The overall aim of this thesis was to examine the role of social support networks and the significant other in breast cancer survivors. This thesis begins with a scoping review of current scientific literature to assess social support in the breast cancer context. The findings from this review showed that studies which have investigated social support networks in women with breast cancer do not often consider whether the actual support needs of the patient are met. In addition, there is little evidence from the support sources about the support that they may attempt to provide. Past research has attempted to measure social support and coping but is limited when attempting to understand interactions between the woman with breast cancer and their significant other as a dyadic process. Furthermore, the review indicated the lack of relevant research based in the UK. In Study 1, the perceptions held regarding the male partner were explored in five in-depth interviews with breast cancer survivors to answer the research question of “What support do male partners provide?”. Data were thematically analysed and findings indicated that male partners were perceived to provide instrumental support, whereas female support sources were perceived to provide more emotional support. In addition, the male partner was not always perceived to be the significant other as previous literature has suggested. This finding led to Studies 2A and 2B which aimed to find out more about different social support sources, the types of support provided and identify the significant other. Studies 2A and 2B mark one of the first examples of using ecomaps in this research area 1) as an elicitation tool in semi-structured interviews to collect data regarding an individual’s social support network and 2) as a method of visually presenting social support networks. Studies 2A and 2B illustrate the variety of sources and support provided. The final study, Study 3, presents three case studies of dyads, consisting of a breast cancer survivor and their nominated significant other, who they perceived to have provided them with the most support along the illness trajectory. This thesis contributes to the research literature in several ways. First, it outlines the research gaps in the current scientific research. Second, it provides a novel methodology for investigating the social support networks of breast cancer survivors through the use of ecomapping. Third, it contributes to the emerging knowledge on dyadic coping. The new knowledge generated is of importance when considering the post-treatment phase of the breast cancer trajectory. Finally the limitations and strengths of this work are discussed.

