Background: Inflammatory breast cancer (IBC) is a rare form of breast cancer associated with a poor prognosis. This study describes the incidence, survival, and management of IBC in the province of Ontario. Methods: We conducted a retrospective, population-based, cohort study using data systems held at the Division of Cancer Care and Epidemiology at Queen’s University in Kingston, Ontario. Using the Ontario Cancer Registry (OCR), we identified all primary, pathologically confirmed cases of breast cancer. IBC cases were identified using the unique histology code ‘85303’. OCR records were linked to Statistics Canada data, Canadian Institutes of Health Information (CIHI) records of surgical procedures, and cancer centre records detailing radiotherapy and chemotherapy administration. We calculated age-adjusted incidence rates of IBC for cases diagnosed between 1984 and 2005. Using the Kaplan Meier product-limit method and log-rank statistics we compared overall survival for IBC and non-IBC, and assessed temporal and regional variations in IBC survival. We described the management of IBC for patients diagnosed between 1984 and 2004, and assessed variations over time and across cancer centres. Results: Age-adjusted incidence rates of IBC increased from 0.57/105 women-years in 1984-1987 to 1.15/105 women-years in 2003-2005 (p<0.0001). 10-year survival was 21.5% for IBC compared to 61.7% for non-IBC (p<0.0001). For IBC, 10-year survival increased from 12.0% (95% CI: 8.3–16.3) for those diagnosed between 1984-1994 to 24.0% (95% CI: 20.1–28.2) for those diagnosed between 1995-2005. The utilization of combined mastectomy and postoperative radiotherapy increased from 28.9% in 1984-1994 to 46.1% in 1995-2004 (p<0.0001). We observed no statistically significant difference in the utilization of chemotherapy over time. Differences in the utilization of combined mastectomy and postoperative radiotherapy were observed across cancer centres (29.8% at centre C vs. 54.7% at centre A, p<0.0001). We also observed wide variations in the estimates of survival across cancer centres. Discussion: Rates of IBC have increased over time in Ontario and we observed an improvement in the long-term survival. Management has shifted over time towards increased use of mastectomy and postoperative radiotherapy. Additional prognostic information is needed to determine how variations in practice may be related to variations in outcome. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-09-24 16:15:10.068

Metastasis is the leading cause of mortality in human breast cancer. However, there are few predictive, prognostic, or therapeutic targets of breast cancer metastasis. Ezrin, a membrane cytoskeletal cross-linker, is frequently over-expressed in human breast cancer and is required for motility and invasion by cultured epithelial cells. Our group has recently shown that ezrin acts co-operatively with the non-receptor tyrosine kinase, Src, in the transformation of epithelial cells, in which ezrin is phosphorylated on specific tyrosines, such as Y477, by Src (91, 93). We therefore examined whether Src/ezrin interaction also regulates invasion and metastasis of breast cancer. This thesis presents the following results: 1) In a murine system, ezrin and Src are differentially localized in nulliparous, lactating mammary glands and PyMT-induced tumours, with pronounced apical expression in nulliparous mammary glands but non-polarized strong cytoplasmic expression in PyMT-induced tumours. 2) Increased expression and activation of ezrin, Src and Met in PyMT-induced tumours compared to normal breast tissues was observed. A concomitant increased expression of activated Stat3 and HGF was also observed in PyMT-induced tumours, consistent with the establishment of an HGF/Met autocrine loop. 3) In invasive human breast tumours, from a premenopausal patient cohort, ezrin showed significantly greater cytoplasmic localization compared to non-neoplastic epithelial ducts in normal mammoplasties. 4) In a mouse breast carcinoma xenograft model, a Y477F ezrin mutant (not phosphorylatable by Src), significantly reduced local invasion of primary tumours and spreading into visceral organs, yet, it did not significantly affect primary tumour growth rate. 5) Y477F ezrin-expressing tumours exhibited focal areas of incomplete membranous ezrin staining which was absent in control tumours. Moderate/strong cytoplasmic ezrin staining was evident in both tumour groups. Thus, ezrin is differentially localized in non-invasive versus invasive mammary tumours. Our study implicates a role of the Src/ezrin pathway in regulating local invasion and metastasis of breast carcinoma cells and provides a clinically relevant model for assessing the Src/ezrin pathway as a potential prognostic marker and treatment target for invasive breast cancer. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2010-04-28 12:24:25.286

