Class of 2017 Abstract / Objectives: Specific Aim #1: Describe the incidence and degree of severity of cardiac dysfunction in case studies, retrospective chart analyses, and prospective randomized clinical trials for patients treated with pertuzumab containing regimens for neoadjuvant treatment of locally advanced, inflammatory, or early stage HER2+ BC, or for treatment of metastatic HER2+ BC. Specific Aim #2: Describe the frequency of cardiac safety monitoring for patients undergoing treatment with pertuzumab containing regimens for HER2+ BC within these case studies, retrospective chart analyses, and prospective randomized clinical trials. Methods: Case reports, retrospective chart analyses, and prospective, randomized, controlled trials were identified by search of PubMed and Embase databases, as well as through the Google Scholar search engine. The search strategy included the following keywords: epidermal growth factor receptor 2, erbB-2 genes, pertuzumab, cardiotoxicity, left ventricular function, and left ventricular dysfunction. Reviews were ineligible. All studies that examined the cardiac safety of pertuzumab containing regimens for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer were considered eligible for this systematic review, regardless of sample size. Results: So far, the search strategy retrieved 3 studies that evaluated the cardiac toxicity outcomes of pertuzumab containing regimens. All studies were conducted for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer. Conclusions: The incidence of cardiotoxicity due to treatment with pertuzumab containing regimens for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer remains relatively low. However, the potential severity of cardiac effects related to pertuzumab containing regimens is an important consideration when using these regimens in patients who have any existing risk factors for decreased cardiac function. This systematic review providers a more thorough understanding of the incidence and severity of cardiac adverse effects related to pertuzumab containing regimens since the time pertuzumab was first introduced as an option for HER2+ breast cancer patients.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast cancers (BCs) and confers an aggressive tumour phenotype with a poor prognosis. Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody (mAb) approved for treatment of HER2-positive breast cancer (BC), however many eligible patients do not respond. The hypothesis was that molecular imaging strategies that probe: i) the expression of HER2; ii) one of the mechanisms of action of trastuzumab or iii) evaluate the viability of tumour cells by their glucose utilization would be useful in predicting and monitoring the response of BC to treatment with trastuzumab. The relationship between tumour HER2 density, uptake of 111In-DTPA-trastuzumab and response to trastuzumab was evaluated by gamma camera imaging, biodistribution studies and monitoring tumour growth in mice implanted with BC xenografts. There was a non-linear relationship between HER2 expression and uptake of this radiopharmaceutical when tumour uptake was corrected for non-specific IgG accumulation and/or circulating blood radioactivity (r2=0.87-0.99). Tumour response corresponded better with the uncorrected tumour uptake of 111In-DTPA-trastuzumab. HER2 downregulation, a putative mechanism of action of trastuzumab, was noted as decreased tumour uptake on microSPECT/CT of mice bearing MDA-MB-361 xenografts administered 111In-DTPA-pertuzumab. Tumour uptake of 111In-DTPA-pertuzumab was reduced by 53% in mice treated for 3 days with trastuzumab (P<0.05) associated with an early molecular response to the drug. Furthermore, tumour uptake of 111In-DTPA-pertuzumab was reduced by 78% (P<0.001) in mice treated for 3 weeks, which corresponded with a reduction in HER2-positive tumour cells, indicating a therapeutic response. The relationship between changes in tumour uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and response to trastuzumab was examined in mice bearing MDA-MB-361 and MDA-MB-231 BC xenografts, with high or very low HER2 expression, treated with trastuzumab. MicroPET imaging and biodistribution studies detected a 43-60% (P<0.03) reduction in tumour uptake of 18F-FDG in mice with MDA-MB-361 xenografts, treated with trastuzumab compared to PBS-treated controls. In contrast, there was no change in 18F-FDG uptake in MDA-MB-231 xenografts, that did not respond to trastuzumab. I conclude that molecular imaging is a promising tool for monitoring response of BC to treatment with trastuzumab.