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1.
Medicine (Baltimore) ; 100(14): e25175, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832078

RESUMO

RATIONALE: Neo-adjuvant systemic therapy includes endocrine therapy and chemotherapy, which is widely used. Luminal breast cancer is resistant to chemotherapy and is more likely to not respond to chemotherapy before surgery. Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor. Palbociclib with letrozole combination therapy was an effective chemotherapy in metastatic luminal type breast cancer and had fewer side effects; however, the benefit of palbociclib in neoadjuvant systemic therapy is unclear. PATIENT CONCERNS: A 50-year-old female patient visited our hospital with palpable lump in the right breast. The lymph nodes fixed in the ipsilateral axilla. DIAGNOSIS: The patient was diagnosed with invasive ductal carcinoma of the right breast; the nuclear grade was moderate. The ipsilateral fixed lymph node was diagnosed as metastasis. The breast cancer subtype was luminal A type and was positive for estrogen receptor and progesterone receptor, and negative for HER2/neu and Ki-67 marker index <10% on immunohistochemistry. INTERVENTIONS: Neo-systemic therapy was performed with 3 cycles of adriamycin with docetaxel. After follow-up study, the breast and axillary lesions progressed. Palbociclib with letrozole was administered as second neo-systemic therapy for 10 months. Subsequently, breast-conserving surgery with sentinel lymph node biopsy was performed. OUTCOMES: In the postoperative pathologic result, 4 mm invasive lesion remained, and the sentinel lymph node biopsy was negative. The results achieved a residual cancer burden classification class 1. CONCLUSION: Second-line neo-systemic therapy can further reduce the size of the tumor and increase the likelihood of avoiding the side effects of surgery. Palbociclib with letrozole may be a good treatment in the preoperative stage for luminal breast cancer that is resistant to chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Letrozol/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Metástase Linfática/patologia , Mastectomia Segmentar , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos
2.
Eur J Endocrinol ; 184(5): K11-K14, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33667194

RESUMO

Objective: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. Design and methods: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. Results: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05). Conclusions: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.


Assuntos
MicroRNAs/sangue , Puberdade/sangue , Adolescente , Quimioterapia Combinada , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Gônadas/fisiologia , Transtornos do Crescimento/sangue , Transtornos do Crescimento/complicações , Transtornos do Crescimento/tratamento farmacológico , Terapia de Reposição Hormonal , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Injeções Intramusculares , Letrozol/administração & dosagem , Letrozol/farmacologia , Estudos Longitudinais , Masculino , Puberdade/efeitos dos fármacos , Puberdade/genética , Puberdade Tardia/sangue , Puberdade Tardia/complicações , Puberdade Tardia/tratamento farmacológico , Testosterona/administração & dosagem , Testosterona/farmacologia , Ubiquitina-Proteína Ligases/genética
3.
Cochrane Database Syst Rev ; 10: CD006359, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33112418

RESUMO

BACKGROUND: A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration. OBJECTIVES: To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR). SEARCH METHODS: The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects. MAIN RESULTS: Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I2 = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I2 = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I2 = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I2 = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I2 = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I2 = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I2 = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I2 = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I2 = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I2 = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes. AUTHORS' CONCLUSIONS: There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle. In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval. Adequately powered studies are needed to evaluate each treatment more accurately.


Assuntos
Criopreservação , Transferência Embrionária/métodos , Embrião de Mamíferos , Endométrio/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/agonistas , Doação de Oócitos , Aborto Espontâneo/epidemiologia , Viés , Clomifeno/administração & dosagem , Esquema de Medicação , Implantação do Embrião/fisiologia , Endométrio/fisiologia , Feminino , Hormônio Foliculoestimulante/administração & dosagem , Humanos , Letrozol/administração & dosagem , Nascimento Vivo/epidemiologia , Gravidez , Taxa de Gravidez , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
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
5.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
7.
Life Sci ; 260: 118302, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827543

