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.

No description available.

Gene expression profiles have identified five major molecular breast cancer subtypes (Luminal A, Luminal B, Basal-like, HER2+/estrogen receptor− , and Normal Breast-like) that show significant differences in survival. The cost and complexity of gene expression technology has impeded its clinical implementation. By comparison, immunohistochemistry is an economical technique applicable to the standard formalin-fixed, paraffin-embedded material commonly used in hospital labs, and has the advantage of simultaneously interpretation with histomorphology. In this thesis, I hypothesize that a surrogate panel of immunohistochemical biomarkers can be developed to discriminate the breast cancer biological subtypes. The main study cohort consists of over 4000 primary invasive breast tumors, assembled into tissue microarrays. These patients were referred to the British Columbia Cancer Agency between 1986-1992 and have staging, pathology, treatment and follow-up information. In summary, our results demonstrate that (1) the rabbit monoclonal antibody, SP1, is an improved standard for immunohistochemiscal estrogen receptor assessment in breast cancer; (2) the transcription factor, GATA-3, is almost exclusively expressed among estrogen receptor positive tumors but does not seem to predict for tamoxifen response among estrogen receptor positive patients; (3) the proliferation marker, Ki-67, together with HER2 can segregate Luminal A from Luminal B subtypes, which carry distinct risks for breast cancer relapse and death; and (4) the inclusion of the basal markers EGFR and ck5/6 to “triple negative” breast cancers provides a more specific definition of basal-like breast cancer that better predicts patient survival. These results consistently demonstrate that an immunopanel of six biomarkers (estrogen receptor, progesterone receptor, HER2, Ki-67, epidermal growth factor receptor and cytokeratin 5/6) can be readily applied to standard pathology specimens to subtype breast cancer samples based on their underlying molecular biology. These findings have been considered sufficient to justify application of this panel onto NCIC (MA5, MA12) and CALGB (9341 and 9741) clinical trials specimens. This followup work which is underway and will determine if the six marker immunopanel can guide decisions about which patients need aggressive systemic drug treatment, and thereby ensure patients get the most effective, individualized adjuvant systemic therapy for their breast tumor. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Cancer survivors are at greater risk of cardiovascular diseases in comparison to the general population. Cardiovascular disorders are among the most prominent comorbidities in breast cancer patients. In order to gain a better understanding of the prescribing practices and cardiovascular risks associated with oncology drugs, this thesis encompasses a detailed review of the molecular and physiological mechanisms leading to drug‐induced cardiotoxicity and an evaluation of the cardiovascular risks associated with cancer drug therapies. Using a nested case‐control design, we evaluated whether these cancer drugs were associated with adverse cardiovascular outcomes under real‐world conditions of use. Although only few oncology drugs are indicated for breast cancer treatment, we were interested in prescribing practices and whether breast cancer treatments are restricted to labelled indications. The characterization of prescribing practices provides insights on the range of antineoplastic agents that should be considered in the evaluation of treatmentrelated adverse reactions such as cardiotoxicity. We found that selective estrogen receptor modulators demonstrated a better safety profile than aromatase inhibitors based on their mechanism of action on the cardiovascular system. These observations were corroborated by our findings from logistic regression analyses where aromatase inhibitors were associated with a higher risk of heart failure in a heterogeneous population of breast cancer patients. We reported that off‐label prescribing is common strategy in breast cancer treatment. While this practice tends to be associated with specific socio‐demographic and disease characteristics, the majority of off-label encounters are evidence‐based decisions. Because these off‐label treatments have their own inherent safety profiles, a comprehensive approach, covering all antineoplastic agents administered should be adopted in the evaluation of breast cancer treatment-induced cardiotoxicity. Careful monitoring of patients is crucial for the early detection of warning signs of cardiotoxicity to prevent long‐term deleterious effects. The information contained in this thesis provides useful considerations for the prospective surveillance of cancer drug‐induced cardiac events. These findings point to the need for a multi‐disciplinary approach to facilitate the rapid diagnosis and treatment of cardiac complications secondary to cancer therapy and to ensure that treatment decisions will maximize tumor response while minimizing adverse outcomes.

