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1.
Lancet Oncol ; 22(4): 489-498, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33794206

RESUMO

BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Tiazóis/administração & dosagem , Adolescente , Adulto , Idoso , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Antagonistas do Receptor de Estrogênio/administração & dosagem , Feminino , Fulvestranto/administração & dosagem , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética
2.
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 Estrogênicos/genética , Tamoxifeno/administração & dosagem
3.
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 Estrogênicos/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
4.
Lancet Oncol ; 21(11): 1443-1454, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33152284

RESUMO

BACKGROUND: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses. METHODS: POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing. FINDINGS: Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67B and low Ki672W (high-low) and 21·5% (17·1-27·0) with high Ki67B and Ki672W (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported. INTERPRETATION: POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies. FUNDING: Cancer Research UK.


Assuntos
Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/genética , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Idoso , Inibidores da Aromatase/efeitos adversos , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Pós-Menopausa/efeitos dos fármacos , Prognóstico , Receptor ErbB-2/genética
5.
Medicine (Baltimore) ; 99(43): e22652, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120755

RESUMO

RATIONALE: Poorly differentiated neuroendocrine carcinoma of the breast is a rare cancer with poor prognosis. There is no standard treatment for the disease. Neoadjuvant therapies and surgery are considered to be the main treatment when the tumor diameter is greater than 5.0 cm. Neoadjuvant therapies include chemotherapy and endocrine therapy. However, the effect of neoadjuvant endocrine therapy is not clear in the disease. PATIENT CONCERNS: In August 2014, a 28-year-old premenopausal woman noted a mass that was approximately 3.0 cm*2.0 cm in size on her right breast with pain. Subsequently, the mass has been always increasing significantly. In August 2015, the mass was approximately 7.0 cm*5.0 cm in size, accompanied by pain, no nipple retraction and discharge, no orange peel-like skin changes, and no dimples. In addition, she had no salient past history. DIAGNOSES: Histopathological examinations by a biopsy with a thick needle (hollow needle) and surgical resection confirmed poorly differentiated neuroendocrine carcinoma of the right breast. INTERVENTIONS: First and remarkably, she underwent 3 months of neoadjuvant endocrine therapy (goserelin once every 28 days, and letrozole 10 mg every day). Then, she underwent surgery - stage I breast reconstruction by using prosthesis. Adjuvant endocrine therapy has been used since the operation. OUTCOMES: According to response evaluation criteria in solid tumors 1.1, the tumor was shrunk by 78.87% after neoadjuvant endocrine therapy. No salient complications were observed. We have followed her for 48 months, and there are no signs of recurrence and metastasis. LESSONS: Poorly differentiated neuroendocrine carcinoma of the breast is rare and has a poor prognosis. Currently, there is no standard treatment for this disease. Studies show estrogen receptor and progesterone receptor of neuroendocrine carcinoma of the breast are often highly expressed. In the case, it can be observed that estrogen receptor and progesterone receptor are highly expressed. Therefore, neoadjuvant endocrine therapy may be considered in neuroendocrine carcinoma of the breast when the mass is large and the patient refuses neoadjuvant chemotherapy. We hope to provide an attractive evidence for neoadjuvant endocrine therapy of neuroendocrine carcinoma of the breast. However, more cases are still being needed for research.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Gosserrelina/administração & dosagem , Letrozol/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Terapia Neoadjuvante/métodos
6.
Medicine (Baltimore) ; 99(20): e20199, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443342

RESUMO

INTRODUCTION: Resistance ovary syndrome (ROS) is a disease characterized by hypergonadotropic amenorrhea but with normal ovarian reserve. Currently, its pathogenesis is still unclear and the treatment methods are complex. Nevertheless, there are evident negative effects of this disease on females' physical and mental health such as gonadal dysplasia, infertility, anxiety, and depression. This article reports a case of successful ovulation induction and pregnancy with letrozole combined with HMG. This can provide clinical treatment guidelines for the disease. PATIENT CONCERNS: The patient underwent several hormone replacement cycles and ovulation induction cycles. But the dominant follicles were not extracted even after using large doses of gonadotropin. DIAGNOSIS: Resistant ovary syndrome; Primary infertility INTERVENTIONS:: Larger doses of letrozole combined with HMG were injected to stimulate ovulation and sensitize the ovaries during menstruation. This helped to examine the peripheral effects of letrozole in relation to gonadotropin. OUTCOMES: The patient displayed a dominant follicular growth and notable ovulation which resulted in a full-term pregnancy and successful delivery. CONCLUSIONS: The resistance ovary syndrome (ROS) can be treated and the findings from this case provides a possible treatment for ROS patients with infertility.


