DETECT III: A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC).

Abstract

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.

Breast Cancer Update 2014 – Focus on the Patient and the Tumour

“…The next logical step is the determination of the molecular properties of the circulating tumour cells [97,98]. To what extent this can help in therapy planning and prediction of the prognosis are questions to be answered by ongoing clinical studies [99][100][101][102]. The analysis of circulating nucleic acids may be less elaborate than CTC analysis.…”

Detection of effusion tumor cells under different storage and processing conditions

“…5 Besides rare tumor cell enumeration, efforts to identify biomarker expression and tumorspecific mutations, such as HER2 expression in breast carcinoma CTCs and c.2573T>G (p.L858R) or c.2369C>T (p.T790M) EGFR mutations in non-small cell lung cancer (NSCLC), are underway to complement current diagnostic techniques. 6,7 Several similar studies are being conducted on cell-free or circulating tumor DNA (ctDNA) in biofluids besides peripheral blood, such as plasma, cerebrospinal fluid (CSF), pleural and peritoneal fluids, saliva, urine, and stool (reviewed in a commentary by the Liquid Biopsy Consortium, established through the National Cancer Institute 8 ). These investigators employ a variety of methods, including targeted capture massively parallel sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) on CSF, ultrasensitive next-generation sequencing for head and neck squamous cell carcinomas in saliva, and the novel electric field-induced release and measurement platebased technology for EGFR variants in saliva and plasma.…”

“…Peripheral blood is the most common liquid biopsy sample, and the presence of circulating tumor cells (CTCs) has been linked to worse prognosis in many different carcinomas, including breast, 2 colorectal, 3 lung, 4 and others 5 . Besides rare tumor cell enumeration, efforts to identify biomarker expression and tumor‐specific mutations, such as HER2 expression in breast carcinoma CTCs and c.2573T>G (p.L858R) or c.2369C>T (p.T790M) EGFR mutations in non–small cell lung cancer (NSCLC), are underway to complement current diagnostic techniques 6,7 . Several similar studies are being conducted on cell‐free or circulating tumor DNA (ctDNA) in biofluids besides peripheral blood, such as plasma, cerebrospinal fluid (CSF), pleural and peritoneal fluids, saliva, urine, and stool (reviewed in a commentary by the Liquid Biopsy Consortium, established through the National Cancer Institute 8 ).…”

Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network

“…The next logical step was to determine the molecular properties of circulating tumor cells [71,72]. Several clinical studies are currently looking at whether this could help with treatment planning and offer useful information for prognosis [73][74][75][76]. However, isolating the CTCs is still relatively expensive and time-consuming and requires large, cost-intensive equipment which is expensive to run.…”