Investigation of Genetic and Clinical Risk Factors for the Prediction of Early Endocrine Therapy Side Effects..

PhD Theses MedicalBreast cancer is the most common women's cancer worldwide. Prevention trials show that endocrine therapy can significantly reduce the incidence of breast cancer, though benefits must be weighed against side effects. Concerns about side effects are cited as a major reason behind poor uptake and adherence to endocrine therapy. However, research focussed on the risk factors of side effects or their impact on long-term breast cancer outcomes is limited. Hypotheses of this thesis are that there are multiple diverse risk factors for side effects; that risk factors can be used to predict side effect incidence; and that early reported side effects are a sign of endocrine therapy efficacy. Hypotheses were tested through studies of clinical baseline factors, genetic risk factors and sex hormones to explore associations with side effects in women from the IBIS-I and IBIS-II trials. Statistical algorithms combining risk factors were subsequently used to develop side effect prediction models and risk scores. Lastly, a study assessed the effect of reporting side effects on breast cancer incidence during long-term follow-up of IBIS-I and IBIS-II. Markers including menopausal status, BMI, age, reproductive factors, and sex hormones were found to affect the risk of side effects. However, no significant genetic markers were identified. Prediction of side effects using a side effect risk score derived from a logistic regression model, containing clinical and sex hormone factors was possible, but performance was poor. Further investigation of risk factors is required before accurate prediction is possible. Contrary to the initial hypothesis, reporting hot ushes in women randomised to tamoxifen and reporting arthralgia in women randomised to anastrozole was associated with increased risk of breast cancer, particularly oestrogen receptor-positive breast cancer in postmenopausal women. Overall, risk factors were identified that impact a woman's risk of side effects. The negative impact of side effects on breast cancer outcomes was also established