Assuntos
Inibidores da Aromatase/uso terapêutico , Letrozol/uso terapêutico , Insuficiência Ovariana Primária/tratamento farmacológico , Adulto , Inibidores da Aromatase/administração & dosagem , Quimioterapia Combinada/métodos , Feminino , Gonadotropinas/uso terapêutico , Humanos , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/tratamento farmacológico , Injeções Intramusculares/métodos , Letrozol/administração & dosagem , Nascimento Vivo , Ovulação/efeitos dos fármacos , Ovulação/fisiologia , Indução da Ovulação/métodos , Gravidez , Resultado do Tratamento
7.
Am J Epidemiol ; 189(10): 1086-1095, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32338279

RESUMO

The association between use of aromatase inhibitors (AIs) and cardiovascular outcomes is controversial. While some observational studies have assessed the cardiovascular safety of AIs as upfront treatments, their cardiotoxicity as sequential treatments with tamoxifen remains unknown. Thus, we conducted a population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. We employed a prevalent new-user design to propensity-score match, in a 1:2 ratio, patients switching from tamoxifen to AIs with patients continuing tamoxifen between 1998 and 2016. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Overall, 1,962 patients switching to AIs were matched to 3,874 patients continuing tamoxifen. Compared with tamoxifen, AIs were associated with an increased risk of myocardial infarction (hazard ratio (HR) = 2.08, 95% confidence interval (CI): 1.02, 4.27). The hazard ratios were elevated for ischemic stroke (HR = 1.58, 95% CI: 0.85, 2.93) and heart failure (HR = 1.69, 95% CI: 0.79, 3.62) but not cardiovascular mortality (HR = 0.87, 95% CI: 0.49, 1.54), with confidence intervals including the null value. The elevated hazard ratios observed for the cardiovascular outcomes should be corroborated in future large observational studies.


Assuntos
Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiopatias/induzido quimicamente , Idoso , Antineoplásicos Hormonais/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Estudos de Coortes , Feminino , Cardiopatias/mortalidade , Humanos , Pessoa de Meia-Idade , Tamoxifeno/administração & dosagem , Reino Unido/epidemiologia
8.
Drugs Aging ; 37(5): 349-358, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32227289

RESUMO

Breast cancer is a disease of aging, and the incidence of breast cancer is projected to increase dramatically as the global population ages. The majority of breast cancers that occur in older adults are hormone-receptor positive, human epidermal growth factor receptor-2 (HER2)-negative phenotypes, with favorable tumor biology; yet, because of underrepresentation in clinical trials, less evidence is available to guide the complex care for this population. Providing care for older patients with metastatic breast cancer, with coexisting medical conditions, increased risk of treatment toxicity, and frailty, remains a clinical challenge in oncology. In this review, we provide an overview of the current evidence from clinical trials and subanalyses of older adults with hormone receptor-positive, HER2-negative metastatic breast cancer, highlighting data on the safety and efficacy of oral therapies, including endocrine therapy alone or in combination with cyclin-dependent kinase (CDK) 4/6 inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors. In addition, we note the significant underrepresentation of older and frail adults in these studies. Current and future directions in research for this special population, in order to address significant knowledge gaps, include the need to improve long-term adherence to hormonal and targeted therapy, prospective clinical trials that capture clinical and biological aging endpoints, and the need for a multidisciplinary approach with integration of geriatric and oncology principles.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Superfície Celular/metabolismo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Avaliação Geriátrica , Humanos , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico
9.
JAMA Netw Open ; 3(3): e201541, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32207833

