Circulating tumor cell and endothelial cell data from a phase II evaluation of lapatinib and bevacizumab in HER2-overexpressing metastatic breast cancer.
Authors: Rugo HS , Dickler M , Franco S , Stopeck A , Lyandres J , Melisko M , Lahiri S , Arbushites M , Koehler M , Lin Y , Scott J , Park J 
Published: December 2010

Abstract
Abstract #3154
Background: Overexpression of both HER2 and VEGF is associated with worse outcome than overexpression of either receptor alone. In preclinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. Bevacizumab (B) plus trastuzumab and lapatinib (L) plus pazopanib have shown activity in patients (pts) with HER2+ MBC. We evaluated the combination of L+B in a phase 2 trial in HER2+ MBC pts. To explore new biomarkers of treatment effect, we measured circulating tumor cells (CTCs) with two different methods of CTC enumeration: CellSearch (Veridex LLC), and immunomagnetic enrichment followed by flow cytometry (IE/FC), as well as circulating endothelial cells (CECs) in pts receiving study treatment.&#x2028; Methods: This study evaluated L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC pts. The primary endpoint is crude progression-free survival (PFS) at 12 wks. Serial evaluation of CTC and CEC was performed. Blood was obtained from consenting pts at baseline, weeks 2, 6 then every 12 weeks until end of study. CellSearch assay was performed as previously described using 7.5 cc blood in a CellSave tube and the CellSpotter analyzer. For IE/FC, 20 ml of blood was subjected to IE using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. CTC data were correlated with assay method and with best response. CECs were defined as CD34/31+, CD45-, or CD34/146+, CD45-, and were assayed by FC.&#x2028; Results: Enrollment to this study ended in March 2008 (n=52). Clinical data is presented at this meeting (Dickler et al). 47 patients have evaluable CTC and CEC data at baseline and/or first follow-up; 32 patients have response data. CTC determined by CellSearch or IE/FC showed significant correlation at baseline (R=0.58; P=0.012). CTC by CellSearch at first followup correlated with treatment response (P=0.01) with levels above 5 CTC/sample associated with progression; there was no correlation with baseline values. There were too few positive IE/FC values to evaluate correlation with outcome. The change in CEC/CD146 from baseline to first followup for is of borderline significance in this preliminary analysis (P=0.07) between PR (N=2, Mean Change Score/MCS=-4.345) and SD/PD (N=18, MCS=0.8); a decrease of CEC/CD146 from baseline to first followup suggests greater likelihood of response.&#x2028; Conclusions: L+B is an active regimen in pts with MBC. CTC measurements correlated between two separate methodologies, and for the CellSearch assay predicted response to therapy. A decrease in CEC from baseline to first followup correlated with response to this combined targeted therapy, consistent with our previous results with other B-based therapy. PFS and response correlations for the full study cohort will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3154.