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Background: The mTORC1 inhibitor everolimus has been approved in combination with the aromatase inhibitor exemestane for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (HR+ mBC) progressing on prior therapy with a non-steroidal aromatase inhibitor. To date, no predictive biomarkers of tumor sensitivity/resistance for everolimus-based treatments have been identified. We hypothesized that precocious changes in the Standardized Uptake Volume (∆SUV%), as assessed by 18F-Fluorodeoxyglucosepositron-emission tomography (18F-FDG PET/CT), may be a marker of everolimus efficacy. Methods: This was a retrospective study including 31 HR+ HER2- patients treated with everolimus and exemestane in two Italian centers between 2013 and 2018. The objective of the study was to investigate ∆SUV% as a predictive marker of everolimus antitumor efficacy. 18F-FDG PET/CT scans were performed at baseline and after three months of treatment. Patients were defined as long responders (LRs) if disease progression occurred at least 10 months after treatment initiation and long survivors (LSs) if death occurred later than 36 months after starting therapy. ROC analysis was used to determine the optimal cut-off values of ∆SUV% to distinguish LRs from non-LRs and LSs from non-LSs. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: The SUVmax values decreased significantly from baseline to 3 months after therapy (p = 0.003). Dynamic changes of SUVmax (Delta SUV) had a higher accuracy in discriminating long-responders from non-long-responders (AUC = 0.67, Delta SUV cut-off = 28.8%) respects to its ability to identify long survivors from no-long survivors (AUC = 0.60, Delta SUV cut-off = 53.8%). Patients were divided into groups according to the Delta SUV cut-offs and survival outcomes were evaluated: patients with a decrease of ∆SUV% ≥ 28.8% had significantly better PFS (10 months-PFS: 63.2%, 95% CI: 37.9-80.4% and 16.7%, 95% CI: 2.7-41.3% respectively, p = 0.005). As regard as OS, patients with ∆SUV% ≥ 53.8% had longer OS when compared to patients with ∆SUV% < 53.8% (36 month-OS: 82.5% vs. 45.9% vs. p = 0.048). Conclusion: We found two precocious ∆SUV% thresholds capable of identifying HR+ HER2-mBC patients, which would achieve long-term benefit or long-term survival during everolimus-exemestane therapy. These results warrant further validation in prospective studies and should be integrated with molecular biomarkers related to tumor metabolism and mTORC1 signaling.
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INTRODUCTION: Reliable biomarkers of response to mTOR inhibition are yet to be identified. As mTOR is heavily implicated in cell-metabolism, we investigated the relation between BMI variation and outcomes in metastatic breast cancer (mBC) patients treated with everolimus. RESULTS: we found a linear correlation between everolimus exposure duration and BMI/weight decrease. Patients exhibiting >2 kg weight loss or >3% BMI decrease from baseline at the end of treatment (EOT) had a statistically significant improvement in PFS. Interestingly, a similar BMI/weight decrease within the first 8 weeks of therapy identified patients at higher risk of progression. PATIENTS AND METHODS: we performed a retrospective analysis of patients enrolled in the BALLET trial who progressed during the study. Primary end-point was progression-free survival (PFS). Secondary end-point was the identification of other predictors of response. CONCLUSION: A >3% weight loss at EOT is associated with better outcome in mBC patients treated with everolimus. On the contrary, a significant early weight loss represents a predictor of poor survival and could therefore be used as an early negative prognostic marker. As PI3K-inhibition also converges onto mTOR, these findings might extend to patients treated with selective PI3K inhibitors and warrant further investigation.
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EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib changed dramatically the history of metastatic non-small cell lung cancer (NSCLC) harbouring EGFR mutations. However, not enough data are available on the efficacy of these targeted drugs in elderly patients. The aim of this study is to analyse the available clinical data evaluating the efficacy of anti-EGFR therapies in elderly patients with advanced NSCLC carrying EGFR mutations. A literature-based meta-analysis of the results of randomized clinical trials was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. Progression-free survival (PFS), as a measure of the efficacy of treatment, was the primary outcome investigated. The pooled analysis revealed an overall significant improvement in PFS (HR = 0.44, 95% CI 0.28-0.69; p = 0.0004) with the use of EGFR TKIs in EGFR-mutated NSCLC. The data stratification per age subgroups showed that EGFR TKIs were more effective in prolonging PFS in elderly patients, with HR 0.39 (p = 0.008), in comparison with young patients (HR = 0.48; p = 0.04). The results of this study suggest that EGFR TKIs have a significant effect in slowing down diseases progression in elderly patients with advanced NSCLC, therefore representing a valid therapeutic option in this age group.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Idoso , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Notwithstanding the continuous progress made in cancer treatment in the last 20 years, and the availability of new targeted therapies, metastatic Breast Cancer (BC) is still incurable. Targeting the cell cycle machinery has emerged as an attractive strategy to tackle cancer progression, showing very promising results in the preclinical and clinical settings. The first selective inhibitors of CDK4/6 received breakthrough status and FDA approval in combination with letrozole (February 2015) and fulvestrant (February 2016) as first-line therapy in ER-positive advanced and metastatic BC. Considering the success of this family of compounds in hormone-positive BC, new possible applications are being investigated in other molecular subtypes. This review summarizes the latest findings on the use of CDK4/6 inhibitors in HER2 positive BC.
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Neoplasias da Mama/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Fulvestranto , Humanos , Letrozol , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/biossíntese , Triazóis/uso terapêuticoRESUMO
BACKGROUND: The aim of the present study was to evaluate the activity and tolerability of low-dose oral ethinylestradiol (EE) and luteinizing hormone-releasing hormone analogue with concomitant low-dose acetylsalicylic acid (ASA) as a thromboprophylactic agent for advanced castrate-resistant prostate cancer (CRPC). PATIENTS AND METHODS: The patients received an EE dose of 150 µg daily (50 µg 3 times daily) and an ASA dose of 100 mg once daily. The primary endpoint was the prostate-specific antigen response. RESULTS: A total of 32 patients were enrolled. A PSA response was observed in 19 patients (59.3%; 95% confidence interval [CI], 41%-76%). The median progression-free survival was 9.4 months (95% CI, 6.5-14.1 months). The treatment was generally well tolerated and no grade 3-4 toxicity was observed. Only 1 patient interrupted EE because of a cardiac event and 1 patient experienced grade 2 nausea and vomiting. No major bleeding occurred. CONCLUSION: Low-dose EE with concomitant low-dose ASA is safe, showing potential activity in patients with advanced CRPC, and should be investigated further.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aspirina/administração & dosagem , Etinilestradiol/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aspirina/efeitos adversos , Cálculos da Dosagem de Medicamento , Etinilestradiol/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, 'window of opportunity' Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib. The OLTRE trial is expected to identify the surrogate markers of the biological activity of olaparib in the treatment of patients with triple-negative breast cancer.