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

RESUMO

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


Assuntos
Anastrozol/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Administração Oral , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Receptores de Estrogênio , Receptores de Progesterona , Tamoxifeno/uso terapêutico
2.
Br J Cancer ; 124(11): 1795-1802, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33762716

RESUMO

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

3.
Eur J Cancer ; 132: 43-52, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325419

RESUMO

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Glicoproteínas de Membrana/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
4.
Eur J Cancer ; 127: 12-20, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31962198

RESUMO

PURPOSE: To investigate long-term results of patients with hormonal receptor-positive breast cancer treated with breast-conserving surgery (BCS) and consecutive endocrine therapy (ET) with or without whole breast irradiation (WBI). METHODS AND MATERIALS: Within the 8 A trial of the Austrian Breast and Colorectal Cancer Study Group, a total of 869 patients received ET after BCS which was randomly followed by WBI (n = 439, group 1) or observation (n = 430, group 2). WBI was applied up to a mean total dosage of 50 Gy (+/- 10 Gy boost) in conventional fractionation. RESULTS: After a median follow-up of 9.89 years, 10 in-breast recurrences (IBRs) were observed in group 1 and 31 in group 2, resulting in a 10-year local recurrence-free survival (LRFS) of 97.5% and 92.4%, respectively (p = 0.004). This translated into significantly higher rates for disease-free survival (DFS): 94.5% group 1 vs 88.4% group 2, p = 0.0156. For distant metastases-free survival (DMFS) and overall survival (OS), respective 10-year rates amounted 96.7% and 86.6% for group 1 versus 96.4% and 87.6%, for group 2 (ns). WBI (hazard ratio [HR]: 0.27, p < 0.01) and tumour grading (HR: 3.76, p = 0.03) were found as significant predictors for IBR in multiple cox regression analysis. CONCLUSIONS: After a median follow-up of 10 years, WBI resulted in a better local control and DFS compared with ET alone. The omission of WBI and tumour grading, respectively, were the only negative predictors for LRFS.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Braquiterapia/mortalidade , Neoplasias da Mama/tratamento farmacológico , Mastectomia Segmentar/mortalidade , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Taxa de Sobrevida
5.
Lancet Oncol ; 20(3): 339-351, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30795951

RESUMO

BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. FUNDING: Amgen.


Assuntos
Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Denosumab/administração & dosagem , Idoso , Inibidores da Aromatase/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Denosumab/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/efeitos dos fármacos , Modelos de Riscos Proporcionais , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética
6.
Breast Cancer Res Treat ; 164(2): 421-427, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28466122

RESUMO

PURPOSE: Objective cosmetic analysis is important to evaluate the cosmetic outcome after breast surgery or breast radiotherapy. For this purpose, we aimed to improve our recently developed objective scoring software, the Breast Analyzing Tool (BAT®). METHODS: A questionnaire about important factors for breast symmetry was handed out to ten experts (surgeons) and eight non-experts (students). Using these factors, the first-generation BAT® software formula has been modified and the breast symmetry index (BSI) from 129 women after breast surgery has been calculated by the first author with this new BAT® formula. The resulting BSI values of these 129 breast cancer patients were then correlated with subjective symmetry scores from the 18 observers using the Harris scale. The BSI of ten images was also calculated from five observers different from the first author to calculate inter-rater reliability. In a second phase, the new BAT® formula was validated and correlated with subjective scores of additional 50 women after breast surgery. RESULTS: The inter-rater reliability analysis of the objective evaluation by the BAT® from five individuals showed an ICC of 0.992 with almost no difference between different observers. All subjective scores of 50 patients correlated with the modified BSI score with a high Pearson correlation coefficient of 0.909 (p < .001) which was better compared to the old software (r = 0.769; p < .001). CONCLUSIONS: The modified BAT® software improves the correlation between subjective and objective BSI values, and may be a new standard for trials evaluating breast symmetry.