Background: HER2 gene amplification and protein overexpression defined as HER2 positivity (HER2+) breast cancer (BC) is encountered in 15-25% of cases and is characterised by an aggressive behaviour and poor outcome. Despite the high clinical efficacy of anti-HER2 targeted therapy, the response and clinical behaviour of HER2+ tumours is variable. There is evidence indicating that the response of HER2+ BC to anti-HER2 targeted therapy and chemotherapy is related to Oestrogen Receptor (ER) expression. In addition global gene expression profiling studies have demonstrated that ER and HER2 are the main determinant of BC molecular profiles and that HER2+/ER+ (luminal B) are molecularly distinct from HER2+/ER- (HER2 positive) tumours. It is hypothesised that ER+/HER2+ BC is also a distinct molecular class when compared to tumours with single positive or double negative expression. Therefore, this study aimed to investigate the biological impact of ER expression in HER2+ BC with consideration of the molecular classification of BC and key pathways related to expression and behaviour of both proteins in an attempt to understand their variable biological significance and relationship to treatment response and potentially to identify new therapeutic targets. Methods: Methods included assessment of proteins with known associations with HER2 and ER status and correlating their expression with clinicopathological variables, molecular classes, different key BC proteins and outcome. For this purpose, Immunohistochemistry (IHC) was used to stain a number of key targets, including Mitogen Activated Protein Kinases (MAPKs), Phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR) pathway members and other proteins related to HER2 and ER and proliferation in a large well-characterised uniformly treated and annotated cohort of 1835 patients with primary BC. In addition, a cohort of 197 primary BC patients treated with Trastuzumab between 2003 and 2012, were also included. Reverse Phase Protein Array (RPPA) was used to quantify protein expression in six BC cell lines. To assess the effect of HER2 on cell lines with and without ER expression, two HER2 negative cell lines (MCF-7 and MDA-MB-231) were transfected with HER2. Results: The majority of MAPKs pathway members (pan Extracellular Signal- Regulated Kinase (ERK1/2), nuclear phosphorylated (p)-ERK1/2, p-c-jun-N terminal Kinase (JNK1/2), pan p38, p-p38 and p-ATF2 and p-C-JUN) showed positive associations with good prognostic variables and longer survival in the whole (unselected) cohort and in ER+ tumours but many of these associations were lost with HER2 co-expression. Such associations were infrequently observed within ER-HER2+ cases. HER2 overexpression was associated with downregulation of phosphorylated MAPKs within the whole cohort and within ER+ BC (significant for nuclear p-ERK1/2, p-ATF2 and p-p38), but ERK1/2 and p-p38 were associated with HER2 positivity within ER- tumours implying their context specific function. In addition, pan ERK1/2, p-p38 and p-ATF2 were independent predictors of better survival in BC and in ER+ BC. RPPA confirmed the IHC findings and showed similar association where the expression of MAPKs was different in ER+HER2+ cell lines compared to ER-HER2+ and ER+HER2- ones. Regarding the PI3K/Akt/mTOR pathway, p-mTORC1 and Phosphatase and Tensin homolog (PTEN) were negatively associated with HER2 overexpression in ER+ tumours but were (in addition to Akt and PI3K) positively associated with HER2 in ER- tumours. Meanwhile, mTOR exhibited positive associations with favourable prognostic factors within ER+ BC which were decreased with HER2 co-expression and with ER loss. Additionally, p-mTORC1 was associated with prolonged breast cancer specific survival (BCSS) within Akt+ tumours but not within the whole cohort or other subgroups. In this study, using RPPA, mTOR and PTEN were positively associated with ER and negatively with HER2 in ER+ cell lines and p-mTORC1 was positively associated with HER2 in ER- cell lines in addition to other members. Importantly, PI3K, Akt, p-mTORC1 and its downstream p-S6K showed increased expression within ER+HER2+ cell lines compared to ER-HER2+ cell lines but PTEN expression was increased in ER-HER2+ vs ER+HER2+ cell lines. When the biological significance of HER2 and KI67-LI was investigated in ER+ tumours, both HER2 and KI67-LI were associated with poor prognostic variables and adverse outcome in the ER+ tumours. Although KI67-LI rather than HER2 was associated with downregulation of luminal associated biomarkers, HER2 positivity was associated with worse outcome in ER+ tumours, indicating that HER2+ BC are distinct aggressive tumours regardless of their proliferative activity. Investigation of other proteins related to HER2 and ER pathways revealed that nuclear form of both the Carboxyl-terminus of Hsp-70-Interacting Protein (CHIP) and the stem cell protein, Sry-Related HMG Box 9 (SOX9), were negatively associated with HER2. CHIP was positively associated with ER, ER-associated proteins and prolonged outcome in the unselected BC and in ER+ BC but not in ER+/HER2+ and ER-/HER2+ tumours. The phosphorylated form of ER at Serine (SER) 118 was positively associated with good prognostic variables and negatively with HER2 in the unselected series and in the ER+ BC group with an observed decrease in these associations within ER+/HER2+ tumours. Increased loss of association was encountered and even some unfavourable associations were observed within ER-HER2+. Furthermore, it was associated with prolonged survival in ER+ tumours and was a predictor of prolonged survival in patients receiving tamoxifen therapy. Clustering analysis to predict class memberships based on HER2 and ER expressions using a large panel of biomarkers related to ER, HER2 and key pathways’ proteins, generated a decision tree that could be a future model for patients’ stratification which indicated the overwhelming driving effect of HER2 expression. Conclusions: ER+/HER2+ BC is a distinct biological group, having some luminal features but is associated with worst outcome owing to the co-expression of HER2 independently from ER influence. The investigation of MAPKs, PI3K/Akt/mTOR pathways and other proteins highlighted their differential expressions and associations (with key proteins related to ER and HER2) within different BC subgroups based on ER and HER2 expressions indicating that ER+HER2+ stands as a group with unique features from those with single positive or double negative expression. Finally, development of a decision tree is a potentially promising tool for patients’ stratification. Breast cancer cell line studies using the high throughput technique, RPPA, showed good concordance with IHC results, implying that further in vitro studies using relevant cell line models could be possible.