RESUMO

Importance: The association between exposure to hormone-modulating therapy (HMT) as breast cancer treatment and neurodegenerative disease (NDD) is unclear. Objective: To determine whether HMT exposure is associated with the risk of NDD in women with breast cancer. Design, Setting, and Participants: This retrospective cohort study used the Humana claims data set from January 1, 2007, to March 31, 2017. The Humana data set contains claims from private-payer and Medicare insurance data sets from across the United States with a population primarily residing in the Southeast. Patient claims records were surveyed for a diagnosis of NDD starting 1 year after breast cancer diagnosis for the duration of enrollment in the claims database. Participants were 57 843 women aged 45 years or older with a diagnosis of breast cancer. Patients were required to be actively enrolled in Humana claims records for 6 months prior to and at least 3 years after the diagnosis of breast cancer. The analyses were conducted between January 1 and 15, 2020. Exposure: Hormone-modulating therapy (selective estrogen receptor modulators, estrogen receptor antagonists, and aromatase inhibitors). Main Outcomes and Measures: Patients receiving HMT for breast cancer treatment were identified. Survival analysis was used to determine the association between HMT exposure and diagnosis of NDD. A propensity score approach was used to minimize measured and unmeasured selection bias. Results: Of the 326 485 women with breast cancer in the Humana data set between 2007 and 2017, 57 843 met the study criteria. Of these, 18 126 (31.3%; mean [SD] age, 76.2 [7.0] years) received HMT, whereas 39 717 (68.7%; mean [SD] age, 76.8 [7.0] years) did not receive HMT. Mean (SD) follow-up was 5.5 (1.8) years. In the propensity score-matched population, exposure to HMT was associated with a decrease in the number of women who received a diagnosis of NDD (2229 of 17 878 [12.5%] vs 2559 of 17 878 [14.3%]; relative risk, 0.89; 95% CI, 0.84-0.93; P < .001), Alzheimer disease (877 of 17 878 [4.9%] vs 1068 of 17 878 [6.0%]; relative risk, 0.82; 95% CI, 0.75-0.90; P < .001), and dementia (1862 of 17 878 [10.4%] vs 2116 of 17 878 [11.8%]; relative risk, 0.88; 95% CI, 0.83-0.93; P < .001). The number needed to treat was 62.51 for all NDDs, 93.61 for Alzheimer disease, and 69.56 for dementia. Conclusions and Relevance: Among patients with breast cancer, tamoxifen and steroidal aromatase inhibitors were associated with a decrease in the number who received a diagnosis of NDD, specifically Alzheimer disease and dementia.


Assuntos
Antineoplásicos Hormonais , Inibidores da Aromatase , Neoplasias da Mama , Moduladores de Receptor Estrogênico , Doenças Neurodegenerativas , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/mortalidade , Comorbidade , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/efeitos adversos , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/mortalidade , Estudos Retrospectivos , Fatores de Risco , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico
10.
Drugs Aging ; 37(5): 331-348, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32100240

RESUMO

The median age for breast cancer diagnosis is 62 years, but a disproportionate number of patients are over the age of 75 years and the majority of those have hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative cancers. This review provides a logical algorithm to guide providers through the many complicated issues involved in adjuvant systemic therapy decisions in older patients with hormone receptor-positive, HER2-negative breast cancer. For this subtype of breast cancer, the mainstay of treatment is surgery and adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor (AI). Adjuvant chemotherapy is added to the treatment regimen when the benefits of treatment are deemed to outweigh the risks, making the risk-benefit discussion particularly important in older women. Traditional tools for cancer risk assessment and genomic expression profiles (GEPs) are under-utilized in older patients, but yield equally useful information about cancer prognosis as they do in younger patients. Additionally, there are tools that estimate life-limiting toxicity risk from chemotherapy and life expectancy, which are both important issues in the risk-benefit discussion. For very low-risk cancers, such as non-invasive and small lymph node (LN)-negative cancers, the benefits of any adjuvant therapy is likely outweighed by the risks, but endocrine therapy might be considered to prevent future new breast cancers. For invasive tumors that are > 5 mm (T1b or larger) or involve LNs, adjuvant endocrine therapy is recommended. Generally, AIs should be included, though tamoxifen is effective and should be offered when AIs are not tolerated. Bone-preserving agents and high-dose vitamin D are options to preserve bone density or treat osteoporosis, especially in older women who are taking AIs. Where the risk-reducing benefit from adjuvant chemotherapy outweighs the toxicity risk, adjuvant chemotherapy should be considered. Adjuvant chemotherapy has similar benefits in older and younger patients and standard regimens are preferred. Several exciting clinic trials are underway and have included older patients, including those adding molecularly targeted agents, cyclin-dependent kinase (CDK) 4/6 inhibitors and everolimus, to endocrine therapy in the adjuvant setting. The high incidence of breast cancer in older women should drive us to design clinical trials for this population and emphasize their inclusion in ongoing trials as much as possible.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptores de Superfície Celular/metabolismo , Tamoxifeno/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Detecção Precoce de Câncer , Feminino , Avaliação Geriátrica , Humanos , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Receptor ErbB-2/metabolismo , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
11.
Circulation ; 141(7): 549-559, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32065766