Assuntos
Neoplasias da Mama/cirurgia , Mastectomia Segmentar/métodos , Ensaios Clínicos como Assunto , Feminino , Humanos , Fotografação , Software , Inquéritos e Questionários , Resultado do Tratamento
7.
Annu Rev Med ; 67: 1-10, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26332000

RESUMO

Randomized trials have studied bisphosphonates in the adjuvant setting of early breast cancer to investigate their ability to prevent treatment-induced bone loss. Trial results have also suggested their potential to prevent disease recurrence and metastases. These trials are summarized in this review. A recent patient-level meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) finds convincing evidence that adjuvant antiresorptive treatments provide persistent benefits to breast cancer patients in low-estrogen situations and should be considered an important part of the treatment algorithm.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/administração & dosagem , Medula Óssea , Neoplasias Ósseas/secundário , Osso e Ossos/fisiopatologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Estrogênios/sangue , Feminino , Humanos , Taxa de Sobrevida , Microambiente Tumoral
8.
Clin Breast Cancer ; 15(6): 505-11, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26195436

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NACT) is an accepted treatment approach in early-stage breast cancer. In contrast, the potential role of postneoadjuvant chemotherapy after taxane-containing NACT remains unclear. The aim of this study was to evaluate postneoadjuvant chemotherapy and further prognostic factors that predict outcome in women without pathologic complete remission (pCR). PATIENTS AND METHODS: A total of 377 patients with breast cancer who received preoperative chemotherapy were included in this retrospective study. Patients without standard NACT (6 cycles of epirubicin with docetaxel) or primary metastatic breast cancer and locally advanced, inoperable cancer were excluded from further analysis (n = 186). This resulted in a study population of 191 women (30 [15.7%] with pCR; 161 [84.3%] without pCR). Major outcome parameters were event-free survival (EFS) and overall survival (OS). The following parameters were tested for their prognostic role: postneoadjuvant chemotherapy, patient age, breast cancer subtype (luminal/HER2-negative tumors, HER2-positive tumors, and triple-negative tumors), histological grade, pCR, residual lymph node invasion, and residual invasive tumor size. RESULTS: At a median follow-up of 54 months, 51 disease relapses (26.7%) and 21 deaths (11%) were observed. In a comparison of patients with pCR with those without, no significant differences in EFS or OS were observed. Postneoadjuvant chemotherapy was significantly associated with shorter OS in patients without pCR. CONCLUSION: In this population, which included a high percentage of patients with luminal cancers, pCR did not predict for improved OS. Postneoadjuvant chemotherapy showed no discernible benefit even in subgroups with aggressive tumor biology or significant remaining tumor burden. The use of such treatment should therefore be discouraged outside of clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Neoplasia Residual/tratamento farmacológico , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasia Residual/mortalidade , Neoplasia Residual/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
9.
Lancet ; 386(9992): 433-43, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26040499

RESUMO

BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/complicações , Fraturas Ósseas , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/uso terapêutico , Áustria , Densidade Óssea/fisiologia , Neoplasias da Mama/tratamento farmacológico , Denosumab , Método Duplo-Cego , Feminino , Fraturas Ósseas/complicações , Fraturas Ósseas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Suécia , Resultado do Tratamento
10.
Breast Cancer Res Treat ; 151(3): 671-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25981898

RESUMO

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited disorder associated with the occurrence of a wide spectrum of early-onset malignancies, the most prevalent being breast cancer and sarcoma. The presence of TP53 germline mutations in the majority of LFS patients suggests a genetic basis for the cancer predisposition. No special recommendations for the treatment of LFS patients have been made to date, except that of minimizing radiation. We hypothesized that TP53 germline mutations may be associated not only with cancer predisposition, but also with lack of response to chemo- and radiotherapy. Here, we present an Austrian LFS family whose members were intensively treated with chemo- and radiotherapy due to cancers that occurred at a predominantly young age, including eight breast cancers in six patients. Material from seven family members was screened for p53 mutation by Sanger sequencing and immunohistochemistry. A rare missense mutation in the tetramerization domain of exon 10 of the TP53 gene was found to segregate with malignant disease in this family. Lack of response to various chemotherapies and radiotherapy could be ascertained by histopathology of surgical specimens after neoadjuvant treatment, by cancer relapse occurring while receiving adjuvant systemic treatment and by the occurrence of second primaries in areas of adjuvant radiation. Our observations suggest that current standards of cancer treatment may not be valid for patients with LFS. In patients with TP53 germline mutation, cytotoxic treatment may bear not only the risk of tumor induction but also the risk of treatment failure.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/terapia , Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idade de Início , Áustria/epidemiologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Predisposição Genética para Doença , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Pessoa de Meia-Idade , Linhagem , Falha de Tratamento , Resultado do Tratamento , Adulto Jovem
11.
Int J Surg ; 12(12): 1478-83, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25463770