When women are faced with the diagnosis and treatment options for their care, they have high a need for information that persists throughout the course of their illness. When information needs are met, women are able to make informed decisions regarding their care, have increased quality of life, and cope better with their illness. The objective of this study was to identify the information needs of postmenopausal women with early stage breast cancer making treatment decisions regarding endocrine therapy. An integrative review of research was conducted to collate and describe the information needs assessment methodologies used to identify information needs for women with breast cancer. Based on this review and our long-term goal of identifying a list of questions or information needs of women at this stage of their cancer treatment, we conducted a qualitative descriptive study to identify information needs and interviewed 17 post-menopausal women with early stage breast cancer and 4 healthcare providers. Women were asked to describe the questions they had or the information that they needed when endocrine therapy became part of their care. The healthcare providers described the information that they felt was important for women to know in regard to endocrine therapy. A list of 91 questions regarding endocrine therapy was identified; including information needs related to side effects, drug characteristics, financial cost, and survival/recurrence. Most women were not aware that they had a choice about the different types of endocrine treatment and often followed the physician’s recommendations. This study supports the assertion that postmenopausal women with breast cancer wish to be informed that they have a choice and desire information to make the best personal choice in collaboration with the physician. Healthcare professionals need to be aware of both the common and individual patients’ information needs and present options to assist women making the best decisions about their care. / Thesis (Master, Nursing) -- Queen's University, 2010-06-25 15:21:29.869

Background: In 2007, the International Agency for Research on Cancer classified shift-work involving circadian disruption as a “probable carcinogen.” One proposed pathway for this relationship involves nighttime light exposure and subsequent decreases in melatonin production. It is postulated that melatonin, a cancer-protective hormone, may influence patterns of sex hormone production that in turn influence breast cancer risk. The purpose of this study was to investigate the relationships between night shift-work history, melatonin and sex hormone levels among shift-working women. Methods: 82 pre-menopausal nurses who work a rotating shift pattern of two days (7AM-7PM), two nights (7PM-7AM), followed by five days off participated in two study periods approximately six months apart (in summer and winter), each taking place during a day shift of the normal rotating shift pattern. Creatinine-adjusted melatonin metabolite concentrations were measured from morning void urine samples, and estradiol, estrone, progesterone and prolactin concentrations were measured from fasting blood samples taken at the same time. Other pertinent information was collected by measurement (weight, height) and by self-report via questionnaire. We examined melatonin-sex hormone relationships within each of two seasons, and across seasons, to investigate two hypothesized latency periods for influences of melatonin levels on sex hormones. Multivariate linear regression was used to explore relationships, with adjustment for confounders including age and body mass index. Results: An inverse relationship between melatonin and estradiol was suggested in winter (β = -0.13, p = 0.11), and a positive relationship was suggested for increasing estrone with increasing melatonin tertile in summer (p = 0.07), after multivariate adjustments. Melatonin was not associated with other hormones in either season. On investigation of a longer latency period, melatonin in the first season was not associated with sex hormones in the second season. While those working night shifts for 20 years or more had higher mean levels of estradiol, estrone and progesterone, results were not statistically different from those with a shorter history of night work. Conclusions: The results of this study do not provide evidence to support the proposed biological pathway involving altered melatonin and sex hormone levels as intermediates between shift-work and breast cancer risk. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2010-09-14 11:42:06.201

Epidemiological studies have identified psychological stress as a significant risk factor in breast cancer. The stress response is regulated by the HPA axis in the brain and is mediated by glucocorticoid receptor (GR) signalling. It has been found that early life events can affect epigenetic programming of GR, and methylation of the GR promoter has been reported in colorectal tumourigenesis. Decreased GR expression has also been observed in breast cancer. In addition, it has been previously demonstrated that unliganded GR can serve as a direct activator of the BRCA1 promoter in mammary epithelial cells. We propose a model whereby methylation of the GR promoter in the breast significantly lowers GR expression, resulting in insufficient BRCA1 promoter activation and an increased risk of developing cancer. Antibody-based methylated DNA enrichment was followed by qPCR analysis (MeDIP-qPCR) in a novel assay developed to detect locus-specific methylation levels. It was found that 13% of primary breast tumours were hypermethylated at the GR proximal promoter whereas no methylation was detected in normal tissue. RT-PCR and 5’ RACE analysis identified exon 1B as the predominant alternative first exon in the breast. Tumours methylated near exon 1B had decreased GR expression compared to unmethylated samples, suggesting that this region is important for transcriptional regulation of GR. It was also determined that GR and BRCA1 expression was decreased in breast tumour compared to normal tissue. Furthermore, the relative expression of GR and BRCA1 measured by qRT-PCR was correlated in normal tissue but this association was not found in tumour tissue. From this, it appears that lower GR levels with associated decreased BRCA1 expression in tissues may be a predisposing factor for breast cancer. Based on these results we propose a role for GR as a potential tumour suppressor gene in the breast due to its association with BRCA1, also a tumour suppressor gene, as well as its consistently decreased expression in breast tumours and methylation of its proximal promoter in a subset of cancer patients. / Thesis (Master, Biochemistry) -- Queen's University, 2012-09-26 18:19:11.006

