Abstract P1-05-06: Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA): A guide to the management of advanced breast cancer (ABC)
Authors: Rossi G , Lima Barros Costa R , Nagy RJ , Rademaker AW , Gradishar WJ , Santa-Maria CA , Curry-Edwards RL , Jain S , Flaum LE , Zagonel V , Platanias LC , Giles FJ , Talasaz A , Cristofanilli M 
Published: March 2017

Background: Estrogen receptor (ER)-α is expressed in about 70% of breast cancers and drugs that target the receptor function, selective estrogen receptor modulators (SERM) and aromatase inhibitors (AIs) represent the standard of care for patients (pts) with ER+ breast cancer. Nevertheless, prolonged exposure to endocrine therapy may result in acquired resistance and subsequent progression of disease. Recent evidence showed that activating mutations (muts) in the ligand-binding domain of ER-α occur in approximately 20% of pts exposed to endocrine therapies and those genomic abnormalities may represent the driver of endocrine resistance. In this context, ctDNA provides a non-invasive source for real-time next generation sequencing (NGS) studies, in order to understand the biology of ABC and guide and monitor treatment.

Methods: We conducted a retrospective review of 91 pts with ABC, including 57 pts with ER+ tumor, who had longitudinal assessment of their disease by ctDNA analysis. At the time of baseline sampling, 50/57 pts had stage IV cancer. The total number of blood samples collected was 184. 38 (67%) pts had serial samples. The average number of samples for each pt was 3 (range 1-7). The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &gt; 50 cancer genes.

Results: Among the ER+ subgroup (57 pts), we identified 11 pts (19%) harboring ESR1 muts in ctDNA. All 11 pts had metastatic disease: 2 (18%) had bone metastases, 2 (18%) had visceral metastases, 7 (64%) had both sites of disease. The median age was 55 years (range 33-73). 5 pts had inflammatory breast cancer. The most common ESR1 muts were: Y537S (6/11, 55%), D538G (4/11, 36%) and Y537N (3/11, 27%). 7 pts carried polyclonal muts. At the time of testing, 10 pts had already failed at least 1 line of endocrine therapy (average 2, range 1-5), including 6 pts that had received a fulvestrant-containing regimen, 8 pts ≥ 1 line of AIs. After the mut detection, 5 pt were on endocrine therapy and 4 pts were started on/continued chemotherapy. ESR1 muts disappeared in 2 pts (fulvestrant-palbociclib and chemotherapy respectively) who achieved stable disease as best response. Three pts continued to harbour muts and then progressed (one died). 2 pts had tissue NGS and ESR1 mut was not identified. Progression free survival and overall survival were 8 months (ms) and 21.5 ms in ESR1+ subpopulation versus 6.2 ms and 22.2 ms in the ESR1- pts (p = 0.78 and p = 0.97, respectively). At the time of analysis 5 pts were dead, 6 were currently alive.

  ESR1+ (n. pts) ESR1- (n. pts) Pts (total n.)1146 Previous chemotherapies11 (100%)31 (67%) Previous fulvestrant-containing regimens6 (54%)20 (43%) Previous AIs ± targeted therapy8 (73%)27 (59%)

Conclusions: We observed that ESR1 muts, a known driver of endocrine resistance, occurs at a high frequency in heavily pre-treated estrogen receptor positive ABC. Blood-based diagnostics can be used to identify ESR1 muts sometimes not detected by tissue-based sequencing of the metastatic lesions indicating tumor heterogeneity and allowing dynamic monitoring of ABC.

Citation Format: Rossi G, Lima Barros Costa R, Nagy RJ, Rademaker AW, Gradishar WJ, Santa-Maria CA, Curry-Edwards RL, Jain S, Flaum LE, Zagonel V, Platanias LC, Giles FJ, Talasaz A, Cristofanilli M. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA): A guide to the management of advanced breast cancer (ABC) [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 P1-05-06.