ROBERTO HEGG
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina - Docente
LIM/58 - Laboratório de Ginecologia Estrutural e Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/58 - Laboratório de Ginecologia Estrutural e Molecular, Hospital das Clínicas, Faculdade de Medicina
6 resultados
Resultados de Busca
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- Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial(2012) ISMAEL, Gustavo; HEGG, Roberto; MUEHLBAUER, Susanne; HEINZMANN, Dominik; LUM, Bert; KIM, Sung-Bae; PIENKOWSKI, Tadeusz; LICHINITSER, Mikhail; SEMIGLAZOV, Vladimir; MELICHAR, Bohuslav; JACKISCH, ChristianBackground A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. Methods The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1: 1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C-trough) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0.80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12.5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. Findings 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C-trough was 51.8 mu g/mL (coefficient of variation 52.5%) in the intravenous group and 69.0 mu g/mL (55.8%) in the subcutaneous group. The geometric mean ratio of C-trough subcutaneous to C-trough intravenous was 1.33 (90% CI 1.24-1.44). 107 (40.7%) of 263 patients in the intravenous group and 118 (45.4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4.7% (95% CI -4.0 to 13.4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33.2%] of 298 patients in the intravenous group vs 86 [29.0%] of 297 in the subcutaneous group), leucopenia (17 [5.7%] vs 12 [4.0%]), and febrile neutropenia (10 [3.4%] vs 17 [5.7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8.1%] in the subcutaneous group vs 13 [4.4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two-both in the subcutaneous group-were deemed to be treatment related. Interpretation Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.
- Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer(2012) BASELGA, Jose; CORTES, Javier; KIM, Sung-Bae; IM, Seock-Ah; HEGG, Roberto; IM, Young-Hyuck; ROMAN, Laslo; PEDRINI, Jose Luiz; PIENKOWSKI, Tadeusz; KNOTT, Adam; CLARK, Emma; BENYUNES, Mark C.; ROSS, Graham; SWAIN, Sandra M.BACKGROUND The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.)
- Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer(2012) PIRES, L. A.; HEGG, R.; FREITAS, F. R.; TAVARES, E. R.; ALMEIDA, C. P.; BARACAT, E. C.; MARANHAO, R. C.Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.
- Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study(2012) KUTER, Irene; GEE, Julia M. W.; HEGG, Roberto; SINGER, Christian F.; BADWE, Rajendra A.; LOWE, Elizabeth S.; EMERIBE, Ugochi A.; ANDERSON, Elizabeth; SAPUNAR, Francisco; FINLAY, Pauline; NICHOLSON, Robert I.; BINES, Jose; HARBECK, NadiaNEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.
conferenceObject BIOMARKER (BM) ANALYSES OF A PHASE II STUDY OF NEOADJUVANT PERTUZUMAB AND TRASTUZUMAB WITH AND WITHOUT ANTHRACYCLINE (ATC)-CONTAINING CHEMOTHERAPY FOR TREATMENT OF HER2-POSITIVE EARLY BREAST CANCER (BC) (TRYPHAENA)(2012) SCHNEEWEISS, A.; CHIA, S.; HEGG, R.; TAUSCH, C.; DEB, R.; RATNAYAKE, J.; KIERMAIER, A.; MCNALLY, V.; ROSS, G.; CORTES, J.Background TRYPHAENA showed that concurrent administration of trastuzumab (H) plus pertuzumab (P) with ATC in the neoadjuvant setting resulted in similar cardiac tolerability to sequential administration of ATC or to an ATC-free regimen. In addition, neoadjuvant P with H administered in combination with ATC- or carboplatin-based standard chemotherapy (CT) resulted in high pathological complete response (pCR, [ypT0/is]) rates, regardless of the CT regimen, in patients (pts) with HER2-positive BC. The molecular profile of pts who achieved a pCR was compared with those who did not. Methods Baseline core biopsies and sera from over 90% of the 225 pts enrolled in TRYPHAENA were available for BM analyses. The