Abstract PL1: Management of metastatic ER+ breast cancer
Authors: Johnston RD 
Published: March 2017

Abstract
Estrogen receptor positive (ER+) metastatic breast cancer (MBC) is the most common form of the disease, and its prognosis and outcome depends on a variety of clinical factors relating to disease free interval (DFI), response to prior adjuvant therapy, distribution of metastatic disease, and the intrinsic biological subtype of the ER+ tumor. The goals of treatment are to provide effective anti-cancer therapy that will control cancer growth, whilst at the same time maintaining quality of life. International guidelines recommend that for postmenopausal women with ER+ MBC endocrine therapy should be the 1st-line approach for the majority of patients, unless patients have a symptomatic visceral crisis that requires cytotoxic chemotherapy. Aromatase inhibitors (AIs) have been the standard of care with a median progression-free survival (PFS) of 10-13 months reported in previous studies. Recent 1st-line trials aimed at improving upon AIs have investigated either the selective estrogen receptor downregulator (SERD) fulvestrant, or targeted combination of AIs with cyclin dependent kinase (CDK 4/6) inhibitors. While some trials have seen benefit for fulvestrant over AIs in subgroups of endocrine therapy naïve patients (SWOG-O226) or those with non-visceral metastases (FALCON), significant improvement across all subgroups have been reported in two separate phase III trials for both palbociclib (PALOMA-2) and ribociclib (MONALEESA-2) when combined with the AI letrozole. Although it would appear that both endocrine-sensitive and endocrine-resistant disease benefit from combined AI + CDK 4/6 inhibitor therapy, one of the key issues in routine clinical practice is whether all 1st line patients require this approach. In the 2nd-line setting following progression on non-steroidal AIs, further endocrine monotherapy with either the steroidal aromatase inactivator exemestane or the SERD fulvestrant will yield a median PFS of only 3-4 months (EFECT, SOFEA). Much laboratory and translational research has explored mechanisms of resistance to AIs, and trials have since shown that median PFS can be improved to 9-11 months using targeted combinations of either exemestane with the mTOR antagonist everolimus (BOLERO-2), or fulvestrant together with the CDK 4/6 inhibitor palbociclib (PALOMA-3). Studies in endocrine resistance have looked at the impact of acquired key mutations detected in circulating tumour DNA (ctDNA) (ie. ESR1 or PIK3CA) on endocrine responsiveness, and how these evolve during therapy. Likewise, other signalling pathways have been implicated in causing endocrine resistance, and further combination trials are ongoing. While rapid and real progress has been made in ER+ MBC, integrating these novel, well tolerated, targeted combinations into the treatment algorithm of ER+ MBC is a current challenge. In particular, it will be crucial to understand the optimal sequence of endocrine based treatments that will keep patients free of disease progression for as long as possible with a good quality of life.
Citation Format: Johnston RD. Management of metastatic ER+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PL1.