MAX SENNA MANO
Projetos de Pesquisa
Unidades Organizacionais
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
6 resultados
Resultados de Busca
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- Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE(2021) MAMOUNAS, E. P.; UNTCH, M.; MANO, M. S.; HUANG, C-S; GEYER JR., C. E.; MINCKWITZ, G. von; WOLMARK, N.; PIVOT, X.; KUEMMEL, S.; DIGIOVANNA, M. P.; KAUFMAN, B.; KUNZ, G.; CONLIN, A. K.; ALCEDO, J. C.; KUEHN, T.; WAPNIR, I; FONTANA, A.; HACKMANN, J.; POLIKOFF, J.; SAGHATCHIAN, M.; BRUFSKY, A.; YANG, Y.; ZIMOVJANOVA, M.; BOULET, T.; LIU, H.; TESAROWSKI, D.; LAM, L. H.; SONG, C.; SMITT, M.; LOIBL, S.Y Background: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/ axilla at surgery after NACT containing a taxane (+/- anthracycline, +/- platinum) and trastuzumab (+/- pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (w65% versusw82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the TDM1 arm (13.5% versus 3.8%), but there was no grade >3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.220.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.
- Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer(2023) DENKERT, Carsten; LAMBERTINI, Chiara; FASCHING, Peter A.; POGUE-GEILE, Katherine L.; MANO, Max S.; UNTCH, Michael; WOLMARK, Norman; HUANG, Chiun-Sheng; LOIBL, Sibylle; MAMOUNAS, Eleftherios P.; JR, Charles E. Geyer; LUCAS, Peter C.; BOULET, Thomas; SONG, Chunyan; LEWIS, Gail D.; NOWICKA, Malgorzata; HAAS, Sanne de; BASIK, MarkPurpose: In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzu-mab in patients with residual invasive breast cancer after neoad-juvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.Experimental Design: Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molec-ular Subtyping. HER2 expression on paired pre-and post-NAT samples was examined.Results: T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32-3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56-1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44-1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59-1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.Conclusions: T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
- Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial(2015) HURVITZ, Sara A.; ANDRE, Fabrice; JIANG, Zefei; SHAO, Zhimin; MANO, Max S.; NECIOSUP, Silvia P.; TSENG, Ling-Min; ZHANG, Qingyuan; SHEN, Kunwei; LIU, Donggeng; DREOSTI, Lydia M.; BURRIS, Howard A.; TOI, Masakazu; BUYSE, Marc E.; CABARIBERE, David; LINDSAY, Mary-Ann; RAO, Shantha; PACAUD, Lida Bubuteishvili; TARAN, Tetiana; SLAMON, DennisBackground mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. Methods In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2: 1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2) on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395. Findings Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41.3 months (IQR 35.4-46.6). In the full population, median progression-free survival was 14.95 months (95% CI 14.55-17.91) with everolimus versus 14.49 months (12.29-17.08) with placebo (hazard ratio 0.89, 95% CI 0.73-1.08; p=0.1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20.27 months (95% CI 14.95-24.08) versus 13.08 months (10.05-16.56) with placebo (hazard ratio 0.66, 95% CI 0.48-0.91; p=0.0049); however, the protocol-specified significance threshold (p=0.0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. Interpretation Although progression-free survival was not significantly different between groups in the full analysis population, the 7.2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial.
- Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer(2019) SALES, Allan Robson Kluser; NEGRAO, Marcelo Vailati; TESTA, Laura; FERREIRA-SANTOS, Larissa; GROEHS, Raphaela Villar Ramalho; CARVALHO, Bruna; TOSCHI-DIAS, Edgar; ROCHA, Natalia Galito; LAURINDO, Francisco Rafael Martins; DEBBAS, Victor; RONDON, Maria Urbana P. B.; MANO, Max Sena; HAJJAR, Ludhmila Abrahao; HOFF, Paulo Marcelo Gehm; KALIL FILHO, Roberto; NEGRAO, Carlos EduardoThe purpose of the present study was to test the hypothesis that doxorubicin (DX) and cyclophosphamide (CY) adjuvant chemotherapy (CHT) acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Sixteen women (age: 47.0 +/- 2.0 yr; body mass index: 24.2 +/- 1.5 kg/m) with stage II-III breast cancer and indication for adjuvant CHT underwent two experimental sessions, saline (SL) and CHT. In the CHT session, DX (60 mg/m (2)) and CY (600 mg/m(2)) were administered over 45 min. In the SL session, a matching SL volume was infused in 45 min. Muscle sympathetic nerve activity (MSNA) from peroneal nerve (microneurography), calf blood flow (CBF; plethysmography) and calf vascular conductance (CVC), heart rate (HR; electrocardiography), and beat-to-beat blood pressure (BP: finger plethysmography) were measured at rest before, during, and after each session. Venous blood samples (5 ml) were collected before and after both sessions for assessment of circulating endothelial microparticles (EMPs: flow cytometry). a surrogate marker for endothelial damage. MSNA and BP responses were increased (P < 0.001), whereas CBF and CVC responses were decreased (P < 0.001), during and after CHT session when compared with SL session. Interestingly, the vascular alterations were also observed at the molecular level through an increased EMP response to CHT (P = 0.03, CHT vs. SL session). No difference in HR response was observed (P > 0.05). Adjuvant CHT with DX and CY in patients treated for breast cancer increases sympathetic nerve activity and circulating EMP levels and, in addition, reduces muscle vascular conductance and elevates systemic BP. These responses may be early signs of CHT-induced cardiovascular alterations and may represent potential targets for preventive interventions. NEW & NOTEWORTHY It is known that chemotherapy regimens increase the risk of cardiovascular events in patients treated for cancer. Here, we identified that a single cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide in women treated for breast cancer dramatically increases sympathetic nerve activity and circulating endothelial microparticle levels, reduces the muscle vascular conductance, and elevates systemic blood pressure.
