The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study

Justin Stebbing, Rachel Payne, Justine Reise, Adam E Frampton, Miranda Avery, Laura Woodley, Angelo Di Leo, Marta Pestrin, Jonathan Krell, R Charles Coombes, Justin Stebbing, Rachel Payne, Justine Reise, Adam E Frampton, Miranda Avery, Laura Woodley, Angelo Di Leo, Marta Pestrin, Jonathan Krell, R Charles Coombes

Abstract

Background: Analysis of circulating tumor cells (CTCs) provides real-time measures of cancer sub-populations with potential for CTC-directed therapeutics. We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR-positive pool of CTCs, which may in turn lead to clinical benefits.

Patients and methods: Patients with metastatic breast cancer and HER2 non-amplified primary tumors with EGFR-positive CTCs were recruited and lapatinib 1500 mg daily was administered, in a standard two step phase 2 trial.

Results: There were no responses leading to termination at the first analysis with 16 patients recruited out of 43 screened. In 6 out of 14 (43%) individuals eligible for the efficacy analysis, a decrease in CTCs was observed with most of these having a greater decrease in their EGFR-positive CTC pool.

Conclusions: This is one of the first studies of CTC-directed therapeutics and suggests that lapatinib monotherapy is not having any demonstrable clinical effects by reducing the EGFR-positive pool of CTCs in HER2 non-amplified primary tumors. Our attempt to expand the pool of patients eligible for a targeted therapy was unsuccessful; the role of clonal populations in cancer biology and therapeutic strategies to control them will require extensive evaluation in years to come.

Trial registration: Clinical trials.gov NCT00820924.

Conflict of interest statement

Competing Interests: The authors received funding from a commercial source, GlaxoSmithKline. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT 2010 flow diagram for…
Figure 1. CONSORT 2010 flow diagram for patients enrolled in this study.
Figure 2. Six out of fourteen evaluable…
Figure 2. Six out of fourteen evaluable advanced breast cancer patients demonstrated a decrease in the quantity of CTCs in 7.5 ml blood following the first cycle of Lapatinib treatment.
Graphs show CTC measurements and EGFR positivity at screening or baseline and at follow-up after Lapatinib treatment in each patient (A–F). Four patients also showed a decrease in EGFR positive CTCs after lapatinib treatment (A, B, C and F). Serial CTCs were taken with ethical approval (07/Q0401/20) and additional consent.
Figure 3. Eight out of fourteen evaluable…
Figure 3. Eight out of fourteen evaluable advanced breast cancer patients demonstrated a consistent or increased quantity of CTCs in 7.5 ml blood following the first cycle of Lapatinib treatment.
Graphs show CTC measurements and EGFR positivity at screening or baseline and at follow-up after Lapatinib treatment in each patient (A – H). Seven patients also showed an increase in EGFR positive CTCs after Lapatinib treatment (B, C, D, E, F, G and H). Serial CTCs were taken with ethical approval (07/Q0401/20) and additional consent.

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