Abstract IA3-3: Genetic testing for breast and ovarian cancer: From risk assessment to therapeutic targeting

Abstract

Abstract Germline genetic variation can be used in a number of ways to improve the care of patients. First, such information can be used to predict the development of disease. Knowledge of risk can lead to targeted preventative strategies. Finally, understanding the genetic etiology for the development of an individual's cancer has the potential to lead to targeted drug development. Inherited BRCA1 and BRCA2 mutations are a model for this paradigm. Since these genes were identified in 1994 and 1995, much work has been done to establish mutation-associated cancer risks and potential management strategies. Deleterious mutations in both genes are associated with a high risk of breast and ovarian cancer, as well as lower risks of other tumor types. Risk-reducing salpingo-oophorectomy significantly reduces the risk of breast and ovarian cancer in mutation carriers and work is ongoing to establish the optimal timing of this procedure as well as the potential for hormone replacement therapy. Women with BRCA1 or BRCA2 mutations require increased breast screening with the addition of breast MRI at the minimum. Prophylactic mastectomy is a valid option. More recently attention has turned to the impact of the biological basis of disease in BRCA1/2 mutation carriers with breast and ovarian cancer on decisions regarding systemic therapy. Due to the role of BRCA1 and BRCA2 proteins in cellular functions such as homologous DNA repair, an enhanced sensitivity to platinum agents and reduced sensitivity to spindle poisons has been postulated and supported by in vitro studies and early clinical data. An additional pathway to target that has been recently identified is poly(ADP-ribose) polymerase (PARP). PARP is a key enzyme in the base-excision repair pathway. In vitro, PARP inhibitors given to BRCA1 or BRCA2 deficient cell lines have led to cell death through synthetic lethality. Early clinical trials have demonstrated efficacy for PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced breast and ovarian cancer, with objective response rates in heavily pretreated patients of greater than 40%. Genetic testing for BRCA1 and BRCA2 mutations can be seen as a model for translating the biology of a disease into risk assessment, prevention and treatment, thus demonstrating the potential for inherited genetics to directly impact the care of patients. Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-3.