- Neoadjuvant endocrine therapy in breast cancer: current role and future perspectives(2016) BARROSO-SOUSA, Romualdo; SILVA, Danilo D. A. Fonseca Reis; ALESSI, Joao Victor Machado; MANO, Max SennaLuminal breast cancer, as defined by oestrogen and/or progesterone expression by immunohistochemistry, accounts for up to 75% of all breast cancers. In this population, endocrine therapy is likely to account for most of the gains obtained with the administration of adjuvant systemic treatment. The role of adjuvant chemotherapy in these patients remains debatable since it is known that only a small fraction of patients will derive meaningful benefit from this treatment whilst the majority will be exposed to significant and unnecessary chemotherapy-related toxicities, in particular the elderly and frail. Therefore, neoadjuvant endocrine therapy (NET) becomes an attractive option for selected patients with hormonal-receptor positive locally advanced breast cancer. In this review, we discuss the current role of NET and future perspectives in the field.
- Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity(2018) AVILA, Monica Samuel; AYUB-FERREIRA, Silvia Moreira; WANDERLEY JR., Mauro Rogerio de Barros; CRUZ, Fatima das Dores; BRANDAO, Sara Michelly Goncalves; RIGAUD, Vagner Oliveira Carvalho; HIGUCHI-DOS-SANTOS, Marilia Harumi; HAJJAR, Ludhmila Abrahao; KALIL FILHO, Roberto; HOFF, Paulo Marcelo; SAHADE, Marina; FERRARI, Marcela S. M.; COSTA, Romulo Leopoldo de Paula; MANO, Max Senna; CRUZ, Cecilia Beatriz Bittencourt Viana; ABDUCH, Maria Cristina; ALVES, Marco Stephan Lofrano; GUIMARAES, Guilherme Veiga; ISSA, Victor Sarli; BITTENCOURT, Marcio Sommer; BOCCHI, Edimar AlcidesBACKGROUND Anthracycline (ANT) chemotherapy is associated with cardiotoxicity. Prevention with beta-blockers remains controversial. OBJECTIVES This prospective, randomized, double-blind, placebo-controlled study sought to evaluate the role of carvedilol in preventing ANT cardiotoxicity. METHODS The authors randomized 200 patients with HER2-negative breast cancer tumor status and normal left ventricular ejection fraction (LVEF) referred for ANT (240 mg/m(2)) to receive carvedilol or placebo until chemotherapy completion. The primary endpoint was prevention of a >= 10% reduction in LVEF at 6 months. Secondary outcomes were effects of carvedilol on troponin I, B-type natriuretic peptide, and diastolic dysfunction. RESULTS Primary endpoint occurred in 14 patients (14.5%) in the carvedilol group and 13 patients (13.5%) in the placebo group (p = 1.0). No differences in changes of LVEF or B-type natriuretic peptide were noted between groups. A significant difference existed between groups in troponin I levels over time, with lower levels in the carvedilol group (p = 0.003). Additionally, a lower incidence of diastolic dysfunction was noted in the carvedilol group (p = 0.039). A nonsignificant trend toward a less-pronounced increase in LV end-diastolic diameter during the follow-up was noted in the carvedilol group (44.1 +/- 3.64 mm to 45.2 +/- 3.2 mm vs. 44.9 +/- 3.6 mm to 46.4 +/- 4.0 mm; p = 0.057). CONCLUSIONS In this largest clinical trial of beta-blockers for prevention of cardiotoxicity under contemporary ANT dosage, the authors noted a 13.5% to 14.5% incidence of cardiotoxicity. In this scenario, carvedilol had no impact on the incidence of early onset of LVEF reduction. However, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction.(Carvedilol Effect in Preventing Chemotherap-Induced Cardiotoxicity [CECCy] NCTO1724450)(C) 2018 by the American College of Cardiology Foundation.