RESUMO

INTRODUCTION: Limited procedures at the T4 ganglion show low rates of compensatory sweating (CS). The aim of the study was to compare endoscopic sympathetic block (ESB) via clip application with endothoracic sympathicotomy (ETS) via diathermy with special regard on patients' quality of life (Qol). PATIENTS AND METHODS: Treatment success, side effects and patient satisfaction were evaluated in a prospectively gathered database of a tertiary-care referral hospital. Two disease-specific Qol questionnaires were used (Keller, Milanez de Campos). RESULTS: 406 operations were performed in 205 patients (ESB4 N = 114, ETS4 N = 91) with a median follow-up of 12 months. Both procedures improved Qol significantly (P < 0.001) and the degree of improvement was equal in both groups. Palmar and axillary HH were ameliorated after both procedures (P < 0.001). Accordingly, plantar HH decreased after ESB4 (P = 0.002), while remaining unaltered after ETS4. Nineteen patients (9.3%) reported CS and 10 patients (4.9%) judged it as "disturbing". Nine of the latter belonged to the ETS4 group compared to one ESB patient (P = 0.015). Patients developed higher rates of plantar CS after ETS4 compared to ESB4 (P = 0.006). Five patients (2.4%) from both cohorts reported persistence of axillary HH. Recurrence of axillary symptoms was found in 5 ESB4 patients. Satisfaction rates did not differ significantly. CONCLUSION: Patients' Qol and satisfaction rates are similar in both treatment groups for upper limb HH. Outcome and recurrence rates speak in the favor of ETS4, severity of CS and potential reversibility argue for ESB4.


Assuntos
Bloqueio Nervoso Autônomo/métodos , Diatermia/métodos , Hiperidrose/cirurgia , Qualidade de Vida , Simpatectomia/métodos , Adulto , Bloqueio Nervoso Autônomo/efeitos adversos , Bloqueio Nervoso Autônomo/estatística & dados numéricos , Axila , Diatermia/estatística & dados numéricos , Endoscopia/métodos , Feminino , Humanos , Masculino , Satisfação do Paciente , Complicações Pós-Operatórias/etiologia , Recidiva , Instrumentos Cirúrgicos , Inquéritos e Questionários , Sudorese , Simpatectomia/efeitos adversos , Simpatectomia/estatística & dados numéricos , Resultado do Tratamento , Extremidade Superior , Adulto Jovem
12.
Clin Cancer Res ; 20(5): 1298-305, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24520097

RESUMO

PURPOSE: To assess the prognostic value of the PAM50 risk-of-recurrence (ROR) score on late distant recurrence (beyond 5 years after diagnosis and treatment) in a large cohort of postmenopausal, endocrine-responsive breast cancer patients. EXPERIMENTAL DESIGN: The PAM50 assay was performed on formalin-fixed paraffin-embedded whole-tumor sections of patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG-8). RNA expression levels of the PAM50 genes were determined centrally using the nCounter Dx Analysis System. Late distant recurrence-free survival (DRFS) was analyzed using Cox models adjusted for clinical and pathologic parameters. RESULTS: PAM50 analysis was successfully performed in 1,246 ABCSG-8 patients. PAM50 ROR score and ROR-based risk groups provided significant additional prognostic information with respect to late DRFS compared with a combined score of clinical factors alone (ROR score: ΔLRχ(2) 15.32, P < 0.001; ROR-based risk groups: ΔLRχ(2) 14.83, P < 0.001). Between years 5 and 15, we observed an absolute risk of distant recurrence of 2.4% in the low ROR-based risk group, as compared with 17.5% in the high ROR-based risk group. The DRFS differences according to the PAM50 ROR score were observed for both node-positive and node-negative disease. CONCLUSION: PAM50 ROR score and ROR-based risk groups can differentiate patients with breast cancer with respect to their risk for late distant recurrence beyond what can be achieved with established clinicopathologic risk factors.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Pós-Menopausa , Prognóstico , Resultado do Tratamento
13.
Int J Surg ; 12(4): 334-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24486930

