Doctoral Degrees (General Surgery)

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    Bone health in post-menopausal patients with breast cancer treated with aromatase inhibitors: factors predicting the risk for osteoporosis.
    (Stellenbosch : Stellenbosch University, 2018-12) Baatjes, Karin Jeanné; Kotze, Maritha J.; Conradie, M.; Apffelstaedt, Justus P.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Surgical Sciences: Surgery.
    ENGLISH ABSTRACT: Aromatase inhibitors (AI), the gold standard for treatment of postmenopausal women with hormone-sensitive breast cancer, add an additional burden to the risk of osteoporosis in the postmenopausal population. Individual variation in AI associated bone loss is related to clinical risk factors as well as genetic variations in drug metabolism. The aim of the study is to identify postmenopausal breast cancer patients at highest risk for AI- associated bone loss by utilizing clinical, biochemical and genetic parameters. In parallel, clinically meaningful patient reports were developed from a secure online genomics database resource, enriched during the study. This prospective study was conducted at the Tygerberg Hospital Breast Clinic in affiliation with Stellenbosch University. Postmenopausal women with endocrine sensitive breast cancer, aged 50 to 80 years, were enrolled after obtaining informed consent. A baseline questionnaire documented demographic-, lifestyle- and medical history before commencing AI treatment. Clinical, biochemical and bone mineral density (BMD) measurements were obtained at baseline. Cytochrome P450 19A1 (CYP19A1) genotyping was performed using real-time polymerase chain reaction (PCR), and a screening algorithm applied to select patients for whole exome sequencing (WES). Results relevant to breast cancer diagnosis, comorbidities and treatment response were integrated into an adaptable report format for clinical application. Descriptive statistics were used to analyze the data. A total of 101 participants were recruited, with a mean age of 61±7 years. Thirty-two women fulfilled global criteria for bone protection at baseline [BMD T-score ≥-2SD (n=18); BMD T-score -1.5SD to < -2SD with risk factors (n=14)]. In women with osteoporosis, significantly lower body weight, body mass-, fat mass- and lean mass index were documented (p <0.001). Low vitamin D status was present in more than 90% of the cohort tested (n=95). After one year of AI treatment, 72 patients remained in the study, of whom 10 (14%) experienced more than 5% bone loss at the lumbar spine. Genotyping for the CYP19A1 rs10046 in 72 patients revealed that patients with two copies of the A-allele are 7,37 times more likely to have a higher percentage bone loss at the total hip compared to those without this allele (CI of 1.101- 49.336, p=0.04). At the lumbar spine, CYP19A1 rs10046 AA homozygotes were 10.79 times more likely to have a higher percentage bone loss compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). Extended genetic testing using Sanger sequencing and WES in the 10 patients with more than 5% bone loss supported the clinical findings. None of the 34 patients without bone loss at the lumbar spine at month 12 were homozygous for the functional CYP19A1 polymorphism. At baseline, a third of women fulfilled global criteria for bone protection. This highlights bone fragility associated with body composition variables of postmenopausal women in our predominantly Mixed Ancestry study cohort. Homozygosity for CYP19A1 rs10046 provides additional information for individual risk stratification to optimize bone health maintenance. New insights gained into the mechanisms impacting bone health merit continued health outcome studies embedded in routine clinical practice.