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast cancers (BCs) and confers an aggressive tumour phenotype with a poor prognosis. Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody (mAb) approved for treatment of HER2-positive breast cancer (BC), however many eligible patients do not respond. The hypothesis was that molecular imaging strategies that probe: i) the expression of HER2; ii) one of the mechanisms of action of trastuzumab or iii) evaluate the viability of tumour cells by their glucose utilization would be useful in predicting and monitoring the response of BC to treatment with trastuzumab. The relationship between tumour HER2 density, uptake of 111In-DTPA-trastuzumab and response to trastuzumab was evaluated by gamma camera imaging, biodistribution studies and monitoring tumour growth in mice implanted with BC xenografts. There was a non-linear relationship between HER2 expression and uptake of this radiopharmaceutical when tumour uptake was corrected for non-specific IgG accumulation and/or circulating blood radioactivity (r2=0.87-0.99). Tumour response corresponded better with the uncorrected tumour uptake of 111In-DTPA-trastuzumab. HER2 downregulation, a putative mechanism of action of trastuzumab, was noted as decreased tumour uptake on microSPECT/CT of mice bearing MDA-MB-361 xenografts administered 111In-DTPA-pertuzumab. Tumour uptake of 111In-DTPA-pertuzumab was reduced by 53% in mice treated for 3 days with trastuzumab (P<0.05) associated with an early molecular response to the drug. Furthermore, tumour uptake of 111In-DTPA-pertuzumab was reduced by 78% (P<0.001) in mice treated for 3 weeks, which corresponded with a reduction in HER2-positive tumour cells, indicating a therapeutic response. The relationship between changes in tumour uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and response to trastuzumab was examined in mice bearing MDA-MB-361 and MDA-MB-231 BC xenografts, with high or very low HER2 expression, treated with trastuzumab. MicroPET imaging and biodistribution studies detected a 43-60% (P<0.03) reduction in tumour uptake of 18F-FDG in mice with MDA-MB-361 xenografts, treated with trastuzumab compared to PBS-treated controls. In contrast, there was no change in 18F-FDG uptake in MDA-MB-231 xenografts, that did not respond to trastuzumab. I conclude that molecular imaging is a promising tool for monitoring response of BC to treatment with trastuzumab.

I Sverige drabbas närmare 8000 kvinnor av bröstcancer varje år. Bröstcancer är vanligast hos kvinnor över 40 år och utgör 30 % av alla cancersjukdomar hos kvinnor. Cirka 25 % av alla bröstcancerformer är HER2 (human epidermal growth factor receptor) -positiva. HER2-positiv bröstcancer resulterar i en aggressiv fenotyp och en väldigt dålig prognos.  Varje år får cirka 1300 – 1400 bröstcancerpatienter en spridning av sin sjukdom. Vid spridning bildas så kallade metastaser. Som behandling till HER2-positiv bröstcancer förskrivs målinriktat läkemedel tillsammans med cytostatika. Målinriktat läkemedel kan antingen vara antikroppar eller inhibitorer som hämmar HER2-medierad cellsignalering. Trastuzumab har sedan år 2007 använts som behandling vid spridd HER2-positiv bröstcancer. Pertuzumab är ett nyare tillskott i läkemedelsgruppen och används på samma indikation. Dessa två läkemedel är monoklonala antikroppar som binder till HER2. Skillnaden mellan dessa två läkemedel är att de binder till olika platser i HER2 och har olika verkningsmekanismer. Syftet med litteraturarbetet var att undersöka om pertuzumab som tillägg till trastuzumab och cytostatikumet docetaxel (s.k. TD-behandling) förlängde den progressionsfria perioden samt om den ökade livskvalitén hos patienter med spridd HER2-positiv bröstcancer. I bedömningen beaktas också om biverkningsmönstret förändras. Arbetet är en litteraturstudie omfattande fem vetenskapliga studier. De fem vetenskapliga artiklarna identifierades med databasen PubMed.  Arbetet baseras på två kliniska studier och tre kohortstudier. CLEOPATRA-studien är en stor studie som har undersökt effekten av pertuzumab som tillägg till TD-behandling. Utifrån studieresultatet ansågs det att pertuzumab som tillägg till TD-behandling förlängde den progressionsfria överlevnaden signifikant med 6,1 månader.  