RESUMO

BACKGROUND: The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern. METHODS: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). RESULTS: The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14-3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11-2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88-2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82-1.72]). CONCLUSIONS: In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.


Assuntos
Inibidores da Aromatase , Isquemia Encefálica , Neoplasias da Mama , Bases de Dados Factuais , Insuficiência Cardíaca , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/mortalidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/mortalidade , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Reino Unido/epidemiologia
12.
Eur J Cancer ; 126: 11-20, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31891878

RESUMO

BACKGROUND: Adding cyclin-dependent kinase (CDK) inhibitor to endocrine treatment improves outcome in œstrogen receptor (ER) positive metastatic breast cancer, but identifying the subset of patients who benefit is challenging. Response is potentially associated with ER expression heterogeneity. This is because, unlike the primary tumour in the breast that is localized to the organ, the metastatic breast cancer has spread and continues to spread to distant locations in the body such as bones, lungs, liver, axial skeleton, even to the central nervous system like the brain, wherefrom obtaining biopsies are not easy, and also, the metastasised tissues are heterogeneous. Positron emission tomography (PET) with 16α-[18F]fluoro-17ß-œstradiol (FES), briefly referred to as FES-PET, allows whole-body ER assessment. We explored whether FES-PET heterogeneity and FES uptake were related to letrozole and palbociclib outcome, in patients with ER positive, metastatic breast cancer. PATIENTS AND METHODS: Patients underwent a baseline FES-PET and 18F-fluorodeoxyglucose (FDG) PET, the FDG-PET served to help identify active sites of breast cancer with contrast-enhanced computed tomography (CT). FES-PET heterogeneity score (% FES positive lesions divided by all lesions on FDG-PET and/or CT) and FES uptake were related to outcome and 8-week FDG-PET response. Circulating tumour DNA (CtDNA) samples for ESR1 mutation analysis were collected at baseline. RESULTS: In 30 patients with 864 metastatic lesions, baseline FES-PET heterogeneity was assessed. In 27 patients with 688 lesions, response was evaluated. Median time to progression (TTP) was 73 weeks (95% confidence interval [CI] 21 to ∞) in 7 patients with 100% FES positive disease, 27 weeks (14-49) in heterogeneous FES positive disease (20 patients), and 15 weeks (9 to ∞) without FES positivity (three patients; log-rank P = 0.30). Geometric mean FES uptake was 2.3 for metabolic progressive patients, 2.5 (Pvs progression = 0.82) for metabolic stable disease, and 3.3 (Pvs progression = 0.40) for metabolic response (Ptrend = 0.21). ESR1 mutations, found in 13/23 patients, were unrelated to FES uptake. CONCLUSION: This exploratory study suggests that FES-PET heterogeneity may potentially identify the subset of ER positive, metastatic breast cancer patients who benefit from letrozole combined with CDK inhibition. CLINICAL TRIAL INFORMATION: NCT02806050.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estradiol/uso terapêutico , Fluordesoxiglucose F18 , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Estradiol/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Metástase Neoplásica , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Receptores Estrogênicos/metabolismo , Adulto Jovem
13.
Oncol Res Treat ; 43(3): 96-102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945768