BMs and methods of assessment included: HER1/2/3, PTEN, and IGF1R protein expression by IHC (and FISH for HER2); HER1/2/3 mRNA expression by qRT-PCR; c-myc and TOP2A by FISH and PCR-based PIK3CA analyses detecting 8 mutations. Potential relationships between BMs and pCR were measured primarily using categorical analysis methods (chi-square test of association and Cochran–Mantel–Haenszel statistic). Median values were used as cut-offs except for TOP2A and PTEN where cut-offs were applied following a biologic rationale. Results Besides HER2 protein levels, no other measured BM was associated with pCR when BM samples from pts in each treatment arm were considered separately. TOP2A amplification (≥ 2.0 ratio) was observed in 32% of pts and was not associated with response to ATC regimen. There is no strong biologic rationale for correlation between BMs and pCR outcomes after treatment with different CT regimens; therefore, data from all pts were pooled. In the combined analysis, HER2 protein levels remained significantly correlated with pCR and high levels of HER2 mRNA were also indicative of improved pCR rates. PIK3CA mutations were seen in 24% of pts and were not associated with pCR. Conclusion This analysis supports the use of HER2 overexpression as the strongest predictive and clinically relevant BM for pCR after treatment with H + P + CT neoadjuvant regimen for pts with HER2-positive BC.conferenceObject IMMUNOGENICITY OF TRASTUZUMAB INTRAVENOUS AND SUBCUTANEOUS FORMULATIONS IN THE PHASE III HANNAH STUDY(2012) HEGG, R.; PIENKOWSKI, T.; CHEN, S.; STAROSLAWSKA, E.; FALCON, S.; KOVALENKO, N.; AL-SAKAFF, N.; HEINZMANN, D.; KOLAITIS, G.; ISMAEL, G.Background HannaH demonstrated non-inferiority of the fixed-dose subcutaneous (SC) formulation of trastuzumab (H) to the intravenous (IV) formulation, based on pharmacokinetics (Ctrough) and efficacy (pathological complete response [pCR]) (Jackisch et al, EBCC 2012). We report on efficacy and safety in relation to immunogenicity (anti-drug antibodies [ADAs]). Methods Blood samples for ADA testing were drawn at baseline (BL), then day 1 of cycles 2, 5 (pre-surgery), 13 and 18 (post-surgery) and at months 3, 6, 12, 18 and 24 following last H dose. Screening for ADAs to H and rHuPH20 was by bridging immunoassays. Positive (pos) samples were re-tested, with confirmed pos patients (pts) then tested for neutralizing antibodies (abs). Relationship between ADAs (against H and/or rHuPH20) with respect to, efficacy (pCR) and safety (infusion-related reactions, IRRs) was investigated. Results The median follow-up (FU) (including ADA testing) was ∼12.3 months. At BL, 5.9% of pts (17/290) in the IV arm and 4.2% of pts (12/287) in the SC arm were pos for ADAs to H. Post-BL (treatment and FU), 3.4% (10/295) and 6.8% (20/295) pts in IV and SC, respectively were pos for ADAs to H. One pt was confirmed pos twice (non-consecutive time points). At BL, 7.6% of pts (22/290) in the SC arm were pos for ADAs to rHuPH20. Post-BL, the rate was 11.5% (34/295). Titer ranges post-BL were similar to those observed pre-BL. One pt was pos for ADAs to both H and rHuPH20. No neutralizing ADAs to H or rHuPH20 were seen. The pCR rate did not differ significantly between Anti-H ab (AHA)-pos (30% [IV n = 10], 55% [SC n = 20]) and AHA-neg (36.5% [IV n = 10], 41.6% [SC n = 20]) pts. Anti-rHuPH20 status did not correlate with pCR rates (41.2% [pos n = 34] vs 41.7% [neg n = 254]) in the SC arm. In pts given H SC or H IV, occurrences of IRRs were similar in AHA-neg (46.3% [SC n = 255] 37.6% [IV n = 263]) and -pos (40% [SC n = 20] 25% [IV n = 10]) pts. The incidence of pts with an IRR was similar in both anti-rHuPH20 status groups (SC arm only; neg 44.5% [n = 254], pos 41.2% [n = 34]). Conclusion Using a highly sensitive assay, ADAs against both H (IV/SC) and rHuPH20 (SC only) were observed transiently and were of no relevance in terms of efficacy or safety. Immunogenicity monitoring in the study is ongoing.