RESUMO

AIMS: The roles of estrogen receptors (ERs) and the efficacy of anti-estrogen (E2) therapies in pancreatic cancer stay controversial. The main objectives of this study were to investigate the potential roles of ERs in tumor progression and endocrine therapies. MAIN METHODS: The ER expression status in PANC-1 and SW1990 pancreatic cancer cell lines was determined. SRB assay, colony formation assay and proliferation assay were used to investigate the responses of these cells to E2. ERα-selective agonist propylpyrazoletriol (PPT), ERß-selective agonist diarylpropionitrile (DPN), ERα over-expressed SW1990 cells, ERα knock-out PANC-1 cells and patient-derived xenografts (PDX) were applied to investigate the potential roles of ERα in pancreatic cancer. The phosphorylation of ERα-related signaling molecules extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) were investigated. The in vivo anti-tumor efficacy and safety of letrozole (LTZ) combined with leuprorelin acetate (LA) and gemcitabine (GEM) were also preliminarily studied. KEY FINDINGS: PANC-1 cells expressed much more ERα than SW1990 cells, and ERß level was with less diversity. Accordingly, the proliferation of PANC-1 rather than SW1990 cells could be stimulated by E2, and only PANC-1 could respond to LTZ endocrine therapy in female but not male mice. The phosphorylation of ERK1/2 but not AKT was altered by over-expressed or knocking out of ERα with or without the addition of E2 and LTZ. The combination therapy of LTZ and GEM showed acceptable efficacy and safety. SIGNIFICANCE: This study showed the important roles of ERα in tumor progression and endocrine therapies of pancreatic cancer in women.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/fisiopatologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Letrozol/administração & dosagem , Leuprolida/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Tumour Biol ; 42(6): 1010428320925301, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32489146

RESUMO

A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival (p = 0.009) and overall survival (p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/genética , Letrozol/administração & dosagem , Prognóstico , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Letrozol/efeitos adversos , Terapia Neoadjuvante , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Resultado do Tratamento
9.
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
10.
Breast Cancer Res ; 22(1): 22, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070401

RESUMO

BACKGROUND: In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS: Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS: Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION: In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Pós-Menopausa , Receptor ErbB-2/metabolismo , Transcriptoma
11.
Fertil Steril ; 113(2): 417-425.e1, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31973903

RESUMO

OBJECTIVE: To compare live birth and multiple gestation in patients diagnosed with unexplained infertility undergoing intrauterine insemination after ovarian stimulation (OS-IUI) with oral medications versus gonadotropins. DESIGN: Systemic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients undergoing OS-IUI for treatment of unexplained infertility. INTERVENTION(S): Clomiphene, letrozole, or gonadotropins for OS-IUI. MAIN OUTCOME MEASURE(S): Live birth and multiple gestation. RESULT(S): Eight total trials were identified that met the inclusion criteria and comprised 2,989 patients undergoing 6,590 cycles. One study reported a significant increase in both live births and multiple gestations with the use of gonadotropins, two studies found an increased likelihood of live birth with the use of gonadotropins, and two studies found an increased risk of twins with gonadotropins. The relative risk of live birth in subjects receiving gonadotropins was 1.09. The relative risk of multiple gestation in subjects receiving gonadotropins was 1.06. Clinical pregnancy was higher in protocols with lax cancellation policies or higher gonadotropin doses, with subsequent increased relative risks of multiple gestations of 1.20 and 1.15, respectively. Singleton births per subject were similar between the two groups. The results did not change in per-protocol, per cycle, or fixed-effect model sensitivity analyses. CONCLUSION(S): For every birth gained with the use of gonadotropins, a similar increased risk of multiple gestation occurs. The randomized data do not support the use of gonadotropin for OS-IUI in women with unexplained infertility. CLINICAL TRIAL REGISTRATION NUMBER: Prospero CRD4201911998.