Screening, surveillance and preventative medical interventions are being identified as best practices for women at high-risk of developing hereditary breast cancer. Genetic screening for the BRCA1/2 mutations associated with hereditary breast cancer is currently recommended as an appropriate health intervention for younger women who have been affected by breast cancer, as well as for those who have been identified as high-risk due to their family histories of breast cancer. At present, however, little is known about the psychosocial implications of genetic screening for BRCA1/2 mutations on young families. Using the common sense model of self-regulation (Leventhal et al., 1997), adapted for genetics (Cameron, 2003; Marteau & Weinman, 2006) as a guiding framework, the goals of this dissertation were to: (a) examine the relationships between threat representation and psychosocial functioning in BRCA1/2 counselees, (b) explore the impact of fear representation on women’s psychosocial functioning, and (c) assess how BRCA1/2 counselees’ threat representations and fear representations impact family functioning and the psychosocial adaptation of their adolescent daughters. Results indicated that total threat representation, including risk representation, illness representation and fear representation, was found to add to the prediction of mothers’ self-reported levels of anxiety, depressive symptoms and intrusive ideation regarding genetic counseling. Additionally, when the cognitive processes of the threat representation were controlled (i.e., risk representation and illness representation), the subjective-emotional processes (i.e., the fear representation) continued to emerge as a significant predictor of mothers’ self-reported anxiety, depressive and intrusive ideation symptoms. Additionally, support for the association between mothers’ threat representations and adolescent daughters’ reports of depressive symptoms and self-concept were noted. Cumulatively, these results provide support for the role of fear representation within the CSM framework and suggest that fear representation plays an important role in BRCA1/2 counselees’ psychosocial adaptation following genetic counseling.

Radiation therapy has been shown to increase local and regional control as well as overall survival with breast cancer, but the vast majority of patients develop acute skin reactions, which are in part related to microvascular changes. These reactions vary between different skin sites. The aim of this work is to determine the absorbed dose to the skin by measurements and investigate if there is a correlation between the absorbed dose at different areas of the breast and the local changes in microcirculation in the skin after breast cancer radiotherapy. The study includes characterisation of the Gafchromic EBT3 film and Epson Perfection V600 Photo scanner which are used for absorbed dose determination. The measurements were done both on an anthropomorphic female phantom and on a patient undergoing breastcancer radiotherapy. Twenty-one pieces of film (2x1 cm2) were placed on the surface ofthe breast (both for the phantom and patient) and irradiated with a prescribed dose to the target of 2.66 Gy with two opposed fields using 6 MV beam. It was observed that mainly 45-64 % of the prescribed dose was deposited at the surface, both for the phantom and patient. Using laser speckle contrast imaging and polarised light spectroscopy, the regional changes in mean blood perfusion and in mean red blood cell concentration (RBCC) at the end of the treatment with a total prescribed dose of 42.6 Gy, compared to baseline, were measured in both the treated and untreated breast of the same patient. Although marked increases in perfusion were seen in different areas of the treated breast, there was no signicant correlation between the changes in perfusion and the absorbed dose at these areas. However, a statistical correlation was found between the changes in RBCC and the absorbed skin dose at the same areas. To further elucidate the relation between the changes in skin microcirculation and the absorbed radiation dose during breast cancer radiotherapy, future studies using a larger number of patients are needed.

Thesis (MSc (Radiography))--Cape Peninsula University of Technology, 2019 / INTRODUCTION: The Breast Imaging Reporting and Data System (BI-RADS) was developed by the American College of Radiology (ACR). The BI-RADS is an internationally accepted method of assessing and reporting on mammograms and breast ultrasound images. The BI-RADS consists of a lexicon (descriptors) and assessment categories. The ACR aimed to standardise mammography reporting and placing the findings in the appropriate assessment category. The aim of this study was to establish the accuracy of the BI-RADS assessment categories for mammography and breast ultrasound images in women diagnosed with breast cancer. METHOD: Data were retrieved from 77 patients who were diagnosed with breast cancer from 1 January 2013 to 31 December 2014. Seven did not meet the inclusion criteria and were excluded. The study sample size was 70 (n=70) patients. All mammography reports included a BI-RADS assessment category of all patients diagnosed with breast cancer within the study period. These reports were analysed and compared with histopathology results. The BI-RADS assessment category and descriptors were collected from the mammogram reports; the histopathology report indicated the type of breast cancer. All reports were obtained from the patients' folders at the research site. In addition, questionnaires were distributed among radiologists to assess whether their experience and training had an influence on the accuracy of reporting in the BI-RADS assessment categories. Descriptive and inferential statistical analysis was used for data analysis. RESULTS: The most common malignancy diagnosed was invasive ductal carcinoma with a total of 70% (n=54), followed by ductal carcinoma in situ with 10.4% (n=8) and invasive lobular carcinoma with 9.1% (n=7). The histology results confirmed breast cancer for all BI-RADS 4 and 5 assessment categories. The mammogram was able to detect 93.5% of abnormalities and breast ultrasound 84.4% of abnormalities in this study sample. Breast ultrasound was used as an adjunct to mammography and hence an overall combined diagnostic rate was 100%. Mammography descriptors: The more common malignancy findings were spiculated mass margin, 35.1% (n=27). Ultrasound descriptors: The more common malignancy findings were hypoechoic echo pattern, 55.8% (n=43). There was no significant association (p=0.152) between the radiologists' years of experience and BI-RADS 3, 4 and 5 assessment category reporting. Of the 15 responses, 67% agreed that the BI-RADS standardises breast imaging reporting and reduces confusion, 33% agreed that the BI-RADS allows better communication between radiologists and referring physicians, and 40% agreed that the BI-RADS clarifies further management for patients by helping to stratify risk management. CONCLUSION: The outcome of this study indicated that the use of BI-RADS assessment categories is useful for predicting the likelihood of malignancy when used correctly. The outcome of BI-RADS 4 and BI-RADS 5 had a positive predictive value of 100%, which corresponded well with histology results. The descriptor findings suggested that spiculated mass margins, irregular-shaped masses, hypoechoic echo pattern and posterior shadowing were high predictors of malignancy and warranted a placement in the BI-RADS 5 assessment category.

