Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumours

We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab

HER2 testing in breast cancer: Opportunities and challenges

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-25% of breast cancers, usually as a result of HER2 gene amplification. Positive HER2 status is considered to be an adverse prognostic factor. Recognition of the role of HER2 in breast cancer growth has led to the development of anti-HER2 directed therapy, with the humanized monoclonal antibody trastuzumab (Herceptin (R)) having been approved for the therapy of HER2-positive metastatic breast cancer. Clinical studies have further suggested that HER2 status can provide important information regarding success or failure of certain hormonal therapies or chemotherapies. As a result of these developments, there has been increasing demand to perform HER2 testing on current and archived breast cancer specimens. This article reviews the molecular background of HER2 function, activation and inhibition as well as current opinions concerning its role in chemosensitivity and interaction with estrogen receptor biology. The different tissue-based assays used to detect HER2 amplification and overexpression are discussed with respect to their advantages and disadvantages, when to test (at initial diagnosis or pre-treatment), where to test (locally or centralized) and the need for quality assurance to ensure accurate and valid testing results

A Perspective on Challenges and Issues in Biomarker Development and Drug and Biomarker Codevelopment

A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized

Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2–positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a \u3e 10% decline in left ventricular ejection fraction from baseline to a value \u3c 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function

Wnt Signalling Pathway Parameters for Mammalian Cells

Wnt/β-catenin signalling regulates cell fate, survival, proliferation and differentiation at many stages of mammalian development and pathology. Mutations of two key proteins in the pathway, APC and β-catenin, have been implicated in a range of cancers, including colorectal cancer. Activation of Wnt signalling has been associated with the stabilization and nuclear accumulation of β-catenin and consequential up-regulation of β-catenin/TCF gene transcription. In 2003, Lee et al. constructed a computational model of Wnt signalling supported by experimental data from analysis of time-dependent concentration of Wnt signalling proteins in Xenopus egg extracts. Subsequent studies have used the Xenopus quantitative data to infer Wnt pathway dynamics in other systems. As a basis for understanding Wnt signalling in mammalian cells, a confocal live cell imaging measurement technique is developed to measure the cell and nuclear volumes of MDCK, HEK293T cells and 3 human colorectal cancer cell lines and the concentrations of Wnt signalling proteins β-catenin, Axin, APC, GSK3β and E-cadherin. These parameters provide the basis for formulating Wnt signalling models for kidney/intestinal epithelial mammalian cells. There are significant differences in concentrations of key proteins between Xenopus extracts and mammalian whole cell lysates. Higher concentrations of Axin and lower concentrations of APC are present in mammalian cells. Axin concentrations are greater than APC in kidney epithelial cells, whereas in intestinal epithelial cells the APC concentration is higher than Axin. Computational simulations based on Lee's model, with this new data, suggest a need for a recalibration of the model

A positive role for PEA3 in HER2-mediated breast tumour progression

Overexpression of HER2 is associated with an adverse prognosis in breast cancer. Despite this, the mechanism of its transcriptional regulation remains poorly understood. PEA3, a MAP kinase (MAPK)-activated member of the Ets transcription factor family has been implicated in the transcriptional regulation of HER2. The direction of its modulation remains controversial. We assessed relative levels of PEA3 expression and DNA binding in primary breast cultures derived from patient tumours (n=18) in the presence of an activated MAPK pathway using Western blotting and shift analysis. Expression of PEA3 in breast tumours from patients of known HER2 status (n=107) was examined by immunohistochemistry. In primary breast cancer cell cultures, growth factors induced interaction between PEA3 and its DNA response element. Upregulation of PEA3 expression in the presence of growth factors associated with HER2 positivity and axillary lymph node metastasis (P=0.034 and 0.049, respectively). PEA3 expression in breast cancer tissue associated with reduced disease-free survival (P<0.001), Grade III tumours (P<0.0001) and axillary lymph node metastasis (P=0.026). Co-expression of PEA3 and HER2 significantly associated with rate of recurrence compared to patients who expressed HER2 alone (P=0.0039). These data support a positive role for PEA3 in HER2-mediated oncogenesis in breast cancer

Trastuzumab in the Adjuvant Treatment of HER2-Positive Early Breast Cancer Patients: A Meta-Analysis of Published Randomized Controlled Trials

BACKGROUND: Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. METHODS: Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. FINDINGS: With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms. CONCLUSION: This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation

The economic pressures for biosimilar drug use in cancer medicine

The main rationale for using biosimilar drugs is for cost saving. The market development for biosimilar drugs will therefore depend on the degree to which cost saving measures are required by nations, medical insurers and individuals and the absolute savings that could be gained by switching from original drugs. This paper is designed to discover the degree to which financial constraints will drive future health spending and to discover if legal or safety issues could impact on any trend. A structured literature search was performed for papers and documents to 27 August 2011. Where multiple sources of data were available on a topic, data from papers and reports by multinational or national bodies were used in preference to data from regions or individual hospitals. Almost all health systems face current significant cost pressures. The twin driver of increasing cancer prevalence as populations age and cancer medicine costs rising faster than inflation places oncology as the most significant single cost problem. For some countries, this is predicted to make medicine unaffordable within a decade. Most developed countries have planned to embrace biosimilar use as a cost-control measure. Biosimilar introduction into the EU has already forced prices down, both the price of biosimilar drugs and competitive price reductions in originator drugs. Compound annual growth rates of use have been predicted at 65.8% per year. Most developed countries have planned to embrace biosimilar use as a major cost-control measure. Only legal blocks and safety concerns are likely to act against this trend. For centralised healthcare systems, and those with a strong tradition of generic medicine use, biosimilar use will clearly rise with predictions of more than 80% of prescriptions of some biologic drugs within 1 year of market entry in the USA. Delaying the implementation of such programmes however risks a real crisis in healthcare delivery for many countries and hospitals that few can now afford