MAX SENNA MANO
Projetos de Pesquisa
Unidades Organizacionais
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject THE ENCHANTTM TRIAL: AN OPEN LABEL MULTICENTER PHASE 2 WINDOW OF OPPORTUNITY STUDY EVALUATING GANETESPIB (STA-9090) MONOTHERAPY IN WOMEN WITH PREVIOUSLY UNTREATED METASTATIC HER2 POSITIVE OR TRIPLE NEGATIVE BREAST CANCER (TNBC)(2012) CAMERON, D.; MANO, M. S.; VUKOVIC, V.; TEOFILOVICI, F.; BRADLEY, R.; AWADA, A.Background Hsp90 is a molecular chaperone required for proper folding and activation of many cancer-promoting proteins. Several Hsp90 clients are oncoproteins known to play a key role in the pathobiology of breast cancer, including HER2, p95-HER2, EGFR, ER, PI3K, AKT, and VEGFR. The inactivation of these oncoproteins by Hsp90 inhibition is a promising approach for breast cancer therapy. Ganetespib is an Hsp90 inhibitor which has shown anti-tumor activity in heavily pretreated patients with lung, breast, and other cancers. Ganetespib is well tolerated without severe liver or common ocular toxicities. In a phase 2 trial, 22 breast cancer patients who had received up to 3 prior lines of chemotherapy including trastuzumab were treated with ganetespib monotherapy. In patients with HER2+ disease, the objective response rate (ORR) was 15% (2/13) and the SD rate was 46% (6/13). Only 3 patients presented with TNBC; one of those patients achieved SD with substantial tumor shrinkage on treatment. Methods This is a single arm international open-label Phase 2 study in patients with HER2 amplified, or triple negative breast cancer. Patients must not have received any prior therapy in the metastatic setting. Prior adjuvant therapy is allowed. Primary endpoint: ORR. Main secondary endpoints include disease control rate, and progression free survival. Additionally, fresh biopsies and serum samples are collected from all patients for determination of predictors of response and mechanisms of resistance to treatment. Patients are treated with ganetespib 150 mg/m2 is given twice weekly of a 4-week cycle for up to 12 weeks. A total of 70 patients are planned for accrual. At the time of submission, the study is receiving IRB approvals in several centers.conferenceObject A randomized, open-label, phase II study of lapatinib/capecitabine, lapatinib/vinorelbine, or lapatinib/gemcitabine in patients with ErbB2-amplified metastatic breast cancer progressing after taxane treatment: Results of an interim analysis (GLICO-0801/EGF111792)(2012) GOMEZ, Henry Leonidas; NECIOSUP, Silvia P.; TOSELLO, Celia; XAVIER, Patricia; NASCIMENTO, Yeni Neron do; FANELLI, Marcelo; ISMAEL, Gustavo; BINES, Jose; SAMPAIO, Carlos; LERZO, Guillermo Luis; CAPO, Adolfo Miguel; MANO, Max S.; FEIN, Luis; WERUTSKY, Gustavo; BARRIOS, Carlos H.Background: Lapatinib-capecitabine is approved for the treatment of ErbB2-amplified metastatic breast cancer (MBC) after failure to anthracyclines, taxanes and trastuzumab. GLICO-0801 evaluates different lapatinib-based chemotherapy combinations as 1st/2nd line treatment for ErbB2 amplified MBC progressing after taxane treatment. We present the results of a planned safety interim analysis. Methods: This is an open-label, randomized, international, phase II trial exploring lapatinib (L) 1250mg qd in combination with capecitabine 2000mg/m2 d 1-14 (Arm A) or vinorelbine 25mg/m2 d 1 and 8 (Arm B) or gemcitabine 1000mg/m2 d 1 and 8 (Arm C). Primary objective is to determine the clinical benefit rate (defined as CR+PR+SD for ≥24 weeks). This trial is registered at www.clinicaltrials.gov number: NCT01050322 Results: The first83 randomized patients (pts) (Arm A=29, B=28 and C=26) were included in this analysis. Of them, 65 (78%) have discontinued therapy with mean number of cycles of 4.7, 6.2 and 7.5 in arms A, B and C respectively. Eighteen (21%) pts are still on treatment. Median age was 52y (29-84); 80 pts (96%) had PS 0-1; 51 (61%) were postmenopausal. Fifty-six pts (67%) had visceral metastasis, 52 (63%) were treated as 2nd line therapy and 36 (43%) had received prior trastuzumab. Most reported adverse events (AE) (87%) were grade 1-2. The most common AE (any grade) in arm A: diarrhea 72%, hand-foot syndrome 45%, vomiting 39%, anemia 36%; in arm B: diarrhea 75%, neutropenia 68%, nausea 43%, vomiting 39%; in arm C: diarrhea 