Phase 3 DETECT III Study Suggests CTC Count to be Possible Biomarker for HER2-Directed Therapy in MBC

The study found that favorable outcomes after treatment with lapatinib (Tykerb) were demonstrated by early declines in circulating tumor cell counts (CTCs) in patients with metastatic breast cancer who initially had HER2-negative primary tumors but positive HER2 CTCs.

Data from the phase 3 DETECT III study (NCT01619111) showed favorable outcomes after treatment with the HER2-directed lapatinib (Tykerb) were indicated by early declines in circulating tumor cell (CTC) counts in patients with metastatic breast cancer (MBC) who initially had HER2-negative primary tumors but positive HER2 CTCs; ultimately suggesting this could serve as a clinical biomarker.

“CTC clearance rate at the time of the final visit, which was the primary end point of this trial, did not differ significantly between the standard arm and lapatinib arm,” lead author Tanja Fehm, MD, of Heinrich-Heine University Düsseldorf, Germany said in a poster presentation during the 2020 San Antonio Breast Cancer Symposium.

In the randomized DETECT III trial, 105 patients with initially HER2-negative MBC and HER2-positive CTCs were randomized to either the combination of lapatinib plus standard therapy versus standard therapy alone. The efficacy of the study drug was evaluated by CTC clearance rate, progression-free survival (PFS), and overall survival (OS). Along with the effectiveness of lapatinib, investigators also looked at the association between CTC results and the PFS and OS to decide if CTCs could be used an early predictive marker for response to treatment.

CellSearch technology was used to perform CTC numeration and HER2 phenotyping. One tumor cell was the cut off level for CTC positivity, and CTC was defined as HER2 positive if the immunohistochemistry score was 2+ or 3+.

Tumor biology is known to have important implications for response on targeted therapies in the metastatic setting, and CTCs were hypothesized to potentially serve as a real-time liquid biopsy to detect tumor biology changes. Although the data is limited on whether treatment decisions can be based on the CTC phenotype, it has been demonstrated that patients with HER2-negative MBC may have HER2-positive CTCs in the peripheral blood. This study aimed to determine whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. The study authors also aimed to evaluate the significance of CTCs as an early predictive marker for response to therapy.

Overall, there was no detection of CTCs after initial positive CTC detection in 33.3% of the patients given standard therapy versus 15.4% given lapatinib at the time of the final visit, which was not significantly different (P =.18).

“In addition, there was no significant difference between the 2 study arms with regard to clearance of HER2-positive CTCs [57.1% vs 50.0%; P =.63],” Fehm continued. “Patients in the lapatinib arm showed a numerically but not significantly better PFS compared to patients in the standard arm. However, patients in the lapatinib arm had a significantly improved OS by univariate and multivariate cox regression analysis.”

PFS with lapatinib compared with standard care had a hazard ratio of 0.69 (95% CI, 0.42-1.14) and a P value of .14. The OS hazard ratio for these patients was 0.54 (95% CI, 0.34-0.86; P =.008) with univariate cox regression. With the multivariate cox regression, which was adjusted for metastasis-free interval of less or more than 24 months, visceral or non-visceral metastases, hormone receptor status, adjuvant or neoadjuvant chemotherapy, and metastatic-treatment line, the hazard ratio was 0.55 (95% CI, 0.34-0.90), and the P value was .016.

Although there was a hazard ratio of 0.92 (95% CI, 0.42-2.05) and a P value of .085, the CTC clearance at the end of study treatment was not associated with OS. Better OS was observed in patients with no evidence of CTCs at first follow-up CTC assessment compared with patients with CTCs, with a hazard ratio of 0.36 (95% CI, 0.17-0.76) and P value of .005.

With a median time after baseline of 73 days, investigators found there was no significant difference for the CTC clearance rate or clearance rate of HER2-positive CTCs between the 2 arms of the trial at the time of first follow-up CTC assessment. The CTC clearance rates for lapatinib regimen and the standard regimen were 28.2% and 26.7%, respectively (P =.89). For HER2-positive CTCs, the clearance rate was 59.0% with lapatinib and 53.3% with standard treatment (P =.64).

“In conclusion, HER2 directed therapy with lapatinib had a positive impact on OS in patients with initially HER2 negative primary tumor, but HER2 positive CTCs,” Fehm said. “Based on these results, HER2 positive CTCs might serve as a suitable biomarker to predict clinical benefit in this cohort of patients. This finding could of clinical relevance as other HER2 drugs become available.”


Fehm T, Mueller V, Banys-Paluchowski M, et al. 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. Poster presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD3-12.