Abstract SY31-02: Clinical utility trials for CTC and ctDNA in ER+ advanced breast cancer
Authors: Bidard Francois-Clement 
Published: August 2019

Abstract
Background: In ER+ HER2- metastatic breast cancer (MBC) patients, current first line treatment options are either endocrine therapy (ET, given either as single agent or, more recently, in combination with cdk4/6 inhibitor) or chemotherapy (CT). Given its good risk/benefit ratio, endocrine therapy (ET) is the preferred 1stline therapy in these patients, but not all benefit from such strategy for which predictive biomarkers are lacking. During first line ET, resistance may also appear following the emergence of ESR1-mutated subclones. On grounds of prior clinical validity studies, the clinical utility of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) as a tool to improve the outcome of 1st line ER+ HER2- MBC patients has been / is investigated in large phase 3 trials.
CTC clinical utility trial: In the STIC CTC phase III trial (NCT01710605, coordinated by Institut Curie), the baseline CTC count (CellSearch, Menarini SB) was compared to the clinician's choice to treat patients with either single agent ET or frontline CT. N=778 ER+ HER2- MBC have been randomized between the CTC-driven choice to the clinician-driven choice. #60% of patients had a concordant prognostic evaluation. In the 2 subgroups (#40% of patients) with discordant treatment recommendations (depending on clinician or CTC count standpoint), frontline CT yielded significantly longer PFS. An unplanned analysis also suggested that CT was associated with a longer OS. Relying on CTC count as a modern prognostic biomarker, the STIC CTC trial was the first to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT than from single agent ET, challenging current standards and deserving further studies.
ctDNA clinical utility trial: The phase III PADA-1 trial (NCT03079011, coordinated by Unicancer UCBG and GYNECO) is testing the clinical utility of real time ESR1mut detection (at baseline, at 1 month and then every 2 months) through ctDNA analysis in N=1000 ER+ HER2- MBC patients treated with aromatase inhibitor (AI) and palbociclib. Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations) during first line AI-palbociclib therapy are randomized in a second step between switching to Fulvestrant-palbociclib or keeping the same regimen (AI-palbociclib until disease progression, a cross-over being then proposed). ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. &gt;90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Whereas the study is ongoing, preliminary results confirmed that ESR1mut is a rare event in untreated AI-"sensitive" ER+ HER2- MBC patients and primarily associated with a prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Palbociclib therapy, suggesting that this combination may retain early antitumor efficacy.
Discussion: Demonstrating clinical utility is paramount for new cancer biomarkers such as CTC and ctDNA. Large prospective interventional trials are however required, such as those discussed here.
Citation Format: Francois-Clement Bidard. Clinical utility trials for CTC and ctDNA in ER+ advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY31-02.