Abstract OT1-10-01: DETECT III/IV study trial – The multicenter study program in patients with HER2-negative metastatic breast cancer and circulating tumor cells

Abstract

Background: The collaborative DETECT study program represents one of the largest study program on metastatic breast cancer worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trial translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT III trial is a multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. Patients with persisting HER2-negative circulating tumor cells (CTCs) can be included within the DETECT IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative metastatic breast cancer. Within the DETECT IV study setting postmenopausal patients with hormone-receptor positive metastatic breast cancer are treated with everolimus or ribociclib and endocrine therapy, while women with triple negative metastatic breast cancer or a hormone-receptor positive tumor and indication for chemotherapy receive eribulin. Specific aims: The DETECT study program comprises all breast cancer subtypes and therefore offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in a controlled setting of a single large clinical trial. The primary endpoint of the DETECT III trial is the comparison of patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone, with regard to the CTC clearance rate. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups (Progression free survival, overall response rate and dynamic of CTCs). Primary objective of the DETECT IV trial is to evaluate CTC clearance rate within the everolimus/ribociclib cohort and additionally assess progression-free survival defined as time interval from date of recruitment until progressive disease within the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” may give new information about CTCs potential function as liquid biopsy in order to determine their relevance for therapy prediction. Citation Format: Krause S, Friedl T, Romashova T, Fasching PA, Schneeweiss A, Müller V, Taran F-A, Arkadius P, Marie T, De Gregorio A, Meier-Stiegen F, Huober J, Janni W, Fehm T. DETECT III/IV study trial – The multicenter study program in patients with HER2-negative metastatic breast cancer and circulating tumor cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-10-01.

Clinical utility of circulating tumor cells: an update

“…Interestingly, in the CirCe T-DM1 trial, patients with at least 1 HER2-amplified CTC per 7.5 mL had a low HER2-amplified/HER2-negative ratio, suggesting that these HER2-amplified cells reflect a minor subclone, which may explain the lack of efficacy of anti-HER2 therapy. The results of the DETECT III trial [114], which randomizes patients with HER2-negative metastatic BC and detectable HER2-positive CTC to standard treatment or to standard treatment in combination with lapatinib, are therefore eagerly awaited. In this phase III multicenter trial, HER2-positive CTCs were identified by IHC or FISH after the detection of CTCs by CellSearch Ò .…”

“…The primary endpoint of the trial is the CTC clearance rate, which may provide interesting insights into the activity of anti-HER2 agents in these patients. Patients with HER2-negative CTCs may be eligible for inclusion in other studies of the DETECT program: patients with hormone receptor-positive BC and an indication for endocrine therapy receive everolimus or ribociclib in combination with endocrine therapy [114] in the DETECT IVa study, whereas those with an indication for chemotherapy or hormone receptor-negative BC receive eribulin (DETECT IVb). The DETECT program also includes a large number of translational studies [115]: for instance, in DETECT III, HER2-positive CTCs will be analyzed for the presence of PIK3CA mutations.…”

Circulating Biomarkers in Breast Cancer

“…The primary endpoint is CTC clearance, and the secondary endpoints are PFS, overall, all response rate, and dynamic of CTCs. 111 DETECT IV (NCT02035813) is a phase II trial with cohort A having HRpositive MBC patients treated with endocrine therapy combined with everolimus or ribociclib, and with cohort B having triple negative or higher risk HR-positive MBC patients treated with mitotic inhibitor eribulin. The primary endpoints are CTC clearance rate in cohort A and PFS in cohort B.…”

Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors

“…Indeed, it has been proven that, during treatment, ER+ MBCs can develop ER-CTCs; it has been hypothesized that this phenomenon may reflect the acquisition of therapy resistance by the primary tumor [98]. An interventional trial is currently testing the possibility of using the HER2 status of CTCs to stratify MBC patients [99]. Moreover, CTC expression of protein death-1 ligand correlates with MBC OS, suggesting that CTC evaluation may be useful to predict the sensitivity to specific immunotherapies [100].…”