Trastuzumab (Herceptin (R)): Monoclonal antibody in the treatment of HER2/neu-overexpressing breast cancer in the metastatic and (neo)adjuvant situation

Trastuzumab (Herceptin (R)) is a humanized monoclonal antibody that specifically targets HER2/neu (human epidermal growth factor receptor-2) breast cancer cells, which are overexpressed in about 25-30% of breast carcinomas. After phase I and II trials, several phase III studies of trastuzumab alone or in combination with various chemotherapies were conducted. Patients with HER2/neu overexpression levels of 3+ determined by immunohistochemical assay or gene amplification (fluorescence in situ hybridization) derive most clinical benefit from trastuzumab. Taking into consideration efficacy and side effect profile, the combination of trastuzumab and paclitaxel showed an improvement of all clinical parameters, including overall survival, for the first time in the history of palliative breast cancer therapy. The application of trastuzumab has meanwhile become an established part of systemic therapy of metastastic breast cancer, and excellent data of its application in the adjuvant setting now exist (NSABP-B31, NCCTG-N9831, HERA), with significantly better relapse-free survival in the treatment arms with trastuzumab. Ongoing trials investigate the role of trastuzumab in the neoadjuvant setting. Trastuzumab is generally well tolerated. Cardiotoxicity is the main concern, thus monitoring of cardiac function is recommended

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Do Robots Dream of Virtual Sheep: Rediscovering the "Karel the Robot" Paradigm for the "Plug&Play Generation"

We introduce ”C-Sheep”, an educational system designed to teach students the fundamentals of computer programming in a novel and exciting way. Recent studies suggest that computer science education is fast approaching a crisis - application numbers for degree courses in the area of computer programming are down, and potential candidates are put off the subject which they do not fully understand. We address this problem with our system by providing the visually rich virtual environment of ”The Meadow”, where the user writes programs to control the behaviour of a sheep using our ”CSheep” programming language. This combination of the ”Karel the Robot” paradigm with modern 3D computer graphics techniques, more commonly found in computer games, aims to help students to realise that computer programming can be an enjoyable and rewarding experience and intends to help educators with the teaching of computer science fundamentals. Our mini-language-like system for computer science education uses a state of the art rendering engine offering features more commonly found in entertainment systems. The scope of the mini-language is designed to fit in with the curriculum for the first term of an introductory computer program ming course (using the C programming language)

C-Sheep: Controlling Entities in a 3D Virtual World as a Tool for Computer Science Education

One of the challenges in teaching computer science in general and computer programming in particular is to maintain the interest of students, who often perceive the subject as difficult and tedious. To this end, we introduce C-Sheep, a mini-language-like system for computer science education, using a state of the art rendering engine, usually found in entertainment systems. The intention is to motivate students to spend more time programming, which can be achieved by providing an enjoyable experience. Computer programming is an essential skill for software developers and as such is always an integral part of every computer science curriculum. However, even if students are pursuing a computer science related degree, it can be very difficult to interest them in the act of computer programming, the writing of software, itself. In the C-Sheep system this is addressed by using the visual gimmickry of modern computer games, which allows programs to provide instant visualisation of algorithms. This visual feedback is invaluable to the understanding of how the algorithm works, and - if there are unintended results - how errors in the program can be debugged. The C-Sheep programming language is a (100% compatible) subset of the ANSI C programming language. Apart from just being a tool for learning the basics of the C programming language, C-Sheep implements the C control structures that are required for teaching the basic computer science principles encountered in structured programming. Unlike other teaching languages which have minimal syntax and which are variable free to provide an environment with minimal complexity, C-Sheep allows the declaration and use of variables. C-Sheep also supports the definition of sub-routines (functions) which can be called recursively. "The Meadow" virtual environment is the virtual world in which entities (in our case sheep) controlled by C-Sheep programs exist. This micro world provides a graphical representation of the algorithms used in the programs controlling the virtual entities. Their position and orientation within the virtual world visualise the current state of the program. "The Meadow" is based on our proprietary "Crossbow" game engine which incorporates a virtual machine for executing CSheep programs. The Crossbow Engine is a compact game engine which is flexible in design and offers a number of features common to more complex engines. The Crossbow Virtual Machine used with C-Sheep in "The Meadow" - an improvement on the ZBL/0 virtual machine - is a module of the Crossbow Engine. The C-Sheep system also provides a counterpart library for C, mirroring the CSheep library functions of the virtual machine. This allows C-Sheep programs to be compiled into an executable using a normal off-the-shelf C/C++ compiler. This executable can then be run from within the native working environment of the operating system. The purpose of this library is to simplify the migration from the educational mini-language to real-world systems by allowing novice programmers to make an easy transition from using the C-Sheep system to using the C programming language

