Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders.

Abstract

For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. Various mechanisms of resistance have been described. In order to reduce or overcome endocrine resistance, there has been substantial interest in developing potent and orally bioavailable selective estrogen receptor degraders (SERDs) for metastatic disease and select patients with early-stage estrogen receptor positive breast cancer. At least 11 oral SERDs have entered clinical development. We review current studies in both the metastatic and neoadjuvant/adjuvant setting and present the available evidence of benefit and toxicity for these novel agents. Further characterization of changes to tissue-based biomarkers such as estrogen receptor, progesterone receptor and Ki67 expression and blood-based biomarkers such as ctDNA and estrogen receptor 1 mutation may help to refine therapeutic strategies, combinations, and patient selection to identify women who are most likely to benefit from these novel endocrine agents. Although SERDs have clear therapeutic potential based on nonclinical studies and have demonstrated early signs of activity in phase I and II studies in the metastatic setting, ongoing research is needed to clarify when and in whom these agents may have greatest clinical benefit.