RESUMO

INTRODUCTION: The adverse effect of fractures by different aromatase inhibitor (AI) drugs has not been thoroughly assessed in real-world studies. OBJECTIVE: To assess the adverse events of fractures of real-world breast cancer patients caused by AI therapy through the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The FAERS data from January 2004 to December 2018 were sorted out and analyzed for correlations between fractures and AI use. Disproportionate analysis and Bayesian analysis were adopted to quantify the signal, the association between the AIs and fractures. The onset time and outcome of fractures after different AI regimens were also compared. RESULTS: Out of 23,064 adverse reports, 657 fracture reports (2.85%) were analyzed. Anastrozole showed a positive association with 4 detection methods, while letrozole and exemestane did so with 2. More exemestane-related reports (44.62%) resulted in initial or prolonged hospitalization than anastrozole (30.12%, p = 0.013) and letrozole (29.43%, p = 0.006). The fracture onset time showed no significant difference among anastrozole, letrozole, and exemestane (median onset time: 46.95, 34.25, and 40.58 months, respectively; p = 0.236). CONCLUSIONS: Anastrozole should be prescribed with more medical care. Analysis of FAERS data identified fracture risk tendencies with AI regimens, which supported continuous monitoring, risk evaluations, and further comparative studies.


Assuntos
Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fraturas Ósseas/induzido quimicamente , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Idoso de 80 Anos ou mais , Aromatase/metabolismo , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Seguimentos , Fraturas Ósseas/enzimologia , Fraturas Ósseas/patologia , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Estados Unidos , United States Food and Drug Administration , Adulto Jovem
14.
Support Care Cancer ; 28(4): 1587-1596, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31853701

RESUMO

BACKGROUND: Evidence is mixed regarding the effect of exercise programs on improving musculoskeletal symptoms and quality of life. Previous meta-analyses have not focused specifically on the musculoskeletal symptoms. Therefore, this meta-analysis aimed to evaluate the effect of exercise on these outcomes in breast cancer survivors taking aromatase inhibitors. METHODS: PubMed, CINAHL, EMBASE, Web of Science, Wan Fang, CNKI, VIP, and CBM were searched for randomized control trials or quasi-experimental studies from the establishment of the database to May 2019. Studies comparing exercise programs with usual care among breast cancer survivors taking aromatase inhibitors were included. The primary outcome was the degree of musculoskeletal symptoms, as assessed by scores of pain, stiffness, and grip strength. The secondary outcome was the total quality of life score. RESULTS: A total of 9 studies involving 743 participants were included. Exercise programs were more effective than usual care in improving musculoskeletal symptoms among breast cancer patients taking AIs. The subgroup scores of pain (SMD = -0.46, 95% CI -0.79 to -0.13, P = 0.006), stiffness (SMD = -0.40, 95% CI -0.71 to -0.08, P = 0.01), and grip strength (SMD = 0.43, 95% CI 0.16 to 0.71, P = 0.002) benefited from exercise interventions. Similar effects were found for the quality of life scores (SMD = 2.24, 95% CI 0.28 to 4.21, P = 0.03). CONCLUSIONS: Results indicate that exercise relieves musculoskeletal symptoms and improves quality of life, which can be used to motivate patients to exercise actively under professional guidance. Due to a small sample size, further research is required to ensure the effectiveness of exercise on musculoskeletal symptoms and quality of life.


Assuntos
Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Sobreviventes de Câncer , Terapia por Exercício/métodos , Exercício Físico/fisiologia , Doenças Musculoesqueléticas/induzido quimicamente , Doenças Musculoesqueléticas/terapia , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/complicações , Feminino , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Lancet Oncol ; 21(2): 250-260, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31859246

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. METHODS: We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. FINDINGS: The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9-25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8-13·3 months; HR 0·59, 95% CI 0·54-0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3-29·1) versus 14·9 months (14·0-16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0-13·3 months; HR 0·55, 95% CI 0·49-0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8-23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42-0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5-7·3 months; HR 0·56, 95% CI 0·49-0·64). INTERPRETATION: Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , 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 , Ensaios Clínicos Fase III como Assunto , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration
16.
Breast Cancer Res Treat ; 179(2): 275-285, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31606823