Studier som hade analyserat data från CLEOPATRA, har visat att tilläggsbehandlingen förlängde också tiden till sjukdomsförsämring och förbättrad livskvalité hos patienten. Behandlingen visade statistiskt signifikant förbättrad progressionsfri överlevnad hos alla åldersgrupper. Den visade inte heller att tilläggsbehandling med pertuzumab gav ökad risk för svåra biverkningar. Många av biverkningarna som registrerades var av grad 1 och 2.  Slutsatsen är att pertuzumab som tillägg till TD-behandling som förstahandsbehandling hos patienter med metastaserande HER2-positiv bröstcancer är fördelaktig. / In Sweden, about one in ten women develop breast cancer, which makes this the most common type of cancer disease in women. The risk of getting cancer increases with age. Almost 8000 women are diagnosed with breast cancer every year in Sweden. Human epidermal growth factor receptor 2 (HER2) – positive breast cancer, is an aggressive phenotype. About 25 % of the breast cancer tumors are overexpressing HER2 on the cell surface. HER2 is a subunit of the dimeric tyrosin kinase EFGR (HER) that stimulates cell proliferation. Every year, about 1300- 1400 patients advance in their illness and form metastases. Pertuzumab and trastuzumab, are both HER2 monoclonal antibodies. Pertuzumab inhibits the HER2 from heterodimerization with HER3, while trastuzumab inhibits HER2 homodimerization. Since 2007 trastuzumab and cytostatics were approved for treatment of metastatic HER2-positive breast cancer. The aim of this study was to evaluate if pertuzumab as an addition to trastuzumab and docetaxel (cytostatic) could prolong the time patients with metastatic HER2-positive breast cancer experienced free from progression of their illness in comparison with treatment with only trastuzumab and docetaxel. This study was based on scientific articles identified from the database PubMed. Five studies were selected, one of the studies was the CLEOPATRA-study. CLEOPATRA compared the efficiency and safety of the two selected treatments. Three studies further analyzed and followed up results of the CLEOPATRA-study. Study five investigated the effect of pertuzumab in patients with metastatic HER2-positive breast cancer, where disease progression had occurred during trastuzumab treatment. The primary endpoint was progression-free survival (PFS) and overall survival (OS). All articles showed that PFS increased in patients treated with pertuzumab as addition to trastuzumab and docetaxel. Overall survival was also improved during and after the follow-up. The conclusion of this study was that pertuzumab, trastuzumab and docetaxel as treatment for metastatic HER2-positive breast cancer is promising and should be used as first-line treatment of metastatic breast cancer with HER2 overexpression.

Background: Chemotherapeutic agents directed against human epidermal growth factor receptor 2 (HER-2) have significantly improved the prognosis of patients who are positive for this receptor. However, cardiomyopathy remains as a common adverse effect of using these agents. Materials and Methods: Literature search was conducted via PubMed using the keywords of "Trastuzumab Cardiomyopathy," "Lapatinib Cardiomyopathy" and "Pertuzumab Cardiomyopathy," which provided 104 results. These articles were then screened for relevance to the targeted subject based on their title and abstracts. Case reports and articles that were not discussing any aspect of cardiomyopathy secondary to targeted therapy for breast cancer and articles not in English were eliminated. After elimination, a bibliography search among selected articles was done and a total of 46 articles were identified. The collected articles were then meticulously analyzed and summarized. Results: The use of human epidermal growth factor receptor 2 (HER-2) receptor targeted chemotherapy in breast cancer is limited because of a higher incidence (19-22%) of cardiomyopathy. The incidence of cardiomyopathy is not dose dependent and in most cases it is reversible after discontinuation of the drug and treatment with heart failure medications. Severe adverse outcomes including death or permanent disability are rare. Conclusion: HER-2 targeted chemotherapy for breast cancer has a higher incidence of associated reversible cardiomyopathy. Patients should be monitored by serial echocardiography starting at the beginning of the treatment and followed by every 3 months until the completion of chemotherapy. Co-ordination between oncologists and cardiologists is needed to develop evidence-based protocols to prevent, identify, monitor and treat trastuzumab-induced cardiomyopathy.

