Abstract P3-01-19: HER2-positive circulating tumor cells (CTCs) in advanced breast cancer (BC): A feature independent of BC subtype
Authors: Shah AN , Gerratana L , Davis AA , Zhang Q , Zhang Y , Rossi G , Wang C , Strickland K , Yang H , Flaum L , Abu-Khalaf M , Behdad A , Ye Z , Platanias L , Gradishar WJ , Cristofanilli M 
Published: May 2019

Abstract
Introduction: HER2 overexpression is observed on CTCs in advanced BC (ABC), but their significance is not known. We aimed to describe clinical, pathologic, and molecular associations with HER2 overexpression on CTCs in ABC patients (pts).
Methods: We conducted a retrospective analysis of data from ABC pts treated at Thomas Jefferson University and Northwestern University who had evaluation of CTCs and circulating tumor DNA (ctDNA). CTCs were enumerated with the CellSearch immunomagnetic kit (Menarini Silicon Biosystems), HER2 expression on CTCs was evaluated using the CellSearch CXC Kit, and ctDNA was analyzed using the Guardant360 NGS assay (Guardant Health). Associations with the presence of HER2+ CTCs were explored through univariate and multivariate logistic regression. Kruskal-Wallis testing evaluating HER2+ CTCs as a continuous variable was also conducted to confirm consistency of findings. Time to development of HER2+ CTCs was evaluated using Cox proportional hazards regression analysis.
Results: Baseline CTCs were evaluated in 209 pts (10% stage III, 90% stage IV) of whom 41% had no detectable CTCs, 23% had 1-4 CTCs, and 36% had &gt;5 CTCs (stage IV aggressive). Twelve percent had CTC clusters. At least 1 HER2+ CTC was seen in 33% of pts at baseline draw. Of 39 patients with HER2+ BC, only 18% had HER2+ CTCs. Of patients with HER2+ CTCs, 55% had hormone receptor positive BC, 28% had triple negative BC, and 18% had HER2+ BC. On univariate logistic analysis, BC subtype or HER2 status was not associated with the presence of HER2+ CTCs. IBC pts represented 52% of pts and were less likely to have HER2+ CTCs (OR 0.40 95% CI 0.19-0.84). Bone metastases were associated with an increased likelihood of HER2+ CTCs (OR 2.46, 95% CI 1.12-5.38); however, other sites of metastases and number of metastatic sites were not correlated with HER2+ CTCs. Aggressive disease features including &gt;5 CTCs and presence of CTC clusters were strongly associated with HER2+ CTCs (OR 15.72, 95% CI 6.89-35.8 and 8.97, 95% CI 3.23-24.89, respectively). Of 168 pts with ctDNA analysis, ERRB2 aberrations were seen in 22% of pts and were significantly associated with HER2+ CTCs (OR of 3.74, 95% CI 1.45-9.63). On multivariate analysis, the associations with &gt;5 CTCs and ERBB2 alterations in ctDNA remained statistically significant. The associations of HER2+ CTCs with bone disease, &gt;5 CTCs, CTC clusters, and ERBB2 alterations in ctDNA, and the inverse relationship with IBC were consistent when HER2+ CTCs were evaluated as a continuous variable with Kruskal-Wallis testing. Among pts without HER2+ CTCs at baseline, the time to detection of HER2+ CTCs correlated with the presence of bone metastases (HR 3.40, 95% CI 1.14-10.19), &gt;5 CTCs (3.77, 95% CI 1.33-10.70), and visceral disease (HR 3.00, 95% CI 1.07-8.44).
Conclusions: HER2+ CTCs are common in ABC, independent of HER2 status of the tumor, and, in fact, common in the luminal BC. HER2+ CTCs were also strongly associated with CTC characteristics of aggressive disease with poor survival (CTCs clusters and &gt;5 CTCs) and ERBB2 aberrations in ctDNA. Further studies will be investigating the role of HER2+ CTCs in endocrine resistance and the potential of anti-HER2 therapy in this unique CTC-defined setting.
Citation Format: Shah AN, Gerratana L, Davis AA, Zhang Q, Zhang Y, Rossi G, Wang C, Strickland K, Yang H, Flaum L, Abu-Khalaf M, Behdad A, Ye Z, Platanias L, Gradishar WJ, Cristofanilli M. HER2-positive circulating tumor cells (CTCs) in advanced breast cancer (BC): A feature independent of BC subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-19.