Trastuzumab In Breast Cancer Patients Research Articles

Neoadjuvant trastuzumab and sequential chemotherapy with cisplatin, vinorelbine, and docetaxel for stage II-III breast cancer patients: Final results of a single institution phase II study.

e11527 Background: Several studies demonstrated the efficacy of neoadjuvant trastuzumab in breast cancer patients. However, cardiotoxicity intrinsic and increased by combining anthracyclines or chest wall radiotherapy remains a ticklish issue, mainly when is durable and occurs in potentially healable young patients. Methods: A phase II study of neoadjuvant trastuzumab and sequential chemotherapy was started in the late 2007 at Humanitas CCO and enrolled 42 patients with stage II-III HER2-positive breast cancer. Treatment consisted of 18 administrations of weekly trastuzumab combined with a sequential regimen including 3 courses of cisplatin 80 mg/m2 d1 + vinorelbine 25 mg/m2 d1 and d8 q3w followed by 3 courses of docetaxel 100 mg/m2d1 q3w. Peg-filgrastim was given in each course. Postoperative trastuzumab q3w was administered for one year. Radiant and endocrine therapy were delivered according to standard practice. Primary objective was the rate of pathologic complete response (pCR), now defined as no evidence of residual invasive cancer, both in breast and lymph nodes. A first report of the study was presented as poster at ASCO 2010. Results: With regard to real patient characteristics observed in the daily clinical practice, no restrictive sample selection was established and the eligible patients were accrued consecutively. Median age was 48 (range 23-71). Twenty-three patients (55%) had stage III tumors and 7 of them stage IIIB, including 4 cases of tumor spreading to skin (T4b) and 3 cases of inflammatory carcinoma (T4d). Seventeen patients (40%) had tumor with no expression of hormone receptors and 36 (86%) with ki67≥14%. The rate of pCR was 26% (11/42). Among 29 women initially candidate to radical mastectomy, 13 of them (45%) finally received breast-conserving surgery and 8 skin-sparing mastectomy. Treatment was well tolerated and produced only moderate alopecia and no case of significant LVEF decrease. Conclusions: Neoadjuvant trastuzumab combined with the above non-anthracycline-containing sequential chemotherapy may be considered a safe and effective regimen in HER2-positive breast cancer patients. Clinical trial information: 2006 000392 15.

Cardiac side effects of trastuzumab in breast cancer patients – single centere experiences

Aim of the studyThe aim of this study was to present our own experiences concerning risk factors for cardiac side effects in the study group.Material and methodsThe study was performed in 120 patients with HER2-overexpressing breast cancer who received immunotherapy in the Clinical and Experimental Oncology Department, between 2006 and 2011.ResultsLVEF reduction > 10% of the baseline fraction was observed in 10 (8%) patients. Symptomatic heart failure occurred in two individuals. Due to persistent cardiotoxicity five patients (4%) had to discontinue therapy prematurely. Risk factors for cardiac toxicity in the analyzed group included: previous radiotherapy to the left side of the chest (p = 0.05), higher BMI (p = 0.05), negative steroid receptor status (p = 0.045) and low baseline LVEF (p < 0.001). Patients receiving radiotherapy were more likely to develop cardiotoxicity if presenting older age (p = 0.0003).ConclusionsPrevious radiotherapy to the left side of the chest, negative steroid receptor status, high BMI and low baseline LVEF were associated with increased risk of cardiac dysfunction. There was no difference between patients receiving adjuvant therapy and those treated due to metastatic disease.

452 Preclinical Pharmacokinetics, Radiation Dosimetry and Toxicity of 111In-BzDTPA-pertuzumab, an Agent for Imaging Early Response to Trastuzumab in Breast Cancer Patients

452 Preclinical Pharmacokinetics, Radiation Dosimetry and Toxicity of 111In-BzDTPA-pertuzumab, an Agent for Imaging Early Response to Trastuzumab in Breast Cancer Patients

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Molecular imaging techniques for protein therapeutics rely on reporter labels, especially radionuclides or sometimes near-infrared fluorescent moieties, which must be introduced with minimal perturbation of the protein's function in vivo and are detected non-invasively during whole-body imaging. PET is the most sensitive whole-body imaging technique available, making it possible to perform biodistribution studies in humans with as little as 1 mg of injected antibody carrying 1 mCi (37 MBq) of zirconium-89 radiolabel. Different labeling chemistries facilitate a variety of optical and radionuclide methods that offer complementary information from microscopy and autoradiography and offer some trade-offs in whole-body imaging between cost and logistic difficulty and image quality and sensitivity (how much protein needs to be injected). Interpretation of tissue uptake requires consideration of label that has been catabolized and possibly residualized. Image contrast depends as much on background signal as it does on tissue uptake, and so the choice of injected dose and scan timing guides the selection of a suitable label and helps to optimize image quality. Although only recently developed, zirconium-89 PET techniques allow for the most quantitative tomographic imaging at millimeter resolution in small animals and they translate very well into clinical use as exemplified by studies of radiolabeled antibodies, including trastuzumab in breast cancer patients, in The Netherlands.