Avec un taux de survie à 5 ans inférieur à 5%, l'adénocarcinome pancréatique (PDAC) est l'un des cancers les plus agressifs et pour lequel les thérapies existantes sont largement insuffisantes. Ce cancer est caractérisé par un tissu fibreux dense et un stroma très développé, en constante interaction avec la tumeur, favorisant le développement d'un environnement propice à la progression tumorale. Actuellement, la gemcitabine est la seule chimiothérapie approuvée capable de prolonger légèrement la survie des patients. Une thérapie ciblée dirigée contre l'EGFR, l'erlotinib, a prouvé que le ciblage de cette famille pourrait être une stratégie intéressante dans cette pathologie mais qu'une sélection des patients était indispensable pour augmenter les réponses thérapeutiques. Deux récepteurs de cette famille, HER2 et HER3, dimérisent pour former une entité particulièrement agressive et impliquée dans la croissance tumorale des PDACs. Diverses techniques récemment développées sont utilisées pour quantifier ces dimères, afin d'étudier leur rôle, mais également pour tenter de les cibler, et empêcher leur signalisation dans différents cancers. A l'heure actuelle, le pertuzumab est le seul anticorps monoclonal dirigé contre le récepteur HER2, capable de bloquer sa dimérisation, et utilisé en clinique. Dans un premier temps, nous nous sommes intéressés au rôle de HER3 en tant que cible et marqueur pronostique de l'effet du pertuzumab sur les PDAC exprimant faiblement HER2. Puis dans une deuxième partie, nous avons étudié et comparé les effets de différents anticorps monoclonaux dirigés contre HER2 et/ou HER3, sur la prolifération tumorale de tumeurs du pancréas. L'ensemble de ces résultats a permis d'établir que le ciblage du dimère HER2/HER3 s'avère être une stratégie prometteuse pour inhiber la croissance des tumeurs du pancréas exprimant faiblement HER2, et que le récepteur HER3 pourrait être un marqueur pronostique de l'effet du pertuzumab. / With a 5-year survival lower than 5%, PDAC is one of the worst cancers in terms of mortality, and for which existing therapies are unsatisfying. This cancer is characterized by a dense fibrotic tissue and an over-developed stroma, in continual interaction with the tumor, promoting the development of an ideal environment for tumor progression.To date, gemcitabine is the only approved chemotherapy able to slightly increase patients' survival. The use of erlotinib, an EGFR targeting therapy, underlined that EGFR family targeting could be an interesting treatment strategy in this pathology, but that a better patients' selection is essential to increase therapeutic response. Two receptors of this family, HER2 and HER3, are able to dimerize to consititute an aggressive entity, involved in PDAC tumoral growth. Various recently developed techniques are used to quantify those dimers, in order to study their role, but also to target them and block their signaling in cancer cells. Pertuzumab is currently the only HER2-targeting monoclonal antibody able to block its dimerization and used in clinic. We first evaluated the role of HER3 as therapeutic target and prognostic marker of pertuzumab efficacy on HER2-low expressing PDACs. We then studied and compared therapeutic effects on pancreatic tumor proliferation of different antibodies targeting HER2 and/or HER3. Taken together, those results demonstrated that HER2/HER3 dimers targeting is a promising strategy to inhibit low-HER2 expressing pancreatic tumor growth, and that HER3 could be a pronostic marker for pertuzumab efficacy in those cancers.

