# Circulating Tumor Cells in Metastatic Breast Cancer: Clinical Applications and Future Possibilities
## 4 Therapy Selection Based on CTCs
### Therapy Interventions Based on Molecular Characteristics of CTCs  
Beyond simple enumeration of CTCs, assessment of their predictive features for therapy interventions is the focus of other trials. The aim of the Circ T-DM1 trial was the evaluation of HER2-directed treatment for patients with histologically HER2-negative metastatic disease and HER2-amplified CTCs [13]. To date, such patients receive no HER2-targeted treatment because the indication is based on the histological receptor status of the primary tumor and/or metastasis. Blood samples from 154 heavily pretreated patients were evaluated in the CirCe T-DM1 study. The HER2 status of the detected CTCs was assessed using fluorescence in situ hybridization (FISH). At least one HER2-amplified CTC was detected in 14 patients. However, the response to targeted therapy with the antibody-drug-conjugate trastuzumab-emtansin was low. Among 11 patients treated within this trial, only one reached partial response and four had achieved stable disease. One possible explanation for the negative result of the study was the very low incidence of HER2-positive CTCs. The majority of patients harbored only one HER2-amplified tumor cell alongside several HER2-negative CTCs. Indeed, \begin{table}
\begin{tabular}{l c c c} \hline \hline  & **ER** & **PR** & **HER2** \\ \hline Change of receptor status (total) & 19.3\% & 30.9\% & 10.3\% \\ Conversion to negative in case of initially positive receptor status (\(+\rightarrow-\)) & 22.5\% & 49.4\% & 21.3\% \\ Conversion to positive in case of initially negative receptor status (\(-\rightarrow+\)) & 21.5\% & 15.9\% & 9.5\% \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Discrepancy between receptor status of the primary tumor and the metastasis (modified after: [11])in the group of patients with at least one HER2-positive CTC, only 4.4% of CTCs evaluated using FISH were HER2-amplified. Therefore, the clinical relevance of this minor subpopulation seems limited. Another approach is currently under investigation in the German DETECT studies, the largest research program on CTC-based therapy interventions worldwide (www.detect-studien.de) [1]. Here, patients with histologically HER2-negative disease are screened for HER2-positive CTCs (Figure 1). Within the phase III trial DETECT III (NCT01619111), they receive standard treatment +/- HER2-directed therapy with lapatinib. Patients with HER2-negative CTCs may participate in the DETECT IV trial (NCT02035813), which investigates the dynamics of CTCs under treatment with ribociclib or eribulin. Another of the DETECT studies, the phase III trial DETECT V is open for patients with HER2-positive disease (NCT02344472). These trials are still recruiting. The first results are expected in 2021. \begin{table}
\begin{tabular}{c c c} \hline  & & **Breast Cancer** \\ Prognosis & \(\bullet\) & Detection of \(\geq\)5 CTCs per 7.5 mL blood (CellSearch) at time of diagnosis of distant metastasis or progression is strongly associated with worse survival \\  & \(\bullet\) & Most important references: [5; 6; 10; 14; 15; 16; 17; 18; 19] \\ \hline  & \(\bullet\) & Persistence of CTCs after first cycle of chemotherapy correlated with response to treatment; patients do not benefit from a switch to another chemotherapy regimen (SWOG 80500 trial) \\  & \(\bullet\) & Most important references: [9; 10; 20; 21; 22; 23] \\ \hline  & \(\bullet\) & HR+ HER2- breast cancer: CTC-based choice of first-line therapy is not inferior to therapy of physician’s choice (STIC CTC trial); implementation in the clinical routine unclear due to approval of endocrine-based combination therapy with \\ CTC-based therapy interventions & \(\bullet\) & HER2- breast cancer: Patients do not benefit from T-DM1 in case of histologically \\  & \(\bullet\) & HER2-negative disease and HER2-amplified CTCs (Circc T-DM1 trial) \\  & \(\bullet\) & Further studies ongoing (e.g., DETECT trials) \\  & \(\bullet\) & Most important references: [12; 13; 20; 24; 25] \\ \hline \end{tabular}
\end{table}