Abstract P3-01-02: Detection of circulating tumor cells (CTC) in blood and disseminated tumor cells (DTC) in bone marrow at surgery identifies breast cancer patients (pts) with long-term risk of distant recurrence and breast cancer-specific death
Authors: Magbanua MJM , Yau C , Wolf D , Lee JS , Chattopadhyay A , Scott JH , Yoder E , Hwang S , Alvarado M , Ewing CA , Delson AL , van't Veer L , Esserman L , Park JW 
Published: May 2019

Abstract
We examined the prognostic impact of CTCs and DTCs detected at the time of definitive surgery in pts diagnosed with early breast cancer (EBC).
Methods: Blood and bone marrow samples from 742 treatment-naïve EBC pts, not eligible for neoadjuvant therapy, were collected immediately prior to surgery. 87% were hormone receptor (HR)-positive, and 71% were node-negative. DTCs (n=584) were enumerated using an EPCAM-based method involving immunomagnetic enrichment and flow cytometry (IE/FC). CTCs were enumerated either by IE/FC (n=288) or CellSearch (n=380). Optimal cutoffs for CTC-/DTC-positivity were selected using Monte-Carlo cross validation. Multivariate Cox regression analysis was performed to determine correlation between levels of CTCs/DTCs vs. distant recurrence-free survival (DRFS) and breast cancer-specific survival (BCSS). The overall median follow-up was 7.1 years for DRFS and and 9.1 years for BCSS, but extended up to 13.3 years in subset analyses (Table 1).
Results: CTC-positivity by CellSearch was associated with HER2-positivity (Fisher p=0.01). Using optimized cutoffs in multivariate analyses, we found that CTC-positive pts by CellSearch had a statistically significant increased risk of distant recurrence (HR 4.93, p=0.0067). Moreover, pts who were CTC-positive by IE/FC had a statistically significant increased risk of breast cancer-specific death (HR=3.54, p=0.0138). DTC status, by itself, was not prognostic; however, when combined with CTC status by IE/FC (n=273), positive detection for both (CTC+DTC+) was significantly associated with increased risk of distant recurrence (HR=3.09, p=0.0270) and breast cancer-specific death (HR=4.55, p=0.0205).
Table 1.Multivariate analysis to determine the prognostic significance of CTCs and DTCs detected at the time of surgery in treatment naive early breast cancer patients. Adjusted for age at diagnosis, tumor size, pathologic stage, HR and HER2 status, node status and grade. DRFS BCSS Variable and Method% positiveHR [95% CI]Wald p-valueMedian f/u [range] Years*HR [95% CI]Wald p-valueMedian f/u [range] Years*CTC+ vs. CTC- by CellSearch94.93[1.56-15.6]0.00676.4 [0.16-13.8]4.50[0.76-26.5]0.09627.5 [0.71-15.0]CTC+ vs. CTC- by IE/FC401.92[0.93-3.95]0.07599.8 [0.09-18.5]3.54[1.29-9.72]0.013813.3 [1.93-18.5]DTC+ vs. DTC- by IE/FC181.46[0.75-2.81]0.26317.5 [0.09-18.5]1.48[0.64-3.42]0.35429.8 [1.55-18.5]CTC+DTC+ vs. CTC-DTC- by IE/FC8**3.09[1.14-8.40]0.02709.8 [0.09-18.5]4.55[1.26-16.39]0.020513.3 [1.93-18.5]*f/u - follow-up; **double positive
Conclusions: We demonstrate the impact of quantitative evaluation of CTCs and DTCs by IE/FC. Our large single institution dataset, in which CTCs and DTCs have been contemporaneously quantitated, has the longest patient follow-up. Simultaneous detection of CTCs and DTCs at the time of definitive surgery in treatment naïve EBC pts is an independent prognostic factor associated with increased long-term risk of distant recurrence and death due to breast cancer. Given the lack of early endpoints for low-risk patients, liquid biopsy may be an important consideration for future studies.
Citation Format: Magbanua MJM, Yau C, Wolf D, Lee JS, Chattopadhyay A, Scott JH, Yoder E, Hwang S, Alvarado M, Ewing CA, Delson AL, van't Veer L, Esserman L, Park JW. Detection of circulating tumor cells (CTC) in blood and disseminated tumor cells (DTC) in bone marrow at surgery identifies breast cancer patients (pts) with long-term risk of distant recurrence and breast cancer-specific death [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 P3-01-02.