Postmenopausal women rely on hormone replacement therapy to manage menopausal symptoms. Few studies have assessed the consequences of estrogen progestin replacement therapy (EPRT), a formulation prescribed to postmenopausal women with an intact uterus. The aim of this thesis was to conduct a systematic review and meta-analysis assessing the association between breast cancer risk and EPRT use among postmenopausal women. Electronic databases, handsearching and advice from experts were used to locate studies. A fixed effects model was used to calculate the combined estimate and its standard error. Statistical tests for association and homogeneity were performed. The association between breast cancer risk and EPRT exposure was significant for both case control (OR = 1.38; 95% CI 1.23--1.56; chi2 = 48.30, p < 0.0001) and cohort studies (RR = 1.42; 95% CI 1.29--1.57; chi 2 = 27.95, p < 0.0001). Results indicate that postmenopausal women on EPRT have a higher breast cancer risk, particularly with long term use and testosterone derived formulations.

This Ph.D. project sought to determine the expression, regulation, and function of the KIT-SCF receptor-ligand system in human epithelia] ovarian cancer. The expression of c- KIT and SCF in normal ovaries, in cultured ovarian surface epithelium (OSE), and in epithelia] ovarian tumors was analyzed. Normal OSE expressed SCF, but not c- KIT ; however, epithelia] invaginations and inclusion cysts often expressed KIT protein. Of 15 benign ovarian tumors and tumors of low malignant potential, 87% expressed c- KIT , and 92% of these co-expressed SCF, suggesting the possibility of autocrine growth regulation. Of 35 malignant ovarian cancers, 71% expressed c- KIT (92% co-expressed SCF), with a trend for decreased c- KIT expression in advanced stage disease. Of 34 patients with malignant tumors for whom follow-up information was available (median follow-up time of 24 months), 9 had tumors that did not express c- KIT , 8 (89%) of whom have died and the remaining 1 has recurrent disease. Of the 25 patients with tumors expressing c- KIT , 56% are still alive, eight of whom have no evidence of disease. Importantly, statistical analysis indicated that patients whose tumors did not express c- KIT had a significantly shorter (p < 0.05) disease-free survival time than patients who had KIT-expressing tumors. Studies were carried out to identify intraovarian growth regulatory factors which may regulate c- KIT and SCF expression in ovarian cancer cells, and to determine whether activated KIT can affect the proliferation and survival of these cells. HEY cells, which co-expressed KIT and SCF, were treated with transforming growth factor (TGF)-α, TGF-β, and dibutyryl cyclic AMP (dbcAMP) and their cellular proliferation and expression of c- KIT and SCF were examined. A series of transfection studies were carried out to determine if enforced c- kit expression inhuman ovarian carcinoma cells could regulate cellular proliferation. Transient transfection of c- kit into HEY cells resulted in decreased proliferation. Similarly, stable transfection of c- kit into A2780-cp cells, which do not express endogenous c- KIT , also resulted in a decreased proliferative rate. In contrast to the ovarian cancer cells, increased proliferation was documented for NIH 3T3 fibroblast cells transiently transfected with c- kit . Together, these results suggest that the positive prognostic value of c- KIT expression in ovarian tumors is related to its negative growth regulatory function in ovarian cancer cells. (Abstract shortened by UMI.)

Abstract Not Available.

Background. Decision support interventions (DSIs) are interventions used by patients and their practitioners to help make difficult shared healthcare decisions. The efficacy of these interventions is well established. However, there are no formal comparisons of the efficacy of different delivery methods. Interactive computerized delivery methods have the advantage of allowing patients to control the flow of information and to receive feedback on their comprehension. Objective. To compare the efficacy of an interactive computerized DSI for women considering long term hormone replacement therapy (HRT), to that of a validated audio-booklet-based version of the same intervention. Study design. Fifty-one peri- and post-menopausal women aged 40--70 who were literate in English, and who showed no evidence of cognitive impairment, were randomized to use either the computerized or the standard audio-booklet version of the DSI. The patients were interviewed with a pre- and post-intervention questionnaire. Interventions. (1) Standard audio-booklet-based decision aid: A 40-minute audio tape guided participants through an illustrated booklet describing the risks and benefits of post-menopausal HRT. (2) Interactive computer based decision aid: The computerized version of the DSI presents identical information as synchronized text/audio/animation. (Abstract shortened by UMI.)

