Trastuzumab

Posttranslational modification catalyzed by phosphopantetheinyl transferases (PPTases) has previously been used to site-specifically label proteins with structurally diverse molecules. PPTase catalysis results in covalent modification of a serine residue in acyl/peptidyl carrier proteins and their surrogate substrates which are typically fused to the N- or C-terminus. To test the utility of PPTases for preparing antibody-drug conjugates (ADCs), we inserted 11 and 12-mer PPTase substrate sequences at 110 constant region loop positions of trastuzumab. Using Sfp-PPTase, 63 sites could be efficiently labeled with an auristatin toxin, resulting in 95 homogeneous ADCs. ADCs labeled in the CH1 domain dis-played in general excellent pharmacokinetic profiles and negligible drug loss. A subset of CH2 domain conjugates underwent rapid clearance in mouse pharmacokinetic studies. Rapid clearance correlated with lower thermal stability of the particular antibodies. Independent of conjugation site...

Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lun...

Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pretreatment DOS functional maps for predicting LABC response to NAC. Locally advanced breast cancer patients (n=37) underwent DOS breast imaging before starting NAC. Breast tissue parametric maps were constructed and texture analyses were performed based on grey-level co-occurrence matrices for feature extraction. Ground truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS textural features computed on volumetric tumour data before the start of treatment (i.e., 'pretreatment') to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naive Bayes, and k-nearest ...

According to the World Health Organization, the incidence of malignant neoplasms and endocrine, blood, and immune disorders will increase in the upcoming decades along with the demand of affordable treatments. In response to this need, the development of biosimilar drugs is increasing worldwide. The approval of biosimilars relies on the compliance with international guidelines, starting with the demonstration of similarity in their physicochemical and functional properties against the reference product. Subsequent clinical studies are performed to demonstrate similar pharmacological behavior and to diminish the uncertainty related to their safety and efficacy. Herein we present a comparability exercise between a biosimilar trastuzumab and its reference product, by using a hierarchical strategy with an orthogonal approach, to assess the physicochemical and biological attributes with potential impact on its pharmacokinetics, pharmacodynamics, and immunogenicity. Our results showed that the high degree of similarity in the physicochemical attributes of the biosimilar trastuzumab with respect to the reference product resulted in comparable biological activity, demonstrating that a controlled process is able to provide consistently the expected product. These results also constitute the basis for the design of subsequent delimited pharmacological studies, as they diminish the uncertainty of exhibiting different profiles.

According to the World Health Organization, the incidence of malignant neoplasms and endocrine, blood, and immune disorders will increase in the upcoming decades along with the demand of affordable treatments. In response to this need, the development of biosimilar drugs is increasing worldwide. The approval of biosimilars relies on the compliance with international guidelines, starting with the demonstration of similarity in their physicochemical and functional properties against the reference product. Subsequent clinical studies are performed to demonstrate similar pharmacological behavior and to diminish the uncertainty related to their safety and efficacy. Herein we present a comparability exercise between a biosimilar trastuzumab and its reference product, by using a hierarchical strategy with an orthogonal approach, to assess the physicochemical and biological attributes with potential impact on its pharmacokinetics, pharmacodynamics, and immunogenicity. Our results showed that the high degree of similarity in the physicochemical attributes of the biosimilar trastuzumab with respect to the reference product resulted in comparable biological activity, demonstrating that a controlled process is able to provide consistently the expected product. These results also constitute the basis for the design of subsequent delimited pharmacological studies, as they diminish the uncertainty of exhibiting different profiles.

Human epidermal growth factor receptor 2 (HER2) plays a central role as a prognostic and predictive marker in breast cancer specimens. Reliable HER2 evaluation is central to determine the eligibility of patients with breast cancer to targeted anti-HER2 therapies such as trastuzumab and lapatinib. Presently, several methods exist for the determination of HER2 status at different levels (protein, RNA, and DNA level). In this review, we discuss the main advantages and disadvantages of the techniques developed so far for the evaluation of HER2 status in breast cancer specimens. Each technique has its own advantages and disadvantages. It is therefore not surprising that no consensus has been reached so far on which technique is the best for the determination of HER2 status. Currently, emphasis must be put on standardization of procedures, internal and external quality control assessment, and competency evaluation of already existing methods to ensure accurate, reliable, and clinically me...