RESUMO

INTRODUCTION: There are no published data on standardized scoring systems for morbidity after breast cancer surgery. Aim of the study was to establish the Clavien Dindo Classification (CDC) as assessment tool and to identify risk factors for morbidity after breast surgery investigating new techniques including oncoplastic surgery and neoadjuvant chemotherapy. PATIENTS AND METHODS: Between 2008 and 2010, data were retrospectively evaluated from 485 women with breast cancer who underwent surgery at a university hospital. The CDC was used to assess the severity of postoperative complications. Multivariable analyses were adjusted by body-mass index, smoking, diabetes mellitus and tumour size. RESULTS: Overall complications (CDC 1-4) were reported in 28.7%. Second surgery related to major complications (CDC 3-4) was mandatory in 4.7%. Axillary dissection was an independent predictor for CDC 1-4 in all patients (P = 0.008, OR of 1.81, 95%CI 1.17-2.82). We found no independent predictor for CDC 3-4. Oncoplastic surgery increased the rate of wound infections (P = 0.010, OR: 2.94, 95%CI 1.30-6.67) and necroses (P < 0.001, OR: 8.38, 95%CI 3.28-21.4). Axillary dissection elevated wound infection (P = 0.040, OR: 2.07, 95%CI 1.03-4.14) and seroma rates (P < 0.001, OR: 2.46, 95%CI 1.51-4.01). Neoadjuvant chemotherapy had no impact on morbidity. CONCLUSION: The CDC is a valid assessment tool for future clinical trials and may be useful for hospital quality control. While axillary dissection and oncoplastic surgery raised morbidity, no single factor predicted for morbidity related second surgery.


Assuntos
Neoplasias da Mama/cirurgia , Mastectomia/efeitos adversos , Áustria/epidemiologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Feminino , Humanos , Mastectomia/métodos , Morbidade , Terapia Neoadjuvante , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Risco
14.
Clin Cancer Res ; 19(2): 500-7, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23213055

RESUMO

PURPOSE: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. EXPERIMENTAL DESIGN: A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. RESULTS: The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95-2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30). CONCLUSION: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.


Assuntos
Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Citocromo P-450 CYP2D6/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Resultado do Tratamento
15.
Langenbecks Arch Surg ; 398(2): 221-30, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22941244

