Abstract P3-01-08: HER2-negative metastatic breast cancer with HER2-positive circulating tumor cells (CTCs): A new CTC-defined HER2-positive subgroup
Authors: Shah AN , Gerratana L , Zhang Q , Davis AA , Zhang Y , Flaum L , Behdad A , Platanias L , Gradishar WJ , Cristofanilli M 
Published: May 2019

Abstract
Introduction: CTCs can overexpress HER2 discordant from tumor HER2 expression. We aimed to describe characteristics of a CTC-defined group of pts with metastatic breast cancer (MBC) that is tumor HER2- and CTC HER2+ (HER2 tumor- CTC+).
Methods: We retrospectively analyzed data from pts treated at Northwestern University who had serial evaluation of CTCs and circulating tumor DNA (ctDNA). We included pts with pathologically confirmed HER2- MBC and HER2+ CTCs. CTCs were enumerated with the CellSearch immunomagnetic kit (Menarini Silicon Biosystems), HER2 expression on CTCs was determined using the CellSearch CXC Kit in 7.5 cc whole blood, and ctDNA was analyzed using the Guardant360 NGS assay (Guardant Health).
Results: Among 98 pts with HER2- MBC and CTC analysis, 46 (47%) had at least 1 HER2+ CTC. In this cohort the median age was 53. At initial BC diagnosis, 80% had early stage or locally advanced BC and 20% had de-novo metastatic disease. Baseline histology was 65% ductal, 20% lobular, 2% mixed ductal and lobular, and 13% unknown. Pathology of metastatic tumor was hormone receptor positive (HR+)/HER2- in 78% and triple negative in 22%. Detailed HER2 immunohistochemistry (IHC) and FISH results from metastases were available from 63% of pts of whom 72% had an IHC score of 0 or 1 and 28% had an IHC score of 2 with negative FISH testing. The median time from the most recent pathologic metastatic tumor assessment to the detection of a HER2+ CTC was 6.5 mo. Twenty-two pts had simultaneous (within 8 weeks) HER2- tumor confirmation and HER2+ CTC detection. The median lines of endocrine therapy (ET) for MBC prior to detection of HER2+ CTCs was 1 (range 0-5, 41% no ET, 17% 1 line, 41% &gt;2 lines). Pts received a median of 2 (range 0-10) prior systemic therapies for MBC prior to detection of HER2+ CTCs, (20% 0 lines, 41% 1-3 lines, and 39% &gt;4 lines). Among these 46 pts, CTCs were analyzed longitudinally in 104 samples, with HER2+ CTCs detected in 77 samples. Number of HER2+ CTCs at initial detection ranged from &lt;5 in 24%, 5-50 in 43%, and &gt;50 in 33%, with a median of 11.5 HER2+ CTCs. CTC clusters were noted in 37% of pts. At initial detection the proportion of CTCs that were HER2+ was 0-25% in 13% of pts, 26-50% in 46% of pts, and 51-100% in 41% of pts. Seven pts had ERBB2 aberrations in ctDNA. Of 12 pts with tumor sequencing, 2 had ERBB2 mutations, 1 had ERBB3 amplification, and 1 had overexpression of ERBB3 RNA. After detection of HER2+ CTCs, 18 pts received HER2 directed therapy (with chemotherapy in 13 pts, with endocrine therapy in 4 pts, and as monotherapy in 1 pt). Imaging demonstrated a partial response or stable disease in 9 pts (clinical benefit rate 50%), including in 1 pt with trastuzumab monotherapy, progressive disease in 8 pts, and not evaluated in 1 pt.
Conclusions: HER2+ CTCs are frequently detected simultaneously or soon after HER2- tumor assessment in MBC. Within this newly defined subgroup, the several responses seen with HER2 targeted therapy serve as a proof of concept that HER2 tumor- CTC+ patients can benefit from HER2 targeted therapy. Future studies are needed to determine a clinically relevant threshold for HER2+ CTCs to guide further study of HER2 therapy combinations in HER2 tumor- CTC+ pts.
Citation Format: Shah AN, Gerratana L, Zhang Q, Davis AA, Zhang Y, Flaum L, Behdad A, Platanias L, Gradishar WJ, Cristofanilli M. HER2-negative metastatic breast cancer with HER2-positive circulating tumor cells (CTCs): A new CTC-defined HER2-positive subgroup [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 P3-01-08.