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1.
Cancer Discov ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635570

RESUMO

Personalized medicine aims to match the right drug with the right patient by utilizing specific features of the individual patients' tumor. However, current strategies of personalized therapy matching only provide treatment opportunities for less than 10% of cancer patients. A promising method may be drug profiling of patient biopsies with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival (PFS) compared to their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude, that therapy matching by scFPM is clinically feasible, and effective in advanced aggressive hematologic cancers.

2.
Breast ; 60: 98-110, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34555676

RESUMO

AIM: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. METHODS: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. RESULTS: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. CONCLUSIONS: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.

3.
Appl Immunohistochem Mol Morphol ; 29(10): 728-733, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34121071

RESUMO

BACKGROUND: Androgen receptor (AR) expression is a potential therapeutic target in breast cancer (BC) as it is frequently expressed in the luminal A and B subtypes and in approximately one third of basal-like cancers. As AR-positive BC displays a distinct biological behavior, we aimed to analyze AR expression in the particular context of BC brain metastases (BM). MATERIALS AND METHODS: Patients with newly diagnosed BC BM treated with neurosurgical resection were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, biological tumor subtypes and overall survival were obtained by retrospective chart review. Formalin-fixed and paraffin-embedded specimen containing BM tissue were retrieved from the Neuro-Biobank. Immunohistochemical staining of AR was performed and AR expression in the tumor-cell nucleus was evaluated. RESULTS: Fifty-seven BM samples from 57 individual patients with BC were available for this analysis. AR expression of ≥1% tumor cells was evident in 20/57 (35.1%) BM specimens; the median AR-expression rate was 10% (range: 1% to 60%). AR expression was observed in 11/21 (52.4%) BM of the luminal/human epidermal growth factor receptor 2 (HER2)-negative subtype, 3/13 (23.1%) of the luminal/HER2-positive subtype, 2/7 (28.6%) of the HER2-positive subtype and 4/16 (25.0%) of the triple-negative subtype (P=0.247). Median survival from diagnosis of BM was 10 months (range: 0 to 104 mo) in the entire cohort. No significant association of overall survival and AR expression ≥1% was observed (15 vs. 13 mo; P>0.05). CONCLUSION: AR is expressed in more than one third of BC BM with the highest rates among the luminal/HER2-negative BC subtype and may therefore be a potential prognostic and predictive biomarker in this particular BC population.

4.
Ther Adv Med Oncol ; 13: 17588359211009002, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995593

RESUMO

Background: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown. Methods: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into 'TP', 'other-HER2-targeted therapy' and 'no-HER2-targeted therapy' according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM). Results: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%. Conclusion: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

5.
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.

6.
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
7.
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
8.
Clin Cancer Res ; 25(9): 2737-2744, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30647078

RESUMO

PURPOSE: Brain metastases (BMs) are a rare but devastating condition in estrogen receptor (ER)-positive metastatic breast cancer (MBC). Although endocrine therapy (ET) is the mainstay of treatment in this disease subtype, only case reports have been published concerning the activity of ET in BMs henceforth. Therefore, we aimed to systematically investigate the impact of ET after diagnosis of BM on outcome and clinical course of disease in patients with ER-positive MBC. EXPERIMENTAL DESIGN: Patient characteristics, detailed information about BMs including diagnosis-specific graded prognostic assessment class (DS-GPA), and clinical outcome were obtained by retrospective chart review for all patients treated for ER-positive breast cancer BMs between 1990 and 2017 at an academic care center. Overall survival (OS) was measured as the interval from diagnosis of BM until death or last date of follow-up. RESULTS: Overall, 198 patients [female: 195/198 (98.5%); male: 3/198 (1.5%)] with ER-positive breast cancer BMs were available for this analysis. Eighty-eight of 198 patients (44.4%) received ET after diagnosis of BM including aromatase inhibitors (AIs; letrozole, anastrozole, exemestane), tamoxifen, and fulvestrant. Median OS was significantly longer in patients receiving ET after diagnosis of BM compared with patients who did not (15 vs. 4 months, P < 0.001; log-rank test). No significant difference in terms of OS was observed between patients receiving AIs, tamoxifen, or fulvestrant. In patients with concomitant leptomeningeal carcinomatosis (LC), ET prolonged median OS significantly as well (7 vs. 3 months, P = 0.012; log-rank test). In a multivariate analysis including DS-GPA and ET, only treatment with ET after diagnosis of BM (HR, 0.69; 95% confidence interval, 0.48-0.99; P = 0.046) was associated with prognosis (Cox regression model). CONCLUSIONS: Continuing ET after BM diagnosis was associated with a significantly prolonged OS in this large single-center cohort. No substantial differences between substances were observed. These findings should be validated in a prospective cohort.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Continuidade da Assistência ao Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
9.
Curr Treat Options Oncol ; 19(4): 18, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29527635

