Application of Personalised Medicine Using an Integrated Service and Research Approach: Evaluation of Vitamin D in Breast Cancer Patients
Prof Maritha Kotze
Title of the project
Application of personalised medicine using an integrated service and research approach: Evaluation of vitamin D in breast cancer patients.
The high global incidence of cancer drives the development of novel approaches for prevention and treatment at an affordable yet efficient manner. BRCA1 and BRCA2 are the most frequently mutated tumour suppressor genes in familial breast cancer and loss of expression is associated with an increased risk of many common cancers. Although carriers of BRCA1/2 germline mutations have a significantly increased lifetime risk (60-85%), incomplete mutation penetrance implicates the involvement of other genetic and environmental factors as modifiers of disease risk and metastatic potential. These include vitamin D deficiency suggested to promote malignancy by causing DNA repair defects and activation of mechanisms underlying drug resistance (Graziano et al. 2016).
Clinical trials are generally considered the best way to determine whether an intervention benefits health. Unfortunately, clinical trials are very expensive and generally designed according to the guidelines for pharmaceutical drugs, assuming that the only source of the agent is the trial. This approach is not suitable for measurement of health outcomes related to vitamin D/25(OH)D concentrations, which are determined by both genetic and environmental factors. Lack of data from well-designed prospective randomized clinical trials involving genomics underscores the need for development of a cancer genomics database/registry and biobank, currently underway with CANSA support (2015-2017). As explained on the informed consent form used in health outcome studies, data can be extracted from this resource to 1) study the role of genetics in health and disease and to 2) provide information that could help clinicians improve the medical treatment of their patients at the point of care. Application of new knowledge gained through patient follow-up and comparative effectiveness studies involving the implementation of advanced molecular technologies, may translate into immediate clinical benefits. Given the strong link between breast cancer and features of the metabolic syndrome that tend to run a chronic disease course, but may remain unrecognised until complications develop, a chronic disease screening program has been implemented as part of the above-mentioned data/biobank development. The questionnaire used as a screening step to direct appropriate genetic testing was designed to assist with monitoring of treatment response over time. Vitamin D/25(OH)D concentrations are routinely determined in prospective participants treated with aromatase inhibitors due to increased risk of bone fractures. Those patients with vitamin D deficiency receive vitamin D and calcium supplementation according to standard practice, in addition to anti-cancer treatment. It is important to raise 25(OH)D to a level at which one can expect beneficial effects and then measure the achieved concentration. In this study the genetic contribution to vitamin D levels will be studied in relation to breast cancer development, recurrence and treatment response. The aim is to determine the measurement range associated with high risk clinical outcomes. Breast cancer patients with vitamin D deficiency (<20 ng/ml) at increased risk for adverse outcome will be selected for WES and their genetic profile compared with vitamin D sufficient (>30 ng/ml) patients.