RESUMO

PURPOSE: Squamous cell cancer (SCC) of the pharyngoesophageal junction area has a poor prognosis mainly due to late symptom manifestation and diagnosis. Treatment of choice is still pharyngolaryngoesophagectomy, substantially affecting quality of life. Limited surgical procedures have been adopted as well. The aim of this retrospective study was to evaluate whether the extent of resection influences postoperative safety and mortality. METHODS: From 1984 to 2006, 66 patients were operated at a single tertiary referral center. Nineteen patients (28.8 %) had SCC of the hypopharynx and 47 patients (71.2 %) had SCC of the cervical and cervicothoracic esophagus. Thirty-five patients (53.0 %) underwent cervical esophageal resection (CE) and 31 underwent total esophagectomy (TE). In 39 patients (59.1 %), the larynx was preserved. Thirteen patients (19.7 %) underwent multimodal treatment. RESULTS: Overall postoperative morbidity was 69.7 % and reoperation rate reached 28.8 %. TE (P = 0.03) and larynx preservation (P = 0.02) were followed by a higher rate of non-lung infections compared with CE and pharyngolaryngectomy, respectively. Pulmonary complications have been observed more frequently after larynx preservation (P = 0.02). Hospital mortality was 9.1 %. Four patients died after TE (12.9 %) and two patients died after CE (5.7 %). In all of them, the larynx had been preserved (15.4 %). Overall, 53 patients (80.3 %) died until follow-up. One-year and 5-year survival in patients with the major tumor burden at the cervicothoracic site was 35.7 and 0 %. CONCLUSIONS: CE can be recommended as long as R0 resection is warranted. The advantage of larynx preservation is gained by higher morbidity and mortality rates and may not be recommended as standard procedure. Surgery may not be appropriate for advanced SCC in the cervicothoracic region.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Faringectomia/métodos , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Esofagectomia/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Faringectomia/mortalidade , Complicações Pós-Operatórias , Prognóstico , Qualidade de Vida , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do Tratamento
16.
Breast Cancer Res Treat ; 134(1): 237-44, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22350732

RESUMO

While cancer research has been focused on tumor cells for many years, evidence is growing that the tumor stroma and in particular cancer-associated fibroblasts (CAFs) in particular play essential roles in the progression of human malignant disease. In human lung cancer, CAFs expressing the transmembrane protein podoplanin were shown to have significant influence on the patients' prognosis. In this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs in a large series of patients with invasive breast cancer. Podoplanin expression was evaluated immunohistochemically in 367 breast cancers. Tumors with ≥10% distinct podoplanin staining were considered as positive (CAF+). Cytoplasmic podoplanin expression of tumor cells was considered as positive when ≥5% of tumor cells showed a distinct podoplanin expression. In normal breast tissue, no podoplanin-expressing fibrocytes were found. Thirty-three patients (9%) with breast cancer showed podoplanin expression in CAFs. In 28 patients (8%), a podoplanin expression in tumor cells was observed. A strong negative correlation of CAF+ with estrogen receptor status (p<0.001), and a significant association with higher histological grading (p<0.001) was seen. In multivariable analysis, CAFs+ was an independent prognostic factor for disease free (1.78 Hazard ratio; p=0.026) and overall survival (2.304 Hazard ratio; p=0.002) in patients with breast cancer. Podoplanin-expressing CAFs contribute to the prognosis of invasive breast cancer, indicating a highly aggressive subgroup. CAFs may present a highly selective target for anti-cancer therapies in patients with invasive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Fibroblastos/metabolismo , Glicoproteínas de Membrana/metabolismo , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/mortalidade , Carcinoma Lobular/secundário , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estatísticas não Paramétricas
17.
J Clin Oncol ; 30(7): 722-8, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22271481

RESUMO

PURPOSE: Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor-positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. PATIENTS AND METHODS: Endocrine receptor-positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. RESULTS: Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. CONCLUSION: Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/uso terapêutico , Tamoxifeno/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Áustria , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Estudos Prospectivos , Taxa de Sobrevida , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos
18.
Ann Surg Oncol ; 19(2): 519-26, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21743980

RESUMO

INTRODUCTION: Our study aims to determine whether patients with lobular-type breast cancer have significantly improved rates of breast conservation (BCT) after neoadjuvant chemotherapy (nCT). METHODS: Patients who received nCT and surgery within three prospective trials between 1995 and 2007 at the Medical University of Vienna were retrospectively analyzed. RESULTS: 325 patients had median follow-up of 53 months; 21% had lobular cancer, and 70% of these women were initially scheduled for mastectomy (MX). Twenty-one finally received BCT, yielding a MX-BCT turnover rate of 45%. Of patients primarily scheduled for BCT, 20% had to finally undergo MX in lobular cancer. The 256 patients with ductal-type breast cancer finally had a MX-BCT turnover rate of 52% (p = 0.561 versus lobular) and a BCT-MX turnover rate of 15% (p = 0.933 versus lobular). Secondary MX after initial BCT was necessary in 2% (ductal) and 10% (lobular, p = 0.110). There was no difference in local recurrence in lobular- as compared with ductal-type breast cancer patients after BCT (2.7% versus 10%, p = 0.135), nor was a difference seen in lobular breast cancer patients when comparing BCT with MX (2.7% versus 3.4%, p = 0.795). Tumor type was not an independent predictor for either BCT or local recurrence. CONCLUSION: We do not suggest excluding patients with lobular-type breast cancer who are primarily scheduled for MX from nCT, since BCT rates may still increase by 45% without influencing the oncologic outcome.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Mastectomia Segmentar , Terapia Neoadjuvante , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento
19.
Ann Surg Oncol ; 19(6): 1808-17, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22207051