Assuntos
Clomifeno/administração & dosagem , Fármacos para a Fertilidade Feminina/administração & dosagem , Gonadotropinas/administração & dosagem , Infertilidade/terapia , Letrozol/administração & dosagem , Ovário/efeitos dos fármacos , Indução da Ovulação , Ovulação/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Clomifeno/efeitos adversos , Feminino , Fertilidade/efeitos dos fármacos , Fármacos para a Fertilidade Feminina/efeitos adversos , Gonadotropinas/efeitos adversos , Humanos , Infertilidade/diagnóstico , Infertilidade/etiologia , Infertilidade/fisiopatologia , Inseminação Artificial , Letrozol/efeitos adversos , Nascimento Vivo , Masculino , Ovário/fisiopatologia , Indução da Ovulação/efeitos adversos , Gravidez , Taxa de Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
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.
Pharm Dev Technol ; 25(4): 397-407, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31893979

RESUMO

Chemotherapy using cytotoxic agents, such as letrozole (LTZ), is one of the most effective treatments for hormone-dependent breast cancer. Nevertheless, nonspecific targeting of the drug constructs several remarkable systemic toxicities. In this study, we synthesized solid lipid nanoparticles (SLNs) by solvent emulsification evaporation method as LTZ carriers. Nanoparticles were also modified with a cancer cell-targeting ligand, folic acid (FA), and then characterized. Cell membrane damage and cell viability were investigated by lactate dehydrogenase (LDH) and 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays, respectively. Caspase-3 activity and TUNEL assays were performed to verify induced apoptosis. Scanning electron microscopy (SEM) exhibited uniform and spherical morphology of the SLNs-LTZ and FA-SLNs-LTZ. The X-ray diffraction (XRD) confirmed LTZ was dispersed as amorphous in the SLNs. The cell culture results revealed that FA-SLNs-LTZ was significantly more cytotoxic than SLNs-LTZ and free drug against MCF-7 cancer cells in vitro, with a 50% inhibitory concentration (IC50) value of 81 ± 0.89 nM, but both nanoformulations had negligible cytotoxicity toward MCF-10A normal cells and they showed promising biocompatibility. Taken together, these findings indicated the evidence of apoptosis as a mechanism of cell death. This study suggests the potential of FA-SLNs-LTZ for inducing apoptosis in a target-specific manner with minimal systemic side effects.


Assuntos
Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/metabolismo , Receptores de Folato com Âncoras de GPI/metabolismo , Letrozol/administração & dosagem , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Caspase 3/metabolismo , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Letrozol/farmacologia , Metabolismo dos Lipídeos , Células MCF-7 , Nanopartículas/metabolismo
14.
Lancet Oncol ; 21(1): 33-43, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838010

RESUMO

BACKGROUND: In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer. METHODS: CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I-IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0-1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427. FINDINGS: Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2-206·0). At surgery, 23 (46·9%; 95% CI 32·5-61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9-61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3-4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3-4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group. INTERPRETATION: Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy. FUNDING: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Aminopiridinas/administração & dosagem , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Pós-Menopausa , Prognóstico , Purinas/administração & dosagem
15.
Anticancer Drugs ; 31(1): 85-89, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609762

RESUMO

CDK4/6 inhibitors in association with aromatase inhibitors have led to a paradigm shift in the management of metastatic positive hormone-receptors breast cancer. Liver toxicity is common with these agents, but no data are reported on the sequential use of these CDK4/6 inhibitors in case of confirmed efficacy and intolerable toxicity. In this article, we report the successful use of Palbociclib in a metastatic positive hormone-receptors breast cancer patient after initial response to Ribociclib, which was interrupted for grade 4 liver toxicity.


Assuntos
Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Piperazinas/efeitos adversos , Purinas/efeitos adversos , Piridinas/efeitos adversos , Aminopiridinas/administração & dosagem , Neoplasias da Mama/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Feminino , Humanos , Letrozol/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/administração & dosagem , Piridinas/administração & dosagem , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Ácido Zoledrônico/administração & dosagem
16.
Clin Cancer Res ; 26(4): 821-827, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31662331

RESUMO

PURPOSE: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR. PATIENTS AND METHODS: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR. RESULTS: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1-2 diarrhea and acneiform rash being the most common toxicities. CONCLUSIONS: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptores Estrogênicos/metabolismo , Trastuzumab/administração & dosagem , Resultado do Tratamento , Adulto Jovem
17.
Drug Des Devel Ther ; 13: 3867-3877, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814708