Organizing pneumonia is a clinical and histological condition in which the onset is usually subacute with respiratory symptoms and pulmonary infiltrates. It may be unknown origin (cryptogenic) or associated with other illnesses, infectious diseases or drugs. We present a 60 year-old female patient with a previous history of breast cancer, who was being treated with trastuzumab, an antiHER2 monoclonal antibody. She was diagnosed with casual pulmonary infiltrates that had histological changes compatible with organizing pneumonia. The pulmonary infiltrates disappeared on withdrawing trastuzumab treatment. Due to the increasing use of biological therapies in different medical areas, we believe it is of interest to report this pulmonary involvement attributed to the monoclonal antibody trastuzumab.

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. The majority of patients with metastatic breast cancer who initially respond to trastuzumab develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse despite trastuzumab-based therapy. In this review, we discuss potential mechanisms of antitumor activity by trastuzumab, and how these mechanisms become altered to promote therapeutic resistance. We also discuss novel therapies that may improve the efficacy of trastuzumab, and that offer hope that the survival of breast cancer patients with HER2-overexpressing tumors can be vastly improved.

There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination with taxanes and vinorelbine has been established. In the preoperative setting inclusion of trastuzumab has significantly increased the pathological complete response rate. Results from large phase III trials evaluating adjuvant therapy in HER2-positive early breast cancer indicate that the addition of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has been established. There is modest, but still insufficient, support that the compound passes the blood-brain barrier. Several trials are ongoing both in the adjuvant and metastatic settings and we have to await the results of these to clarify the role of trastuzumab and lapatinib. The clinical problem of tumours developing resistance to HER2-directed therapy is becoming increasingly important. Several issues about optimal selection of patients, prevention of resistance and use of different treatment options are still unresolved. In this article, we summarise the current knowledge on clinical evidence of HER2-directed therapy and the potential mechanisms of underlying resistance, including the possible clinical implications and review new therapeutic options.

 Several distinct historical phases mark the evolution of chemotherapy for breast cancer, including the introduction of single agents in the 1960s, the development of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based regimens in the 1970s, the evaluation of the anthracyclines in the 1980s, and the incorporation of the taxanes in the 1990s. The greatest benefit from the use of standard combination chemotherapy occurs in the adjuvant setting, where absolute improvements in overall survival on the order of 10% have been achieved. In contrast, advances have been more modest in the treatment of metastatic disease, and novel agents and regimens are required for further progress. Of the new cytotoxic drugs introduced in the past decade, the taxanes and capecitabine appear to be the most promising, and have demonstrated activity alone and in combination for the treatment of metastatic disease. The introduction of trastuzumab, an antibody directed against the HER2 receptor protein, heralded the birth of targeted molecular therapy against breast cancer. It is clear that in the near future the further evaluation of trastuzumab combinations and the development of additional molecular agents will propel clinical breast cancer research. One of the main challenges of the new era will be identifying and validating predictive factors so that therapy may be individualized based on tumor biology, rather than empirically selected.

HER-2 overexpression is associated to a poor prognosis in high-risk and metastatic breast cancer (MBC) patients treated with high-dose chemotherapy (HDC). HER-2 status is also a predictive factor and when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant disease-free and/or overall survival improvement has been observed in HER-2+ early and MBC. Unfortunately, in both settings, trastuzumab is associated with an increased risk of cardiac dysfunction (CD). We have reviewed the clinical charts of HER-2-overexpressing MBC patients treated with trastuzumab after HDC. Age, baseline left ventricular ejection fraction (LVEF), radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. In total, 53 patients have been included in the analysis. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 pa...