RESUMO

BACKGROUND: Endocrine therapy with aromatase inhibitors (AIs) is the cornerstone of adjuvant systemic treatment for postmenopausal patients with hormone receptor-positive breast cancer. It has become clear that hormone receptor-positive breast cancer carries a consistent risk of relapse up to 15 years after diagnosis. Extended duration of adjuvant AIs therapy after completing initial standard adjuvant AIs-containing therapy may prevent late recurrence and death. We performed a meta-analysis to assess the real impact of the extended adjuvant therapy with AIs. METHODS: A literature-based meta-analysis of the randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, Embase, Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. The endpoints were disease-free survival (DFS), overall survival (OS), local recurrence, distant recurrence, contralateral breast cancer, non-breast cancer-related death, and toxicity. RESULTS: Eight trials comprising 15,966 patients met the inclusion criteria. The pooled analysis revealed a significant improvement in DFS (RR = 0.79; 95% CI 0.68-0.91), distant recurrence (RR = 0.75; 95% CI 0.58-0.96), and contralateral breast cancer (RR = 0.53; 95% CI 0.40-0.70) in the extended AIs group. While there was not significant improvement in OS (RR = 1.00, 95% CI 0.99-1.01), non-breast cancer-related death (RR = 1.16, 95% CI 0.96-1.41), and local recurrence (RR = 0.82; 95% CI 0.64-1.06), the subgroup analysis showed that the patient with tumor size > 2 cm (HR = 0.74, RD = - 0.31, P = 0.05 vs. HR = 0.85, RD = - 0.16, P = 0.20), node positive status (HR = 0.77, RD = - 0.27, P = < 0.0001 vs. HR = 0.89, RD = -0.12, P = 0.19) and previous chemotherapy use (HR = 0.75, RD = - 0.29, P = 0.003 vs. HR = 0.91, RD = -0.10, P = 0.44) would get a greater DFS benefit with extended AIs. Longer treatment with AIs was associated with an increased risk ratio of bone pain (RR = 1.26, RD = 0.04, P = 0.003), bone fractures (RR = 1.59, RD = 0.02, P = 0.002), osteoporosis (RR = 1.53, RD = 0.07, P = 0.005), myalgia (RR = 1.26, RD = 0.04, P = 0.02), and treatment discontinuation for adverse events (RR = 1.51, RD = 0.06, P = 0.0009). CONCLUSION: After initial standard AIs-containing adjuvant therapy, extended AIs therapy could further bring a DFS benefit for postmenopausal patients with early breast cancer, especially in the patients with high-risk characteristics.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Feminino , Humanos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Razão de Chances , Prognóstico , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Retratamento , Resultado do Tratamento
17.
Intern Med J ; 49(11): 1438-1442, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31713335

RESUMO

Combination ribociclib and aromatase inhibitors are currently the preferred treatment in Australia for newly diagnosed hormone receptor positive metastatic breast cancer in the absence of visceral crisis. In our case series of 32 patients, 28% experienced grade 1 elevations in creatinine, a toxicity that was under-recognised in large phase III studies. Creatinine rise appears to be due to a reversible inhibition of renal efflux transporters rather than an acute kidney injury in the majority of cases.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Creatinina/sangue , Purinas/administração & dosagem , Idoso , Aminopiridinas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , New South Wales , Purinas/efeitos adversos , Receptor ErbB-2/metabolismo , Estudos Retrospectivos
18.
Arch Gynecol Obstet ; 300(6): 1767-1771, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31631248

RESUMO

PURPOSE: Empirical treatment options for unexplained infertility treatment include controlled ovarian stimulation (COS) with clomiphene citrate, letrozole or gonadotropins followed by intrauterine insemination (IUI). Achieving consistent multifollicular development with letrozole generally requires addition of gonadotropins. However, the cost and discomfort of injections remains a drawback of this regimen. Therefore, there is a need for evolving newer cost-effective regimens for COS/IUI using orally administered drugs like letrozole. METHODS: Sixty couples with unexplained infertility (on standard infertility investigations) visiting the infertility clinic at a tertiary centre in North India were randomized into two groups. Group A COS was done by step-up protocol of letrozole from day 2 or 3 of menstrual cycle, starting with 2.5 mg and increased by 2.5 mg per day for next 3 days (2.5 mg, 5 mg, 7.5 mg, 10 mg). Group B COS was done with combination of letrozole and hMG (human menopausal gonadotropin). Starting from day 2 or 3 of menses, tablet letrozole 2.5 mg twice a day was given for 5 days. Intramuscular injection of hMG 150 IU was given every alternate day starting from day 7 and titrated according to the response. HCG was given when leading follicle was 17 mm and IUI done 36 h after HCG. RESULTS: Twenty-eight couples in letrozole step-up group (group A) and 30 couples in letrozole plus hMG group (group B), completed follow up for 44 and 55 cycles, respectively. Mean numbers of follicle ≥ 16 mm in both groups were comparable: 1.74 (± 0.83) in group A and 1.94 (± 0.68) in group B (p = 0.178). Ovulation rate of 90.9% (40/44) was achieved in group A, whereas it was 100% (55/55) in group B (p = 0.022), although there was no significant difference in clinical pregnancy rate per patient, which was 3/28 (10.7%) in group A versus 5/30 (16.67%) in group B (p = 0.707). The mean (SD) cost of medicines was significantly lower in group A Rs. 345.00 (00) compared to group B Rs. 2148.64 (515.67) [p < 0.0001]. There was one case each of hyperstimulation and multiple pregnancies in group B, while none in group A. CONCLUSION: It is possible to achieve multifollicular development with use of novel letrozole step-up protocol, even without addition of gonadotropins, at significantly lower cost.