Human Epidermal Growth Factor Receptor 2 (HER2) is a cell surface receptor tyrosine kinase and plays a role in the signal pathways leading to cell proliferation and differentiation. Overexpression of HER2 is found in various cancers including breast, ovarian, gastric, colon, and non-small-cell lung cancers, which makes it an attractive target for cancer therapy. Specific antibodies, peptides and small molecules are developed by scientists to bind with HER2 as therapeutical agents, dimerization inhibitors and biological makers. Among these molecules, antibodies showed excellent binding affinity and specificity toward HER2. However, uses of antibodies are limited by their high cost of production, long development time, limited ability to penetrate tumor tissue and immunogenicity. Many of these limitations are due to the high molecular weight of antibodies. Compared to antibodies, peptides and small molecule that selectively recognize HER2 have advantages in solubility, permeability and immunogenicity. So far, the design of all peptides and small molecules for binding with HER2 either utilize phage display technique or rely on computational screen of large library of millions of small molecules. These approaches all suffer from the drawbacks of tedious, labor intensive, and time consuming as well as uncertainty of outcome. In this study, it was hypothesized that a novel approach based on molecular interactions of HER2-Pertuzumab complex and Knob-Socket model can be developed to design antibody mimics for targeting HER2. All designed antibody mimics were simulated and docked with HER2 using Molecular Operating Environment (MOE) software to estimate binding energy and analyze the detail interaction map. A series of mimics were then synthesized and characterized. HER2 positive breast cancer cells MDA-MB-361 and ZR-75-1 were used in confocal microscopic and flow cytometric studies to evaluate the binding specificity of all antibody mimics to HER2 in vitro, while human embryonic kidney cell (HEK293) was used as control. After incubation with antibody mimics, high fluorescence intensities were observed on MDA-MB-361 and ZR-75-1 cells, while only background fluorescence were observed on HEK293 cells. Surface plasma resonance (SPR) studies showed that all antibody mimics bind to HER2 protein with KD value in range of 55.4 nM- 525.5 nM. Western blot technique was used to evaluate inhibition capability of antibody mimics on phosphorylation of HER2 downstream signaling Akt and MAPK pathways that were crucial for cell differentiation and survival. When treated with antibody mimics at 10µM for 24 h, more than 85% phosphorylation of Akt pathway was inhibited while phosphorylation of MAPK pathway was not affected. This finding proved that antibody mimics could bind to HER2 extracellular domain and selectively inhibit the dimerization between HER2 and HER3 to block phosphorylation of Akt pathway in a similar way as Pertuzumab. In addition, in vivo studies on tumor bearing nude mice were carried out to investigate the distribution and binding specificity of antibody mimics towards HER2 positive tumor after injecting through vein tail. Signal intensity ratio (SIR) of tumor to muscle revealed about 10-fold increase in tumor retention of HER2-PEP11 compared to the Cy7.5 carboxylic acid and Cy7.5-HER2-PEP22, which confirmed excellent in vivo binding specificity of antibody mimic HER2-PEP11 to HER2 positive tumor. In conclusion, this study demonstrated that a rational design of antibody mimics with both binding specificity and affinity towards HER2 based on the molecular interaction between Pertuzumab and HER2 and Knob-Socket model is feasible.

Health technology assessment: case study on breast carcinoma treatment in the Czech Republic Bc. Lenka Šlegerová January 4, 2019 Abstract This thesis proposes an original method for assessing total costs of med- ical treatment. It defines the semi-Markov model with four states that are associated with specific costs of the treatment, and not with patients' health statuses. This method is applied to individuals' treatment data drawn from the Czech clinical practice in the treatment of the metastatic HER2+ breast cancer. The aim is to assess the cost-effectiveness of adding medication per- tuzumab to the combination of trastuzumab+docetaxel within first-line therapy and to examine whether using individual data on Czech patients and the economic conditions leads to different results from foreign stud- ies. Furthermore, employing censored data from the clinical practice in the thesis complicates the estimation of patients' overall survival in compari- son to clinical-trials data that form random samples. Therefore, survival functions were not only estimated by the Kaplan-Meier estimator but also using the Cox proportional hazard model and the Accelerated failure time model that both control for the effects of included covariates. The addition of pertuzumab does not result in significantly longer pa- tients'...