Challenges, Strengths and Opportunities Related to Implementing Comprehensive Evidence-Based Guidelines on Breast Cancer Survivorship Care by Primary Care Physicians and Nurse Practitioners in Southeastern Ontario

Background Many breast cancer survivors continue to have a broad range of physical and psychosocial problems after breast cancer treatment. As cancer centres move forward with earlier discharge of stable breast cancer survivors to primary care follow-up it is important that comprehensive evidence-based breast cancer survivorship care is implemented to effectively address these needs. Research suggests primary care providers are willing to provide breast cancer survivorship care but many lack the knowledge and confidence to provide evidence-based care. Purpose The overall purpose of this thesis was to determine the challenges, strengths and opportunities related to implementing comprehensive evidence-based breast cancer survivorship guidelines by primary care physicians and nurse practitioners in southeastern Ontario. Methods This mixed-methods research was conducted in three phases: (1) synthesis and appraisal of clinical practice guidelines relevant to provision of breast cancer survivorship care within the primary care practice setting; (2) a brief quantitative survey of primary care providers to determine actual practices related to provision of evidence-based breast cancer survivorship care; and (3) individual interviews with primary care providers about the challenges, strengths and opportunities related to provision of comprehensive evidence-based breast cancer survivorship care. Results and Conclusions In the first phase, a comprehensive clinical practice framework was created to guide provision of breast cancer survivorship care and consisted of a one-page checklist outlining breast cancer survivorship issues relevant to primary care, a three-page summary of key recommendations, and a one-page list of guideline sources. The second phase identified several knowledge and practice gaps, and it was determined that guideline implementation rates were higher for recommendations related to prevention and surveillance aspects of survivorship care and lowest related to screening for and management of long-term effects. The third phase identified three major challenges to providing breast cancer survivorship care: inconsistent educational preparation, provider anxieties, and primary care burden; and three major strengths or opportunities to facilitate implementation of survivorship care guidelines: tools and technology, empowering survivors, and optimizing nursing roles. A better understanding of these challenges, strengths and opportunities will inform development of targeted knowledge translation interventions to provide support and education to primary care providers.

Alcohol: a recently identified risk factor for breast cancer

Acknowledgements: I thank Dr. Barbour Warren, arriet Richardson and Alison James for their helpful input.

Characterization of Glucocorticoid Receptor Promoter Methylation in Breast Cancer

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.