RESUMO

PURPOSE: The number of removed axillary lymph nodes and the ratio of involved to removed lymph nodes are described as independent prognostic factors beside the absolute number of involved lymph nodes in breast cancer patients. The correlation between these factors and prognosis were investigated in trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG). METHODS: This retrospective analysis is based on the data of 7052 patients with endocrine-responsive breast cancer who were randomized in four trials of the ABCSG in the years 1990-2006 and underwent axillary lymph node dissection. The prognostic value of number of removed nodes (NRN), number of involved nodes (NIN), and ratio of involved to removed nodes (lymph node ratio, LNR) concerning recurrence-free survival and overall survival was analyzed. RESULTS: A total of 2718 patients had node-positive disease. No correlation was found between NRN and prognosis. Increasing NIN and LNR were significantly associated with worse recurrence-free survival and overall survival in univariate and multivariate analyses (P < .001). Only in the subgroup of patients with one to three positive lymph nodes and treated with mastectomy (n = 728) was LNR an additional prognostic factor in univariate and multivariate analyses. CONCLUSIONS: For breast cancer patients stringently medicated in the framework of prospective adjuvant clinical trials and requiring a mandatory minimum of removed nodes, NRN does not influence prognosis, and LNR is not superior to NIN as prognostic factor. In patients with one to three positive lymph nodes and mastectomy, LNR could play a role as an additional prognostic factor.


Assuntos
Neoplasias da Mama/patologia , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
20.
Clin Cancer Res ; 17(24): 7828-34, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21998336

RESUMO

PURPOSE: To assess the predictive value of Ki67 expression in postmenopausal hormone receptor-positive early-breast cancer patients, who were either treated with adjuvant tamoxifen (TAM) alone or with TAM followed by anastrozole (ANA). EXPERIMENTAL DESIGN: Expression of Ki67 was determined centrally by immunohistochemistry on whole tissue sections of postmenopausal endocrine-responsive breast cancers from patients who had been enrolled in the prospectively randomized Austrian Breast and Colorectal Cancer Study Group Trial 8, and had received TAM for 5 years, or TAM for 2 years followed by ANA for 3 years. Ki67 expression was evaluated both as a continuous variable and dichotomized to low (≤10%) and high (>10%). Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic parameters. RESULTS: Patients with a high Ki67 expression (394/1,587; 23%) had a significantly shorter RFS (adjusted HR for recurrence = 1.90, 95% CI: 1.37-2.64, P = 0.0001) and OS (adjusted HR for death = 1.78, 95% CI: 1.18-2.70, P = 0.006). In women with breast tumors expressing medium or high ER levels (n = 1,438), the interaction between Ki67 and adjuvant endocrine treatment was significant for RFS (P = 0.03). TAM followed by ANA was superior to TAM alone in patients with low Ki67 (adjusted HR = 0.53, 95% CI: 0.34-0.83, P = 0.005) but not in high Ki67 disease (adjusted HR = 1.18, 95% CI: 0.66-1.89, P = 0.68). CONCLUSIONS: Adjuvant sequencing of TAM and ANA is superior to TAM alone, particularly in postmenopausal women with medium or high ER expressing, low proliferating breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/uso terapêutico , Tamoxifeno/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pós-Menopausa , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagem
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