Two Pluses Make a Minus

Erythropoietin decreases the positive effects of trastuzumab in breast cancer patients.

36 Implementation of adjuvant trastuzumab in breast cancer patients in the Netherlands

36 Implementation of adjuvant trastuzumab in breast cancer patients in the Netherlands

Benefit of adjuvant trastuzumab in breast cancer patients with focal HER2 amplified clones: Data from N9831 Intergroup Adjuvant Trial

520 Background: Targeted therapy using trastuzumab (an anti-HER-2 receptor monoclonal antibody) has significantly improved survival in breast carcinoma patients (pts), but determining which pts will respond to this therapy remains a challenge. We previously reported (Miller DV, ASCO 2004 abstract #568) a subset of pts with breast cancers demonstrating focal HER-2 amplified clones (FHAC) amidst otherwise nonamplified tumor cells by fluorescence in-situ hybridization. These accounted for 21% of the HER-2 amplified but immunohistochemistry (IHC) negative cases and 30% of the HER-2 amplified but IHC equivocal cases. The clinical significance of this phenomenon was unclear at that time. We now report the disease-free survival (DFS) data on 91 FHAC pts with a comparison to the diffusely amplified (DA) cases in this trial group. Methods: Breast tumors were evaluated for HER-2 gene amplification using PathVysion™. FHAC cases demonstrated 2–40% of cells with &gt;10 HER-2 signals and HER-2:CEP17 ratio &gt;5.0, regardless of the overall HER-2:CEP17 ratio. Patient and disease characteristics were compared using chi-square tests. Cox regression models compared DFS between pts randomized to arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) within 91 FHAC and 1571 DA cases. Median follow up was 4.0 years. Results: Age, race, menopausal status, surgical procedure, nodal status, histologic type and grade, and tumor size, were not significantly different between pateints with FHAC and DA. Pateints with FHAC had more frequent hormone receptor positivity compared to DA cases (66% vs 50%; p = 0.004). Hazard ratios between pts with FHAC and DA showed that both groups of pts had similar DFS (A: HR = 0.86, p = 0.65; C: HR = 0.72, p = 0.57). Hazard ratios between arms within FHAC and DA groups demonstrated similar benefit from trastuzumab in each group (FHAC: HR = 0.50, p = 0.30; DA: HR = 0.59, p &lt; 0.0001). Results remained consistent when including hormone receptor status in the model. Conclusions: Based on a small number (n = 91) of pts with FHAC, benefit from trastuzumab appears to be similar whether the population of HER-2 amplified cells with breast carcinomas is focal or diffuse. [Table: see text]

Solamargine induces apoptosis and enhances susceptibility to trastuzumab and epirubicin in breast cancer cells with low or high expression levels of HER2/neu

Trastuzumab is used for breast cancer patients with high expression levels of HER2 (human epidermal growth factor receptor 2)/neu; however, it has no effect on cancers with low levels of HER2/neu. SM (solamargine), a major steroidal alkaloid glycoside purified from Solanum incanum, triggered apoptosis of breast cancer cells (MCF-7 and SK-BR-3 cells) and non-cancerous breast epithelial cells (HBL-100 cells) within 3 h. To extend the application of trastuzumab in breast cancer patients, the regulation of HER2/neu expression by SM was investigated. SM significantly up-regulates HER2/neu expression in breast cancer cells with low and high expression levels of HER2/neu, and synergistically enhanced the effect of trastuzumab in inhibiting cell proliferation. Additionally, HER2/neu and TOP2A [TopoII (topoisomerase II) alpha] genes share the same amplicon on an identical chromosome. Notably, SM co-regulates HER2/neu and TopoIIalpha expression markedly, and enhances TopoII inhibitor-EPI (epirubicin)-induced cytotoxicity to breast cancer cells.

Cardiotoxicity associated with the use of trastuzumab in breast cancer patients

The monoclonal antibody against HER2, trastuzumab (Herceptin®), has become an important player in the treatment of patients with HER2-positive breast cancer. Both in the metastatic and adjuvant setting, the addition of trastuzumab to other systemic treatments has led to a striking increase in tumor response and survival. The downside with the use of this agent, however, is its inherent cardiotoxicity, which is particularly common when anthracyclines are used concurrently. This review will focus on all aspects of the cardiac side-effects of trastuzumab, ranging from epidemiology and pathophysiology to cardiac monitoring, and treatment and prevention.

Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2.

To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity. A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies. Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity. The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.