Abstract PD3-12: Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial

Abstract

Background: It is well-known that tumor biology may change during the course of the disease due to clonal evolution, and such changes might have important implications for response to targeted treatments. Circulating tumor cells (CTCs) could serve as a real-time liquid biopsy to detect changes in tumor biology. It has been demonstrated that patients with HER2-negative metastatic breast cancer (MBC) may have discordant, HER2-positive CTCs in the peripheral blood. However, up to now there is no randomized clinical trial investigating whether treatment decisions based on CTC phenotype provide benefits in terms of improved outcome. The aim of the DETECT III study is to investigate whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. In addition, the significance of CTCs as an early predictive marker for response to therapy will be analyzed. Methods: The randomized phase III DETECT III trial (NCT01619111) compares lapatinib in combination with standard therapy versus standard therapy alone in patients with initially HER2-negative MBC and HER2-positive CTCs. Efficacy of lapatinib treatment is evaluated by CTC clearance rate, progression-free survival (PFS) and overall survival (OS). In addition, we investigate the association between CTC results and both PFS and OS to assess the utility of CTCs as an early predictive marker for treatment response. CTC enumeration and phenotyping was performed using the CellSearch® technology (Menarini Silicon Biosystems; Bologna, Italy). Survival data are analyzed using log rank tests, univariable and adjusted multivariable cox regressions. Results: First results on CTC clearance rates, PFS and OS of 105 prospectively randomized patients will be presented. Conclusion: This first randomized clinical trial in breast cancer patients with treatment decisions being based on the phenotype of CTCs will show whether patients with HER2 negative MBC and HER2 positive CTCs benefit from additional HER2-targeted therapy with lapatinib. This finding might be increasingly important as novel HER2-targeted drugs become available. Citation Format: Tanja Fehm, Volkmar Mueller, Maggie Banys-Paluchowski, Peter A Fasching, Thomas WP Friedl, Andreas Hartkopf, Jens Huober, Christian Loehberg, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Oliver Hoffmann, Lothar Müller, Pauline Wimberger, Eugen Ruckhaeberle, Jens Blohmer, Wolfgang Janni. Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial [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 PD3-12.

Prognostic relevance of the HER2 status of circulating tumor cells in metastatic breast cancer patients screened for participation in the DETECT study program

“…Therefore, study concepts evaluating clinical outcomes of patients whose treatment is based on a result of blood examination, either using CTCs or ctDNA, are becoming a major focus of oncological research. 24,29,30 In this context, our results should contribute to designing future clinical trials.…”

“…Preliminary results indicate that patients may benefit from HER2targeted therapy in this setting. 24 The final results are still awaited. A possible clinical benefit from HER2-targeted therapies in patients with HER2-negative tumors but HER2-positive CTCs was also reported by Wang et al 21 By contrast, Pestrin et al 25 reported disappointing results from their proof-of-concept phase II trial on lapatinib in HER2negative MBC with HER2-positive CTCs.…”

Single-Cells Isolation and Molecular Analysis: Focus on HER2-Low CTCs in Metastatic Breast Cancer

“…Thus, this tool was only able to identify HER2+ CTCs (3+ and 2+). In fact, until the end of the past decade, in order to determine the efficacy of anti-HER2 treatments, the interest of the scientific community focused primarily on the identification of HER2 amplification or overexpression in both tumors and CTCs [ 5 , 7 ].…”

“…A large prospective study, the DETECT III trial (A Multicenter, Phase III Study to Compare Standard Therapy/Lapatinib in HER2-ve MBC Patients with HER2+ CTCs, NCT01619111) investigated whether patients with initially HER2-negative MBC and HER2+ CTCs could benefit from the administration of lapatinib, a tyrosine kinase inhibitor. Preliminary results of the study indicate that the administration of lapatinib in addition to standard therapy had a positive impact on OS, complemented by a higher clearance of HER2+ CTCs [ 7 ].…”

Single HER2-Positive Tumor Cells are Detected in Initially HER2-Negative Breast Carcinomas using the DEPArray™–HER2-FISH Workflow

“…However, some interesting clinical studies are still ongoing and their results are awaited to have a more precise definition who to treat with anti-HER2-treatment, usually not eligible for such an approach. In this context, the DETECT III study, which randomizes patients with HER2-neg metastatic BC and detectable HER2-pos CTCs to standard treatment or to standard treatment in combination with lapatinib, might be of interest [63]. Preliminary results of this study look promising.…”