Background: Late recurrence 5 or more years after diagnosis accounts for least one-half of all breast cancer recurrences, especially in hormone receptor (HR)+ disease. Biomarkers prognostic for late recurrence offer potential to more accurately identify subjects who might benefit from extended adjuvant endocrine therapy, or novel strategies to reduce late recurrence risk.

Methods: CTCs were assessed at a single time point using the CELL SEARCH® assay in patients without clinical evidence of recurrence between 4.5-7.5 years after an initial diagnosis of HER2- stage II-III breast cancer and enrolled in trial E5103; all patients received surgery plus adjuvant chemotherapy and endocrine therapy for at least 5 years if HR+ disease. Patients were followed for evidence of clinical recurrence in accordance with standard care, and the association between CTCs and clinical recurrence was evaluated.

Results: 546 patients without clinical evidence of recurrence enrolled between 2/25/13-7/29/16 and provided a blood sample that yielded a CTC result; 16 (2.9%) subsequently had a recurrence, of whom 15 had HR-positive disease. The median time between enrollment on E5103 and CTC assay was 5.2 years, and median/mean followup after the CTC assay was 1.6 years (range 0-3.9 years). The CTC assay was positive in 27 (4.9%) (median CTC count 1/7.5 ml blood, range 1-15). There were no significant differences in patient characteristics in the CTC+ vs. CTC- cases, including age < 50 years at initial diagnosis (52% vs. 44%), tumor size > 2 cm (63% vs. 59%), >/= 1 positive axillary node (81% vs. 72%), ER and/or PR+ (70% vs. 64%) or poor histologic grade (44% vs 55%). The recurrence rate per person-year in the CTC+ vs. CTC- groups was 19.6% vs. 1.1%, respectively (P<0.01). The median/mean time to recurrence after a positive CTC assay was 2.8 years. In multivariate analysis adjusted for clinical covariates (see table), a positive CTC assay was associated with an 18.3-fold increased risk of recurrence.

Univariate and Multivariate Analysis - Association Between CTC Status and Recurrence

Covariate Hazard Ratio for Recurrence - Univariate Analysis (95% CI) Hazard Ratio for Recurrence - Multivariate Analysis (95% CI) 
Age < 50 years 3.4 (0.95-11.8) 3.0 (0.8-10.9) 
Tumor size > 2 cm 4.2 (0.98-19.2) 2.9 (0.6-13.2) 
>/= 1+ node 2.6 (0.59-11.5) 0.7 (0.1-3.8) 
ER and/or PR+ 8.3 (1.1-63.5) 7.7 (0.7-79.9) 
Poor grade 0.43 (0.14-1.2) 1.2 (0.4-3.8) 
CTC -pos vs CTC-neg 20.9 (7.5-58.3) 18.3 (5.7-58.2) 
Covariate Hazard Ratio for Recurrence - Univariate Analysis (95% CI) Hazard Ratio for Recurrence - Multivariate Analysis (95% CI) 
Age < 50 years 3.4 (0.95-11.8) 3.0 (0.8-10.9) 
Tumor size > 2 cm 4.2 (0.98-19.2) 2.9 (0.6-13.2) 
>/= 1+ node 2.6 (0.59-11.5) 0.7 (0.1-3.8) 
ER and/or PR+ 8.3 (1.1-63.5) 7.7 (0.7-79.9) 
Poor grade 0.43 (0.14-1.2) 1.2 (0.4-3.8) 
CTC -pos vs CTC-neg 20.9 (7.5-58.3) 18.3 (5.7-58.2) 

Conclusions: A single positive CTC assay in patients without clinical evidence of recurrence 5 years after diagnosis of stage II-III HR+, HER2- breast cancer provides independent prognostic information for late recurrence, providing proof of concept for using liquid-based biomarkers for late relapse risk assessment. These findings provide a foundation for further evaluation of this new risk assessment paradigm using CTC and other blood-based assays in this setting, and designing clinical trials to tailor therapeutic risk interventions.

Supported by Breast Cancer Research Foundation (J. Sparano; R. Comis) and Susan G. Komen Foundation (J. Sparano), and by the National Cancer Institute (CA180820, CA180794, CA180790, CA180791, CA180795, CA180802, CA180816, CA180821, CA189859).

Citation Format: Sparano JA, O'Neill A, Alpaugh K, Wolff AC, Northfelt DW, Dang C, Sledge, Jr. GW, Miller KD. Circulating tumor cells (CTCs) five years after diagnosis are prognostic for late recurrence in operable stage II-III breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-03.