No description available.

The epidermal growth factor receptor (EGFR) is a well-recognized proto-oncogene and mediator of cancer cell growth and proliferation. Emerging evidence suggests the paradoxical role of EGFR activation, unique to metastatic breast cancer cells. Previously studies elucidated the role of EGFR mediated activation of Signal Transducer and Activator of Transcription 1, STAT1, is required to induce apoptosis in cells with increased metastatic potential. In this current study, we evaluate the effects of cells with mutations leading to aberrations in phosphatidylinositol 3-kinase, PI3K/AKT/protein kinase B signaling. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) is a key regulator of the PI3K/Akt pathway and is one of the most commonly mutated genes in breast cancer patients. Utilizing human breast cancer cells, MDA-MB-468 and BT-20s, characterized by amplified protein levels of EGFR and mutations in the PI3K signaling, we demonstrate activation of EGFR with EGF leads to increased pSTAT1 expression. We further demonstrate biased EGFR signaling toward STAT1 activation by pharmacological inhibition of downstream kinase activity with MEK1/2 inhibitor, trametinib, and the AKT inhibitor, Uprosertib or in combination with the PI3Kα specific inhibitor Alpelisib, trade name, PIQRAY. Combination MEK and Akt signaling inhibition followed by EGF stimulation show marked increase in apoptotic activity and decreased cell viability. Moreover, we demonstrate changes in EGFR mediated apoptosis in murine breast cancer cell line derived from metastatic lung nodules, delineate from cells derived from the primary tumor. These finding support the notion of differential evolution of cancer cells as they metastasize to secondary organs. Furthermore, EGFR expression was observed to be vital in EGF mediated pSTAT1 in human breast cancer cell lines. To this end we explored alternative stimulators of pSTAT1 using interferon activation. Addition of INFγ led to robust pSTAT1 in cells that did not respond to EGF and levels of pSTAT1 were not attenuated with our combination treatment. Together, our findings demonstrate the differential role of EGFR expression and signaling in metastatic cells and tolerance for novel combination therapies for patients of late stage breast cancer.

A research report submitted in fulfilment of the requirement for the degree Masters in Medicine in Surgery to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2019 / Background: Phyllodes tumours are rare fibroepithelial neoplasms of the breast. The dilemma with phyllodes tumours is their tendency to local recurrence. This retrospective review of phyllodes tumours in a South African population aims to describe the most common histological and clinical features, and describe the clinical and histological risk factors for local recurrence. Methods: All histological reports of patients diagnosed with a phyllodes tumour after surgery at the University of the Witwatersrand Anatomical Pathology Laboratories in Johannesburg were assessed from 1 January 2005 to 30 June 2016. Clinical and histological parameters were analysed. Results: Over the study period, 185 patients were identified. The median age of the patients was 42 years. There were 89 (48.1%) patients with a benign tumour, 34 (18.4%) with a borderline tumour and 62 (33.5%) with a malignant tumour. The size of the tumours ranged from 11 to 460mm, with a median of 85.0mm  79.6 SD. Breast conserving surgery (BCS) was performed on 64.3% of patients and 35.7% of patients had a mastectomy. There was an overall local recurrence rate of 3.78% (2.2% for benign and 8.1% for malignant tumours). No clinical or histological factors, including margin status, were found to significantly predict local recurrence. Most recurrences (71.4%, n=5) occurred within the first two years. Conclusion: Our study did not find any predictors of local recurrence, but we provide further support to the recent suggestion of revising the common practice of wide local excision with a 1cm margin, to an excision with negative margins combined with close follow-up for two years. / TL (2020)