Assuntos
Gonadotropinas/administração & dosagem , Infertilidade Feminina/terapia , Inseminação Artificial , Letrozol/administração & dosagem , Indução da Ovulação/métodos , Adulto , Inibidores da Aromatase/administração & dosagem , Feminino , Humanos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Gravidez , Estudos Prospectivos
19.
Clin Cancer Res ; 25(24): 7485-7496, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31548345

RESUMO

PURPOSE: To investigate the presence of ESR1 mutations in primary estrogen-receptor-positive (ER+) breast cancer treated with extended (>4 weeks) neoadjuvant (presurgical) aromatase inhibitor (NAI) therapy and to identify patients who may gain less benefit from aromatase inhibition (AI) alone based upon on-treatment changes in gene expression. EXPERIMENTAL DESIGN: We evaluated ER, progesterone receptor, and Ki67 by immunostaining, ESR1 mutations by droplet-digital PCR and expression of over 800 key breast cancer genes in paired pre- and post-NAI tumor samples from 87 ER+ breast cancer patients. RESULTS: Cell proliferation and estrogen-regulated genes (ERG) remained suppressed in most tumors indicative of persistent response to NAI. Enrichment of ESR1 mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. ESR1-mutant tumors showed increased expression of ESR1 transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. ESR1 wild-type tumors with high residual proliferation (Ki67r ≥10%; 15/87 tumors) showed lower ESR1/ER expression pre- and post-therapy and lower ERGs. Tumors with ESR1 mutations or Ki67r ≥10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes. CONCLUSIONS: Ligand-independent ER signaling, as a result of ESR1 mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.


Assuntos
Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Mutação , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Resultado do Tratamento
20.
Recenti Prog Med ; 110(7): 347-355, 2019.
Artigo em Italiano | MEDLINE | ID: mdl-31379370

RESUMO

LHRH analogues (LHRHa) are used in the treatment of breast cancer that occurs in young women. Amenorrhoea induced by chemotherapy correlates with a reduced risk of recurrence disease. In premenopausal women, analogous LHRHs are used to suppress ovarian estrogen production, raising estrogen hormone levels to post-menopausal values and improving patient outcomes. Two large clinical studies have investigated the role of complete estrogen blockage in adjuvant hormonal treatment of premenopausal patients. Both studies showed the clinical benefit of ovarian suppression treatment, mainly associated with non-steroidal aromatase inhibitor exemestane in high-risk patients. In the recent years, hormonal treatments made available in clinical practice have considerably prolonged the median survival of patients suffering from endocrine-responsive metastatic breast cancer. Even in the premenopausal setting, CDK4/6 inhibitors in association with endocrine therapy have shown a marked improvement in patient outcomes. The safety and efficacy of this new class of drugs demonstrated in the MONALEESA-7 study in premenopausal women and in the premenopausal subgroups of the PALOMA-3 and MONARCH 2 studies support the use of hormone therapy and analogous LHRH combined with CDK 4/6 inhibitor in patients in premenopausal. Finally, LHRH analogues have been extensively studied in strategies for maintaining ovarian function and fertility preservation during adjuvant chemotherapy in younger patients.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Pré-Menopausa , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Feminino , Preservação da Fertilidade , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos
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