RESUMO

Objective: Frozen-thawed embryo transfer enables surplus embryos derived from IVF or IVF-ICSI treatment to be stored and transferred in subsequent cycles into a more "physiologic environment". This study aimed to investigate the clinical effect of letrozole use or hMG stimulation on pregnancy and neonatal outcomes in ovulatory patients undergoing FET. Methods: This study includes a total of 5901 FET cycles with letrozole use (n = 1569), HMG (n =1827) or letrozole + HMG (n = 2505). In the letrozole group, 2.5 mg of letrozole was administered on menstrual cycle day 3 to 5 for 3 days for patients, and then follicle growth was monitored beginning on day 10. If the follicular diameter was ≥14 mm on the 10th day, no other ovarian stimulation drugs were needed. If the follicular diameter was <14 mm on the 10th day, 150 IU human menopausal gonadotropin (hMG) was added to stimulate follicle growth every two days (hMG + letrozole group). In hMG stimulation group, a total of 150 IU of hMG was injected every two days to stimulate development of follicles from cycle day 10 to 12. Results: Compared with the patients undergoing hMG stimulation, the group receiving letrozole or letrozole+HMG stimulation exhibits significantly higher clinical pregnancy rates per transfer (hMG: 47.02% vs letrozole: 52.07% vs letrozole+HMG: 52.26%) and implantation rates (hMG: 31.76% vs letrozole: 34.36% vs letrozole+HMG: 34.24%). In addition, the letrozole group was associated with a statistically significantly lower incidence of miscarriage (hMG: 14.78% vs letrozole: 10.53% vs letrozole+HMG: 14.13%) and ectopic pregnancies (hMG: 1.83% vs letrozole: 0.97% vs letrozole+HMG: 1.58%) than the letrozole + HMG and HMG groups. Neonatal outcomes are similar among the three groups. Conclusion: Our data demonstrate that the letrozole use may improve clinical pregnancy outcomes and decrease the risk of ectopic pregnancies and miscarriage in ovulatory patients who receive FET cycles.


Assuntos
Criopreservação , Endométrio/efeitos dos fármacos , Letrozol/farmacologia , Menotropinas/farmacologia , Ovulação , Adulto , Estudos de Coortes , Transferência Embrionária , Feminino , Humanos , Letrozol/administração & dosagem , Menotropinas/administração & dosagem , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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.
Breast Cancer Res ; 21(1): 108, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533777

RESUMO

BACKGROUND: The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. METHODS: Postmenopausal women with untreated stage I-III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. RESULTS: Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1-2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (- 73.2%) was superior to both monotherapy arms combined (- 49.9%; p = 0.001) and mVNB (- 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (- 73.2%) was numerically higher compared to LTZ (- 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. CONCLUSIONS: Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. TRIAL REGISTRATION: NCT02802748 , registered 16 June 2016.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Vinorelbina/administração & dosagem , Administração Metronômica , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Letrozol/administração & dosagem , Letrozol/efeitos adversos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Pessoa de Meia-Idade , Pós-Menopausa , Receptor ErbB-2/metabolismo , Receptores de Esteroides/metabolismo , Vinorelbina/efeitos adversos
20.
Lancet Oncol ; 20(10): 1360-1369, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31494037

RESUMO

BACKGROUND: Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches. METHODS: We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR. FINDINGS: We identified 2689 published results and 140 studies (comprising 50 029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0·42; 95% credible interval [CrI] 0·25-0·70), ribociclib plus letrozole (0·43; 0·24-0·77), abemaciclib plus anastrozole or letrozole (0·42; 0·23-0·76), palbociclib plus fulvestrant (0·37; 0·23-0·59), ribociclib plus fulvestrant (0·48; 0·31-0·74), abemaciclib plus fulvestrant (0·44; 0·28-0·70), everolimus plus exemestane (0·42; 0·28-0·67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0·39; 0·22-0·66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8·95; 95% CrI 1·03-76·92). INTERPRETATION: In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer. FUNDING: None.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Aminopiridinas/administração & dosagem , Anastrozol/administração & dosagem , Androstadienos/administração & dosagem , Benzimidazóis/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Everolimo/administração & dosagem , Feminino , Fulvestranto/administração & dosagem , Humanos , Letrozol/administração & dosagem , Metanálise em Rede , Paclitaxel/administração & dosagem , Piperazinas/administração & dosagem , Pós-Menopausa , Intervalo Livre de Progressão , Purinas/administração & dosagem , Piridinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
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