72%, neutropenia 60%, anemia 44%, increase in ALT 44%. The most frequent serious AE reported in arm A: diarrhea in 3 pts (10%) and thrombocytopenia in 2 pts (7%); in arm B: febrile neutropenia in 2 pts (7%) and in arm C: sepsis in 1 pt (4%). There was one toxic death related to chemotherapy in arm C. Conclusions: There were no unexpected toxicities so far in this trial with most AEs being mild to moderate and manageable. This interim analysis supports the continuation of the study.conferenceObject CARDIAC SAFETY OF (NEO) ADJUVANT TRASTUZUMAB IN THE BRAZILIAN COMMUNITY SETTING: A SINGLE CENTER EXPERIENCE(2012) FONSECA, L. G.; TAKAHASHI, T. K.; MAK, M. P.; BARROSO-SOUSA, R.; TESTA, L.; HELENA, V. Petry; COSTA, R. De Paula; HOFF, P. M.; MANO, M. S.Background Trastuzumab-associated cardiotoxicity (TAC) has been established in the context of clinical trials. However, when newly registered agents are used in a broader patient population, their safety profile does not always mirror that of the pivotal trials. Trastuzumab (T) only became available in the Brazilian public sector in 2008 and herein we report our off-trial experience so far. Methods Retrospective, single center cohort of HER-2 positive breast cancer patients (pts) treated with (neo)adjuvant chemotherapy and T from July 2008 to March 2012. 95.3% were treated according to local protocol (11.4% TCH; 83.9% AC-TH). Major cardiac event (MCE) was defined as a left ventricular ejection fraction (LVEF) drop of 10% and absolute drop to < 50 % by echocardiogram (ECHO) or as symptomatic heart failure (HF) regardless of the LVEF value or any cardiac event considered clinically meaningful. A multivariable Cox proportional hazards model was used to control for other cardiac risk factors. Results 237 women were identified: median age 53 y (27-83), 99.6% ECOG-PS 0-1, median body mass index 27.4 kg/m2 (17 – 46), 30.4% had hypertension (HTN), 8.8% had diabetes mellitus (DM), 5.9% had previous cardiopathy. 54.8% had ER-positive tumors; 40.7% received neoadjuvant T; most were stage II or III (22.3% and 37.1%). Median number of ECHO assessments was 2.7 (0-6); 136 pts (57.2%) completed T as planned. 20.2% had MCE (13.9% discontinued T). 3.8% discontinued T due to symptomatic HF and 5% for non-cardiac reasons. 41.6% of MCE pts recovered cardiac function. Median initial LVEF was 64.83 ± 1.5 % (no event) vs 64.81 ± 1.5 % (MCE) p = 0.26; median 3-month LFVE was 64.67 ± 4 % (no event) vs 56.12 ± 3 % (MCE) p = 0.0036. HTN, DM, obesity, age, radiotherapy, use of anthracycline and previous cardiopathy were not significantly associated with TAC. Conclusions Our results suggest that TAC in our routine practice is slightly higher than reported in literature (6 to 17%), possibly reflecting selection bias in clinical trials. Symptomatic TAC was as expected for AC-TH (4%). We failed to identify risk factors for TAC, possibly due to the low number of events. Cardiac function must be closely monitored during T treatment and careful pt selection is crucial.conferenceObject Discordance between Oncotype Dx and Saint Gallen criteria, Adjuvant!, NCCN 2011 guidelines, and initial physician treatment recommendation(2012) PEREIRA, Allan Andresson Lima; SANTINI, Fernando Costa; SHIMADA, Andrea Kazumi; NASCIMENTO, Ellen Caroline; KATZ, Artur; MANO, Max S.Background: The Oncotype Dx recurrence score (RS) assay quantifies the risk of distant recurrence (rDR) and its use has increased despite the lack of prospective studies. Methods: This is a cross sectional retrospective study of consecutive patients (PTS) from our institution with histologically confirmed invasive breast cancer who underwent surgery with curative intent and in whom Oncotype was performed. The main objectives were to compare (1) the predicted rDR by RS and Adjuvant! (2) Risk allocation by RS and St Gallen Criteria, (3) chemotherapy indication according to RS results and NCCN guidelines and (4) to evaluate the impact of RS results on the recommendation of adjuvant chemotherapy (aCT). Results: Between October/2006-June/2011, 74 PTS were evaluated. Forty seven (63,5%) were EC IA and all had estrogen receptor positive; axillary lymph node involvement was seen in 19 PTS (13 micro and 6 macrometastasis). The rDR by RS was low in 50 PTS (67%), intermediate in 19 (26%) and