Grant: Project Grant

Aromatase inhibitors (AIs) are considered gold-standard therapy against hormone-dependent breast tumors which make up 80% of all breast cancers (BC). This treatment significantly reduces the risk of BC recurrence and mortality. However, about 10-15% women will experience early cancer recurrence within 5-years of diagnosis. AIs lower estrogen level by blocking estrogen synthesis from androgens but in some women this mechanism will be inadequate. Obesity has been suggested to contribute to decreased AI efficacy; however, not all obese women will fail to respond to treatment. Therefore, it is likely that other exposures may be involved in interfering with the drugs' effectiveness. AIs may be less effective against external sources of estrogens like environmental contaminants. These have been shown to alter the levels of circulating estrogens and correlate with other BC risk/prognostic factors (obesity, breast density). They have also been linked with inducing epigenetic changes through alterations in DNA methylation. By assessing the levels of environmental contaminants and methylation in a cohort of BC survivors and following their treatment response, our findings will help to further elucidate the mechanisms of AI nonresponse as they relate to these factors. These have never been investigated before in this context even though AI-treatment nonresponse remains a major obstacle to optimal BC management. Currently, nonresponding patients are unable to reap the benefits of first-line targeted therapy and experience significant morbidity due to delayed appropriate treatment. A better understanding of factors driving treatment inefficacy is necessary to spare women the consequences of ineffective treatment, and to inform treatment approaches in high-risk women early in the disease trajectory. Lastly, if environmental contaminants desensitize AIs through methylation, a modifiable DNA event, therapies aiming to reverse this process can be exploited.