MAX SENNA MANO
Projetos de Pesquisa
Unidades Organizacionais
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
7 resultados
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- Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer(2019) MINCKWITZ, G. von; HUANG, C. -S.; MANO, M. S.; LOIBL, S.; MAMOUNAS, E. P.; UNTCH, M.; WOLMARK, N.; RASTOGI, P.; SCHNEEWEISS, A.; REDONDO, A.; FISCHER, H. H.; JACOT, W.; CONLIN, A. K.; ARCE-SALINAS, C.; WAPNIR, I. L.; JACKISCH, C.; DIGIOVANNA, M. P.; FASCHING, P. A.; CROWN, J. P.; WUELFING, P.; SHAO, Z.; CAREMOLI, E. Rota; WU, H.; LAM, L. H.; TESAROWSKI, D.; SMITT, M.; DOUTHWAITE, H.; SINGEL, S. M.; GEYER JR., C. E.BACKGROUND Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. METHODS We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). RESULTS At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. CONCLUSIONS Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone.
- 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.
- Patient-reported outcomes from KATHERINE: A phase 3 study of adjuvant trastuzumab emtansine versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for human epidermal growth factor receptor 2-positive breast cancer(2020) CONTE, PierFranco; SCHNEEWEISS, Andreas; LOIBL, Sibylle; MAMOUNAS, Eleftherios P.; MINCKWITZ, Gunter von; MANO, Max S.; UNTCH, Michael; HUANG, Chiun-Sheng; WOLMARK, Norman; RASTOGI, Priya; D'HONDT, Veronique; REDONDO, Andres; STAMATOVIC, Ljiljana; BONNEFOI, Herve; CASTRO-SALGUERO, Hugo; FISCHER, Hans H.; WAHL, Tanya; SONG, Chunyan; BOULET, Thomas; TRASK, Peter; GEYER JR., Charles E.Background The phase 3 KATHERINE trial demonstrated significantly improved invasive disease-free survival with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. Methods Patients who received taxane- and trastuzumab-containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T-DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and breast cancer module (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6- and 12-month follow-up visits. Results Of patients who were randomly assigned to T-DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and >= 1 postbaseline assessments. No clinically meaningful changes (>= 10 points) from baseline in mean QLQ-C30 and QLQ-BR23 scores occurred in either arm. More patients receiving T-DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6-month follow-up assessment, except for role functioning (23% vs 16%). Conclusion These data suggest that health-related quality of life was generally maintained in both study arms over the course of treatment.
- 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.
- Feasibility of two schedules of weekly paclitaxel in HER2-negative early breast cancer in a Brazilian community setting(2016) SANTANA, Iuri A.; OLIVEIRA, Julia Andrade; LIMA, Julianne Maria da Silva; TESTA, Laura; PIATO, Jose Roberto M.; HOFF, Paulo M.; MANO, Max S.Weekly paclitaxel has been shown more effective and less toxic than the conventional three-weekly administration. The GEICAM 9906 demonstrated effectiveness and safety of a dose-dense schedule of 100 mg/m(2) of paclitaxel given over 8 weeks (w). This schedule has been adopted at our institution in 2009 for HER2-negative disease, and herein, we present the first off-trial experience and compare its safety profile with that of a historical cohort of patients treated with the conventional 80 mg/m(2) over 12 w schedule. Retrospective single-center chart review of patients with locally advanced breast cancer treated with (neo)adjuvant paclitaxel-based therapy from 2008 to 2012 with (1) 80 mg/m(2) for 12 w or (2) 100 mg/m(2) for 8 w. Adverse events were graded according to common terminology criteria for adverse events (CTCAE) 4.0. A total of 326 patients were analyzed. Median age was 52 (+/- 10.9). Seventy and 256 patients received schedule (1) and (2), respectively. No significant difference was observed in the incidence of grade (G) 3/4 toxicity: pneumonitis (2.8 vs 0.3 % p = 0.097); neuropathy (2.8 vs 0.7 % p = 0.303); hand-foot syndrome (1.4 vs 0.3 % p = 0.538); anemia (0 vs 0.6 % p = 0.624); and neutropenia (5.7 vs 6.2 % p = 0.408). Also, no significant difference was seen when comparing all grades toxicity. Schedule (2) had higher dose intensity: 97.72 vs 77.07 mg/m(2) per week (p < 0.0001). Weekly paclitaxel given according to GEICAM 9906 is pragmatic and well tolerated, with safety profile consistent with the conventional schedule. In addition to being convenient to patients, it may also be cost-effective because of a lower number of clinic visits and infusions.