RESUMO

OPINION STATEMENT: Bone health and breast cancer are two connected subjects, because breast cancer patients have a higher prevalence of osteopenia/osteoporosis and reduced bone health parameters than healthy woman of the same age. Therefore, the positive effect of adjuvant bisphosphonate therapy plays an important role in breast cancer treatment. Several randomized trials have studied bisphosphonates in the adjuvant setting in postmenopausal woman and demonstrated their potential to prevent treatment-induced bone loss. The prevention of fractures and the subsequent preservation of patients' quality of life are important arguments for the use of adjuvant bisphosphonates in postmenopausal breast cancer patients. In addition, trials of adjuvant bone-targeted agents showed a reduction of recurrences in and outside bone and an improved outcome in patients treated with bisphosphonates.


Assuntos
Antineoplásicos/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Difosfonatos/uso terapêutico , Osteoporose/prevenção & controle , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Recidiva Local de Neoplasia/prevenção & controle , Osteoporose/induzido quimicamente , Pós-Menopausa
10.
Memo ; 10(3): 181-184, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28989544

RESUMO

During the San Antonio Breast Cancer Symposium in December 2016, the main topics were systemic treatment of breast cancer and molecular research. But several studies were also presented concerning local therapy: Surgical issues on evaluating resection margins, management of ductal carcinoma in situ (DCIS), surgical challenges after neoadjuvant therapy related to assessment of response or treatment of axillary lymph nodes, and studies about outcome after breast reconstruction and radiation therapy were discussed. In this short review, oral presentations of these topics are summarized.

11.
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
12.
Int J Surg Case Rep ; 31: 273-275, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28208110

RESUMO

INTRODUCTION: There is an ongoing debate whether prophylactic drainage or incidental appendectomy should be performed in patients undergoing colorectal surgery. On the other hand, it has been shown that the placement of drains through former trocar sites as well as the use of large (≥10mm) trocars, incomplete fascial closure or closed laparoscopy technique all predispose for the occurrence of trocar site hernias. PRESENTATION OF CASE: We report the case of a 59-year-old male patient who underwent laparoscopic sigmoid colectomy with primary anastomosis for recurrent sigmoid diverticulitis. Preoperative diagnostics revealed no abnormalities other than multiple diverticula in the sigmoid colon. The subsequent surgery was conducted without any complications. Due to inconspicuous intraoperative appearance of the vermiform appendix, no incidental appendectomy was performed. On the 4th postoperative day, the Easy Flow drain - which had been placed prophylactically through the 12mm trocar site in the right lower abdomen - was removed. Four hours after drain removal, trocar-site evisceration of the vermiform appendix occurred, requiring emergency surgery. DISCUSSION AND CONCLUSION: The present case is yet another argument for restricting the use of prophylactic drains in colorectal surgery as well as closing port sites of ≥10mm diameter. Furthermore, incidental appendectomy may be considered since it is able to prevent this type of complication and can be performed with minimal cost and morbidity.

13.
Clin Cancer Res ; 23(14): 3676-3683, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28143867

RESUMO

Purpose: To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification.Experimental Design: 114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured by in situ hybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is).Results: In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6; P = 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR (P = 0.002 and P < 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86-13.90; P = 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)-positive tumors (ypT0 ypN0: 62.5% vs. 24.0%, P = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, P = 0.005; and ypT0/is: 87.5% vs. 28.0%, P < 0.001), and was largely absent in HR-negative tumors.Conclusions: An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated. Clin Cancer Res; 23(14); 3676-83. ©2017 AACR.