high in 5 (7%). According to Saint Gallen, 7 (9%), 51 (69%) and 14 PTS (19%) were classified as low, intermediate and high risk, respectively. There was a statistical significant discordance between risk allocation according to RS and Saint Gallen (Kappa coefficient=-0.002; p=0.971). Among the 55 node-negative PTS, there was also a statistical significant discordance between the predicted average rDR, obtained from Oncotype, and Adjuvant! with median risk of 8,5% vs 15,7%, respectively (p = 0.00001 rank sum Mann Whitney test). The NCCN 2011 would have indicated aCT to 62 PTS. Among 55 classified as low and high risk by RS, the NCCN would have indicated aCT to 46 PTS. In other words, 89% (41) of PTS who would receive aCT by NCCN were classified as low risk by RS, with a statistically significant discordance (Kappa coefficient=0.035, p=0.328). Conclusions: Oncotype changed the medical management in 28 (55%) of 51 PTS in which the initial intention of the physician was known. Of these, 93% were spared aCT. We found no statistical significant concordance among the Saint Gallen, Adjuvant! or NCCN guidelines with Oncotype Dx. The rDR may be overestimated by clinicopathological-based classifications.conferenceObject Feasibility of two schedules of weekly paclitaxel as (neo)adjuvant treatment for patients (PTS) with HER2-negative breast cancer (BC) in the Brazilian community setting(2012) SANTANA, Iuri Amorim; OLIVEIRA, Julia Andrade De; AMARAL, Alan Alves; TESTA, Laura; LANDEIRO, Luciana Garcia; COSTA, Romulo Leopoldo de Paula; HAJIME, Marcelo; FERRARI, Marcela Simonis Martins; PETRY, Vanessa; COHN, Daniela J. B. Heinemann; HOFF, Paulo M.; MANO, Max S.conferenceObject Metronomic chemotherapy (MC) in the neoadjuvant setting: Results of two parallel feasibility trials in patients (pts) with HER2 positive (HER2+) and negative (HER2-) locally advanced breast cancer (LABC) (Traq-Me and TAME)(2012) PETRY, Vanessa; LEAL, Alessandro; ARAI, Roberto J.; MARINHO, Simone; PAIVA, Marcelo; PIATO, Jose R.; ROSA, Marcio; HOFF, Paulo M.; MANO, Max S.conferenceObject Metronomic chemotherapy (MC): Results of two feasibility trials in patients (pts) with HER2 positive (HER2+) and negative (HER2-) locally advanced breast cancer (LABC)(2012) PETRY, Vanessa; LEAL, Alessandro; ARAI, Roberto J.; PIATO, Jose R.; ANDRADE, Felipe; PAIVA, Marcelo; FERRAZ, Marcio R.; MARINHO, Simone; HOFF, Paulo Marcelo; MANO, Max S.Background: In SWOG0012, MC improved pathologic complete response (pCR) compared to standard neoadjuvant chemotherapy (NC). We evaluated the feasibility of MC with a taxane->anthracycline schedule, which has also been shown potentially superior to the inverse sequence. We also evaluated the feasibility of MC in combination with trastuzumab. Methods: The primary objective was feasibility (defined as a febrile neutropenia (FN) rate ≤10%). Secondary objectives were cardiac safety, tolerability and efficacy as measured by objective response and pCR. The original accrual goal was 25 Her2+ pts and 40 Her2- pts. Her2- pts received paclitaxel (100mg/m2) x8 weeks followed by doxorubicin (24mg/m2) x9 weeks combined with oral cyclophosphamide (100mg/day), without G-CSF. Her2+ pts also received weekly trastuzumab (4 mg/kg followed by 2mg/kg) concurrently with the entire CT. Results: Most pts were stage III (Her+: 8/9; Her-: 4/11). The Her2+ cohort was prematurely closed after 2(22%) pts developed G3 pneumonitis (both during the MC phase). Both recovered completely. There was 1 case of asymptomatic LVEF drop to below 50% (during the taxane phase); 1 pt had G2 hand-foot skin reaction (HFS) and another had G2 mucositis. The Her2- cohort was also prematurely closed with only 11 pts due to high rates of mucocutaneous toxicity (G3 HFS in 36%, G3 rash in 9%) and also because of SWOG0221 negative results. There were 2(18%) cases of FN, but no cases of pneumonitis. 1/11(9%) Her2- and 5/9(55%) Her2 + pts had a pCR. VEGF-related biomarkers were collected and will be presented at a later date. Conclusions: The proposed MC schedules proved too toxic to be considered for further clinical development. In addition, MC resulted in unexpectedly high rates of severe pulmonary toxicity when given in combination with trastuzumab. Her2+ but not Her2- pts had an impressively high pCR rate.