada de Decisão Clínica/métodos , Osteoporose/diagnóstico por imagem , Algoritmos , Inibidores da Aromatase/efeitos adversos , Glucocorticoides/efeitos adversos , Humanos , Fraturas por Osteoporose/diagnóstico por imagem , Pandemias , Medição de Risco , Fatores de Risco , Telefone , Listas de Espera
20.
Breast Cancer Res Treat ; 185(3): 697-707, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33159633

RESUMO

BACKGROUND: Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. With a focus on switching between agents, we investigated cardiovascular events over the entire 5-year treatment period. METHODS: Of the 6182 patients enrolled, 6144 started trial treatment and were included in this analysis. Adverse events occurring during study treatment until 30 days after cessation were considered. Eight cardiovascular event types were defined. Cumulative incidence of events were estimated using the Kaplan-Meier method, without consideration for competing events. Multivariable Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) for pairwise comparisons of treatment arms. RESULTS: While on study treatment, 6.5% of patients (n = 397) had any cardiac events reported; for 2.4%, the event was grades 3-5, of which 11 (0.2%) were grade 5. Letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease (HR = 1.81; 95% CI, 1.06-3.08) compared with tamoxifen monotherapy. Patients assigned sequential tamoxifen →letrozole (HR = 1.59; 95% CI, 0.92-2.74) or sequential letrozole → tamoxifen (HR = 1.20; 95% CI, 0.68-2.14) showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events (tamoxifen monotherapy HR = 2.10; 95% CI, 1.42-3.12; tamoxifen → letrozole HR = 1.96; 95% CI, 1.32-2.92; letrozole → tamoxifen HR = 1.56; 95% CI 1.03-2.35) as compared with patients assigned letrozole alone. CONCLUSION: When initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment.


Assuntos
Neoplasias da Mama , Doenças Cardiovasculares , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Letrozol/efeitos adversos , Nitrilas/efeitos adversos , Pós-Menopausa , Tamoxifeno/efeitos adversos , Triazóis/uso terapêutico
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