Critters in the Classroom: A 3D Computer-Game-Like Tool for Teaching Programming to Computer Animation Students

The brewing crisis threatening computer science education is a well documented fact. To counter this and to increase enrolment and retention in computer science related degrees, it has been suggested to make programming "more fun" and to offer "multidisciplinary and cross-disciplinary programs" [Carter 2006]. The Computer Visualisation and Animation undergraduate degree at the National Centre for Computer Animation (Bournemouth University) is such a programme. Computer programming forms an integral part of the curriculum of this technical arts degree, and as educators we constantly face the challenge of having to encourage our students to engage with the subject. We intend to address this with our C-Sheep system, a reimagination of the "Karel the Robot" teaching tool [Pattis 1981], using modern 3D computer game graphics that today's students are familiar with. This provides a game-like setting for writing computer programs, using a task-specific set of instructions which allow users to take control of virtual entities acting within a micro world, effectively providing a graphical representation of the algorithms used. Whereas two decades ago, students would be intrigued by a 2D top-down representation of the micro world, the lack of the visual gimmickry found in modern computer games for representing the virtual world now makes it extremely difficult to maintain the interest of students from today's "Plug&Play generation". It is therefore especially important to aim for a 3D game-like representation which is "attractive and highly motivating to today's generation of media-conscious students" [Moskal et al. 2004]. Our system uses a modern, platform independent games engine, capable of presenting a visually rich virtual environment using a state of the art rendering engine of a type usually found in entertainment systems. Our aim is to entice students to spend more time programming, by providing them with an enjoyable experience. This paper provides a discussion of the 3D computer game technology employed in our system and presents examples of how this can be exploited to provide engaging exercises to create a rewarding learning experience for our students

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

Breast cancer: Monitoring response to neoadjuvant chemotherapy using Tc-99m sestamibi scintimammography

Background: Aim of the study was to assess the value of scintimammography using Tc-99m sestamibi in the evaluation of tumor response to neoadjuvant chemotherapy. Material and Methods: Results were calculated for 9 patients undergoing neoadjuvant chemotherapy. Scintimammography using 740 MBq Tc-99m sestamibi was performed before, during and after chemotherapy, and sestamibi uptake was scored visually and semiquantitatively to evaluate tumor response. Results: In the case of complete response (n = 3) sestamibi uptake decreased 8 days after beginning neoadjuvant chemotherapy and normalized in the following course. Focal uptake decreased more slowly in patients with partial response (n = 3), who showed clear, persisting tracer accumulation after therapy. The patients without response (n = 3) showed a persisting high tumor activity even after chemotherapy was completed. Conclusions: The preliminary data suggest that in contrast to other imaging modalities scintimammography appears to yield early information regarding tumor response to neoadjuvant chemotherapy

Zurich Consensus: Statement of German Experts on St. Gallen Conference 2011 on Primary Breast Cancer (Zurich 2011)

Every 2 years, the International Consensus Conference on the Treatment of Primary Breast Cancer takes place in St. Gallen. Given that the concept of the St. Gallen Consensus Conference mainly reflects an international opinion, it appears useful to adapt the results of the vote for everyday therapy in Germany. A German working group comprising 28 breast cancer experts, amongst whom there are 3 members of the international St. Gallen panel, has therefore commented on this year's St. Gallen Consensus Conference (2011) from the German viewpoint. The focus of interest of this year's St. Gallen Conference was tumour biology as the starting point for decisions regarding individual therapy. There was an intensive discussion in relation to the clinical relevance of predictive and prognostic factors and possible consequences for decisions regarding therapy. Therefore, questions concerning the indication for adjuvant chemotherapy focused especially on the significance of the molecular phenotype of the tumour. In addition, important points for discussion were also the value of complete axillary dissection and the use of accelerated complete breast irradiation