- Exploring disparities in incidence and mortality rates of breast and gynecologic cancers according to the Human Development Index in the Pan-American region(2017) MARTINEZ-MESA, J.; WERUTSKY, G.; MICHIELS, S.; PEREIRA FILHO, C. A. S.; DUENAS-GONZALEZ, A.; ZARBA, J. J.; MANO, M.; VILLARREAL-GARZA, C.; GOMEZ, H.; BARRIOS, C. H.Objective: To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region. Study design: Ecological analysis. Methods: Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed. Results: The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence beta = 4.03 (95% confidence interval [CI] 2.61; 5.45) P < 0.001, breast cancer mortality beta = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR beta = -0.705 (95% CI 0.704; 0.706) P < 0.001; in cervical cancer incidence beta = -3.28 (95% CI -4.78; -1.78) P < 0.001, cervical cancer mortality beta = -4.63 (95% CI -6.10; -3.17) P < 0.001, and cervical cancer-MIR beta = -1.35 (95% CI -1.83; -0.87) P < 0.001; in ovarian cancer incidence beta = 3.26 (95% CI 1.78; 4.75) P < 0.001, ovarian cancer mortality beta = 1.82 (95% CI.0.44; 3.20) P = 0.012, and ovarian cancer-MIR beta = 5.10 (95% CI 3.22; 6.97) P < 0.001; in corpus uteri cancer incidence beta = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality beta = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR beta = -2.30 (95% CI -3.19; -1.40) P < 0.001. Conclusions: A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan-American region.
- Clinical impact of adjuvant radiation therapy delay after neoadjuvant chemotherapy in locally advanced breast cancer(2018) SILVA, Saulo Brito; PEREIRA, Allan Andresson Lima; MARTA, Gustavo Nader; LIMA, Kennya Medeiros Lopes de Barros; FREITAS, Thiago Brasileiro de; MATUTINO, Adriana Reis Brandao; SOUZA, Manoel Carlos Leonardi de Azevedo; AZEVEDO, Renata Gondim Meira Velame de; VIVEIROS, Pedro Antonio Hermida de; LIMA, Julianne Maria da Silva; FILASSI, Jose Roberto; CARVALHO, Heloisa de Andrade; PIATO, Jose Roberto Morales; MANO, Max S.Background: and Purpose: Post-operative radiation therapy (PORT) is usually indicated for patients with breast cancer (BC) after neoadjuvant chemotherapy (NAC) and surgery. However, the optimal timing to initiation of PORT is currently unknown. Material and methods: We retrospectively evaluated data from patients with BC who received PORT after NAC and surgery at our institution from 2008 to 2014. Patients were categorized into three groups according to the time between surgery and PORT: < 8 weeks, 8-16 weeks and > 16 weeks. Results: A total of 581 patients were included; 74% had clinical stage III. Forty-three patients started PORT within 8 weeks, 354 between 8 and 16 weeks and 184 beyond 16 weeks from surgery. With a median follow-up of 32 months, initiation of PORT up to 8 weeks after surgery was associated with better disease-free survival (DFS) (< 8 weeks versus 8-16 weeks: HR 0.33; 95% CI 0.13-0.81; p = 0.02; < 8 weeks versus > 16 weeks: HR 0.38; 95% CI 0.15-0.96; p = 0.04) and better overall survival (OS) (< 8 weeks versus 8-16 weeks: HR 0.22; 95% CI 0.05-0.90; p = 0.036; < 8 weeks versus > 16 weeks: HR 0.28; 95% CI 0.07-1.15; p = 0.08). Conclusion: PORT started up to 8 weeks after surgery was associated with better DFS and OS in locally-advanced BC patients submitted to NAC. Our findings suggest that early initiation of PORT is critically important for these patients. However, the low numbers of patients and events in this study prevent us from drawing firm conclusions.