A recent study showed that the HER2-targeted tyrosine kinase inhibitor lapatinib was associated with improved overall survival in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells (CTCs). These findings were published by Fehm et al in Clinical Chemistry.
About 10% to 20% of all breast cancer tumors express elevated levels of the HER2 protein. These HER2-positive tumors respond well to HER2-targeted therapy. However, the invasive tissue biopsies needed to measure HER2 expression levels in metastatic lesions—which can differ from levels in primary tumors—are not always feasible because of the location of the metastatic site, making it difficult to comprehensively determine HER2 status. Testing the HER2 status of CTCs, which requires onlya blood sample, is a potential alternative to invasive biopsy for identifying patients with metastatic cancer who might benefit from HER2-targeted therapy.
DETECT III
To assess the feasibility of this approach, the DETECT III trial sought to evaluate the efficacy of lapatinib for metastatic breast cancer based on a diagnosis of HER2-positive CTCs at the time of metastatic relapse. It reportedly is the largest randomized trial ever to address this question. Patients eligible for the trial had metastatic breast cancer not treatable by surgery or radiotherapy alone, as well as HER2-negative tumors and/or lesions and HER2-positive CTCs. Patients received either standard therapy (chemotherapy or endocrine therapy) or standard therapy with lapatinib, and the rates of CTC clearance were assessed at various intervals during the trial.
No significant differences were found in CTC clearance rates between the standard therapy and lapatinib arms, regardless of the positivity levels of CTCs and when clearance rates were measured. Patients in the lapatinib arm also showed a modest yet insignificant improvement in progression-free survival compared with those in the standard therapy arm. However, patients receiving lapatinib had a median overall survival of 20.5 months—more than twice as long as patients who underwent standard therapy (9.1 months). The lapatinib-induced boost in overall survival was observed throughout the length of DETECT III, which spanned 5 years.
The study authors speculated that lapatinib may target a specific but small subgroup of CTCs with high tumor-initiating capacity, which would account for the low levels of overall CTC clearance alongside large improvements in overall survival.
“DETECT III is the first clinical study indicating that phenotyping of CTCs might have clinical utility for stratification of [metastatic breast] cancer patients to HER2-targeting therapies,” the authors wrote. “CTC-guided therapy may be useful to optimize treatment strategies and should be further investigated in randomized clinical trials.”
Disclosure: For full disclosures of the study authors, visit academic.oup.com/clinchem.
