Abstract PS2-02: Prognostic relevance of the HER2 status of circulating tumor cells in metastatic breast cancer patients screened for participation in the DETECT study program
Authors: Müller Volkmar , Banys-Paluchowski Maggie , Friedl Thomas WP , Fasching Peter A , Schneeweiss Andreas , Hartkopf Andreas , Wallwiener Diethelm , Rack Brigitte , Meier-Stiegen Franziska , Huober Jens , Rübner Matthias , Hoffmann Oliver , Müller Lothar , Janni Wolfgang , Wimberger Pauline , Jäger Bernadette , Pantel Klaus , Harbeck Nadia , Fehm Tanja 
Published: February 2021

Abstract
Background
Circulating tumor cells (CTCs) have been reported to predict clinical outcome in metastatic breast cancer (MBC). Biology of CTCs may differ from the primary tumor and HER2-positive CTCs are found in some patients with HER2-negative disease. In this analysis, we evaluated the clinical relevance of the HER2 status of CTCs in patients screened for participation in the DETECT trials, the largest study program for CTC-based therapy interventions in MBC.
Methods
Patients with HER2-negative MBC were screened for CTCs using CellSearch. CTCs were labeled with an anti-HER2 antibody and classified according to staining intensity (negative, weak, moderate, or strong staining). Patients with HER2-positive CTCs were invited to participate in the randomized phase III DETECT III trial, which evaluated treatment with physicians' choice therapy with and without lapatinib. Patients with HER2-negative CTCs could participate in the DETECT IVa/b trials which investigated serial blood measurements during in-label systemic therapy. Patients who participated in the screening but were not enrolled in the DETECT III or DETECT IV trials were treated at discretion of their physician and followed up for progression and death.
Results
Screening blood samples were analyzed in 1933 patients with HER2-negative MBC. Out of these, 102 were enrolled in the DETECT III and 213 in the DETECT IVa/b trials, respectively. 1217 out of the 1933 screened patients (63.0%) had ≥ 1 CTC per 7.5 ml blood. ≥ 5 CTCs were detected in 735 patients (38.0%; range 1 – 35,078 CTCs, median 8 CTCs). Patients with ER-positive tumors were more likely to be CTC-positive than patients with ER-negative disease (≥ 1 CTC in 64.7% vs. 57.1% patients, respectively, p = 0.011; ≥ 5 CTCs in 40.8% vs. 29.5%, p &lt; 0.001). CTC status was also associated with ECOG performance status (≥ 1 CTC in 63.2% of patients with ECOG 0 vs. 69.0% with ECOG 1-3, p = 0.020; ≥ 5 CTCs in 36.3% vs. 47.2%, p &lt; 0.001). HER2 status of CTCs was assessed in 1159 CTC-positive patients. At least one CTC with strong HER2 staining was found in 174 (15.0%) patients. The proportion of CTCs with strong HER2 staining among all CTCs of an individual patient ranged between 0.06% to 100% (mean: 15.8%). Patients with ER- and PR-positive tumors were more likely to harbor ≥ 1 CTC with strong HER2 staining. For survival analysis, 52 patients receiving anti-HER2-therapy with lapatinib in the interventional arm of the DETECT III trial were excluded. CTC status was significantly associated with OS (median OS in patients with ≥ 1 CTC: 15.5 [95%-CI: 14.2-16.8] months vs. 37.2 [32.7-41.7] months in CTC-negative patients, p &lt; 0.001, HR 2.359; median OS in ≥ 5 CTCs vs. &lt; 5 CTCs: 12.0 [10.0-14.0] vs. 28.6 [25.5-31.6] months, p &lt; 0.001, HR 2.204). Detection of ≥ 1 CTC with strong HER2 staining was associated with shorter OS (9.7 [7.1-12.3] vs. 16.5 [14.9-18.1] months in patients with CTCs with negative-to-moderate HER2 staining only, p = 0.013). In the multivariate analysis, only age, ER status, PR status, ECOG performance status, therapy line, and CTC status independently predicted OS.
Conclusion
To our knowledge, this is the largest analysis to date regarding the clinical relevance of HER2 status of CTCs in MBC. We confirm the high prognostic value of CTC detection in patients with HER2-negative disease. Presence of ≥ 1 CTC with strong HER2 staining was significantly associated with shorter OS in univariate analysis. However, the CTC-HER2 status did not correlate with survival in multivariate analysis.
* VM and MBP contributed equally to this work
Citation Format: Volkmar Müller, Maggie Banys-Paluchowski, Thomas WP Friedl, Peter A Fasching, Andreas Schneeweiss, Andreas Hartkopf, Diethelm Wallwiener, Brigitte Rack, Franziska Meier-Stiegen, Jens Huober, Matthias Rübner, Oliver Hoffmann, Lothar Müller, Wolfgang Janni, Pauline Wimberger, Bernadette Jäger, Klaus Pantel, Nadia Harbeck, Tanja Fehm. Prognostic relevance of the HER2 status of circulating tumor cells in metastatic breast cancer patients screened for participation in the DETECT study program [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-02.