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This doctoral dissertation, as part of a large and ongoing CIHR-funded study, used a subset of the total sample to evaluate the contribution of interactive health communication (IHC) as a complement to more traditional means of informational support (Care-as-usual) to optimal adjustment of women newly diagnosed with breast cancer (N = 135). According to the study protocol, participants in the experimental group received an IHC educational intervention for an eight-week period. Measures of psychosocial adjustment and information-related variables were administered in interviews at Time 1 (pre-intervention) within 8 weeks of initial diagnosis, and again 8 weeks post-intervention (Time 2). Psychosocial adjustment variables included: depressive symptoms (CESD), anxiety (STAI-Y), well-being (IWB), and quality of life (SF-36)-mental and physical health components. Information-related variables included: the need for information related to cancer, cancer-specialist, and family or friend's informational support, and overall satisfaction with information. Optimism and Constructed meaning were evaluated at Time 1 and 2, respectively. A GLM MANCOVA model tested overall F-ratios and regression coefficients using difference scores. Predictors in the model were: group (experimental versus control), constructed meaning, and optimism. The overall model (df = 8, 121) was significant for Group, F = 3.66, p < .001, effect size eta2 = .20, Constructed Meaning, F = 3.04, p < .004, effect size eta2 = .17, and Optimism, F = 2.95, p < .005, effect size eta2 = .16. Participants in the dissertation experimental group had significant improvements in QOL-physical health and overall satisfaction with information when compared with the control group. Constructed meaning was significantly associated with beneficial changes in all of the adjustment-related variables. The results of this dissertation clarify the potentially significant roles IHC and constructed meaning pl

This study was carried out to investigate the fatty acid composition of tumoral, marginal and normal breast tissue in female breast cancer patients. Patients were recruited from St. Boniface General Hospital. A pre-operative blood sample was drawn. After surgery, sections were obtained from tumoral, marginal and normal breast tissues for histology and biochemical analysis. Extracted lipids from marginal tissue were significantly higher than those in normal or tumoral tissue. The lipid profile in tumoral tissue was significantly different in terms of fatty acid composition compared to normal and marginal tissue with less linoleic and alpha linolenic acid and more long chain polyunsaturated fatty acid of omega-3 and omega-6 series. Marginal tissue showed significantly less alpha linolenic acid compared to normal tissue. An inverse correlation existed between plasma level of 22:6 n-3 and breast cancer stage. We found different lipid profile in tumoral tissue compared to normal and marginal tissue.

One of the best ways to diagnose breast cancer early or to predict therapeutic response is to use serum biomarkers. Unfortunately, for breast cancer, we do not have effective serological biomarkers. We hypothesized that novel candidate tumor markers for breast cancer may be secreted or shed proteins that can be detected in tissue culture supernatants of human breast cancer cell lines. A two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) strategy was utilized to identify and compare levels of extracellular and membrane-bound proteins in the conditioned media. Proteomic analysis of the media identified in excess of 600, 500 and 700 proteins in MCF-10A, BT474 and MDA-MB-468, respectively. We successfully identified the internal control proteins, kallikreins 5, 6 and 10 (ranging in concentration from 2-50 µg/L), as validated by ELISA and confidently identified HER-2/neu in BT474 cells. Sub-cellular localization was determined based on Genome Ontology (GO) for the 1,139 proteins, of which 34% were classified as extracellular and membrane-bound. Tissue specificity, functional classifications and label-free quantification were performed. The levels of eleven promising molecules were measured in biological samples to determine its discriminatory ability for control versus cases. This screen yielded activated leukocyte cell adhesion molecule (ALCAM) as a promising candidate. The levels of ALCAM, in addition to the classical breast cancer tumor markers carbohydrate antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) were examined in 300 serum samples by quantitative ELISA. All three biomarkers effectively separated cancer from non-cancer groups. ALCAM, with area under the curve (AUC) of 0.78 [95% CI: 0.73, 0.84] outperformed CA15-3 (AUC= 0.70 [95% CI: 0.64, 0.76]) and CEA (AUC= 0.63 [95% CI: 0.56, 0.70]). The incremental values of AUC for ALCAM over that for CA15-3 were statistically significant (Delong test, p <0.05). Serum ALCAM appears to be a new biomarker for breast cancer and may have value for disease diagnosis.