Le but de l'étude consiste à évaluer auprès de femmes francophones l'efficacité d'un support d'aide à la décision sur la qualité de la prise de décision en regard de l'hormonothérapie substitutive. Une expérimentation avec un devis avant-après avec groupe unique a été menée auprès de 40 femmes âgées de 47 à 64 ans. Les variables à l'étude ont été mesurées à l'aide des questionnaires et des échelles de mesures portant sur: (1) les connaissances; (2) les attentes; (3) les valeurs; et (4) le niveau de conflit décisionnel en regard des bénéfices et des risques de l'hormonothérapie substitutive. Les résultats de cette étude révèlent une amélioration significative ( p < 0,05) des connaissances et une amélioration des attentes réalistes de la femme par rapport aux risques et aux bénéfices de l'hormonothérapie, après l'utilisation du support d'aide à la décision. Quant aux valeurs, les résultats révèlent une meilleure cohérence des valeurs de la femme par rapport à l'hormonothérapie après l'intervention. Enfin, les résultats démontrent, en général, une diminution significative du niveau de conflit décisionnel. Les femmes se sentent plus informées, supportées et ont la perception qu'elles ont pris une décision efficace. Les résultats de cette étude suggèrent que l'utilisation d'un support d'aide à la décision chez les femmes ménopausées contribue à l'amélioration de la qualité de la prise de décision par rapport à l'hormonothérapie substitutive. Cette étude doit être considérée comme un projet pilote, lequel devra être suivi d'une étude auprès d'un plus grand échantillon afin d'examiner la généralisation possible des résultats à l'ensemble de la population féminine francophone.

Objectives. (1) Primary, to identify factors influencing the decision to take long-term preventive hormone replacement therapy (LTP-HRT) assessed 2 months after the counseling interview with the physician. (2) Secondary, to identify factors influencing the decision to take LTP-HRT assessed after reviewing a decision support intervention and after a counseling interview with their physician and to identify the factors that are associated with women being uncertain regarding the decision to take LTP-HRT. Method. Data, collected from women who were participating in a RCT to evaluate the effectiveness of a decision support intervention, was used to develop multivariate statistical models at three specific time points. The time points were after reviewing the decision support intervention, after a counseling interview with their physician, and 2 months after the counseling interview. The physician was the unit of randomization in the original study and thus multivariate statistical modeling adjusting for correlated observations using Generalized Estimating Equations was utilized. (Abstract shortened by UMI.)

Cette étude descriptive vise à explorer les relations entre les déterminants de la santé, les données socio-démographiques et le point de services par rapport à l'utilisation du test Papanicolaou par les femmes autochtones de la région du Nipissing. L'échantillon se compose de 76 femmes autochtones et métis qui ont répondu à un questionnaire oral téléphonique ou face à face. Il y a des relations significatives entre l'utilisation du test Pap, tel que mesuré par la fréquence d'utilisation et le moment du dernier et du prochain test, et les déterminants de la santé et le point de services. Les résultats peuvent servir de tremplin pour des études ultérieures servant à améliorer la planification des soins de santé pour les femmes autochtones.

Few studies have focused on the amount of support provided by nurses on labour and delivery units. The purpose of this study was to examine the amount of nursing support provided by nurses during the intrapartum period as well as to identify factors that influence the provision of support. Support was operationalized within four categories: physical comfort measures; emotional support; instructional/informational support; and advocacy. The work sampling method was used to determine the percentage of time nurses spent in supportive care activities. Using this approach, each nurse, who met the inclusion criteria, was observed instantaneously at randomly selected times and the activity was recorded. Twelve nurses were observed over six non-consecutive day shifts on a labour unit of a teaching hospital in Montreal. A total of 404 observations were made. Nurses also were interviewed to determine their perceptions of what constituted supportive nursing care as well as the factors that facilitated or inhibited the provision of this care. Findings of the work sampling portion of the study indicated that nurses spent only 12.4% of their total time providing supportive care to labouring women. Interviews with six of the nurses that were observed suggested that their perceptions of the components of supportive care were comparable to what had been identified in the literature and with this study's operational definition of support with one exception: obtaining epidural analgesia was considered a key component of nursing support during labour. Further analysis revealed a major barrier to the provision of supportive care by nurses: the environmental control of labouring women and their partners by health care providers through the use of technology and rigid adherence to policy and procedure. (Abstract shortened by UMI.)