Assuntos
Biomarcadores Farmacológicos , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Trastuzumab/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Centrômero/genética , Cromossomos Humanos Par 17/genética , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Trastuzumab/efeitos adversos
14.
Ther Adv Med Oncol ; 9(11): 679-692, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29344105

RESUMO

Background: The benefit of 5 years of adjuvant endocrine therapy for women with hormone receptor-positive (HR+) breast cancer (BC) is beyond discussion. Nevertheless, the risk of recurrence of luminal BC persists for 15 years or more after diagnosis. Consequently, approaches of extended adjuvant therapy have been investigated in large clinical trials, with the ultimate aim of further reducing the risk of recurrence in patients with HR+ BC. Methods: A review of recently published trial data is presented to provide a solid basis for discussion. A discussion of the side effects of long-term endocrine treatment, multigenetic tests aiming to identify patients at particular risk, and an outlook for further promising targets are additional aims of this review. Conclusion: Extended adjuvant therapy seems beneficial in reducing distant relapse and contralateral BC for a selected group of patients with HR+ BC, particularly if aromatase inhibitors (AIs) are used after initial tamoxifen therapy. However, patients with lower risk of recurrence and initial AI therapy may suffer more from side effects than benefit from extended therapy.

15.
Cancer Med ; 5(9): 2350-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27457217

RESUMO

The response to neoadjuvant chemotherapy in breast cancer patients is usually assessed by pCR and RCB score. However, the prognostic value of these parameters is still in discussion. We showed recently that an epirubicin/docetaxel therapy is associated with an increase in the cell death marker high-mobility group box 1 protein (HMGB1) in the circulation. Here, we investigate whether this increase correlates with the long-term outcome. Thirty-six early breast cancer patients under neoadjuvant epirubicin/docetaxel combination chemotherapy were included in this study. To determine the immediate effect of this treatment on HMGB1, we collected blood samples before and 24-96 h after the initial dose. This time course was then compared to the 5-year follow-up of the patients. HMGB1 levels varied before chemotherapy between 4.1 and 11.3 ng/mL and reacted differently in response to therapy. Some patients showed an increase while others did not show any changes. Therefore, we subdivided the patient collective into two groups: patients with an at least 1.1 ng/mL increase in HMGB1 and patients with smaller changes. The disease-free survival was longer in the HMGB1 increase group (56.2 months vs. 46.6 months), but this difference did not reach significance. The overall survival (OS) was significantly better in patients with an increase in HMGB1 (log rank P = 0.021). These data suggest that an immediate increase in HMGB1 levels correlates with improved outcome in early breast cancer patients receiving neoadjuvant chemotherapy, and may be a valuable complementary biomarker for early estimation of prognosis.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Proteína HMGB1/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Estimativa de Kaplan-Meier , Lactato Desidrogenases/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Resultado do Tratamento
16.
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
17.
Br J Cancer ; 113(7): 1035-45, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26335606

RESUMO

BACKGROUND: Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer. METHODS: DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples, respectively. The CpG island methylator phenotype (CIMP) was assessed by MethyLight in FFPE material from 78 patients with pT2 and pT3 rectal adenocarcinoma. RESULTS: We identified and confirmed two novel three-gene signatures in fresh frozen samples that can distinguish tumours from adjacent tissue as well as from blood with a high sensitivity and specificity of up to 1 and an AUC of 1. In addition, methylation of individual CIMP markers was associated with specific clinical parameters such as tumour stage, therapy or patients' age. Methylation of CDKN2A was a negative prognostic factor for overall survival of patients. CONCLUSIONS: The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Proteínas de Neoplasias/genética , Neoplasias Retais/genética , Neoplasias Retais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Inibidor p16 de Quinase Dependente de Ciclina , DNA de Neoplasias/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico , Análise de Sobrevida
18.
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
19.
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
20.
Breast Care (Basel) ; 4(3): 155-161, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-21160541

RESUMO

Endocrine therapy has become a key part in the adjuvant treatment of hormone responsive breast cancer. The positive effect on relapse risk reduction is well defined, but therapy is not free from bothersome side effects for which estrogen deprivation accounts to a great extent. Since endocrine therapy is usually prescribed for 5 years or longer to optimally display its protective effect, and because physical strain is missing, good tolerability and safety properties are important, particularly in low-risk patients. While tamoxifen has been the standard adjuvant endocrine treatment with well documented efficiency, it is increasingly replaced by third generation aromatase inhibitors due to their better effectiveness and tolerability. Because tamoxifen holds a risk for life-threatening adverse events such as endometrial cancer, pulmonary embolism, and stroke, its recommended duration of therapy is limited to 5 years, also because extension beyond that time did not produce a measurable advantage. While some side effects are present both with tamoxifen and aromatase inhibitors, differences in side effect profiles are well established. Although side effects of aromatase inhibitor-related therapy usually are mild and common to symptoms of menopause, misconception of the symptoms and their mechanism of action, as well as lack of knowledge about how to handle them, can easily lead to dangerous discontinuation of therapy.

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