Brown, ME

Abstract Introduction: Only half of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients (pts) benefit from endocrine therapy (ET). Circulating tumor cells (CTC) are prognostic in pts with MBC using CellSearch® technology. The CTC-endocrine therapy index (CTC-ETI) provides semi-quantitative analyses of CTC-ER (estrogen receptor), BCL2, HER2, and Ki67 expression. We hypothesized that CTC-ETI high (elevated CTC number and/or low expression of ER and BCL2, and high expression of HER2 and Ki-67) might predict resistance to ET in a prospective, multi-institutional clinical trial: COMETI-P2-2012.0 (NCT01701050). Methods: 121 pts with ER+, HER2 negative (-), and progressive MBC after one or more lines of ET or within 12 months (mos) of completing adjuvant ET, who were initiating a new ET, were enrolled after informed consent. CTC and CTC-ETI were determined as previously reported (Paoletti C et al, CCR 2015) at baseline (BL), 1, 2, 3, and 12 mos, and/or at the time of progression. Imaging was performed every 3 mos. Association of CTC levels and CTC-ETI with patient outcomes (progression free survival (PFS); rapid progression (RP) defined as progression within 3 mos) was assessed using logrank and Fisher's exact tests. Trial design estimated 85 PFS and 51 RP events, providing >90% power (2-sided a=0.05); pts with unsuccessful BL CTC-ETI or ineligible were unevaluable. Only baseline (BL) data are reported in this abstract. Results: 32% of enrolled pts had progression within 12 mos of completing adjuvant ET, whereas 40%, 20%, and 8% had 1, 2, ≥3 lines of ET for MBC. CTC-ETI was successfully determined in 93% of pts (90% CI, 88% to 97%). CTC were ≥5 CTC/7.5 ml whole blood in 37/108 (34%) pts evaluable for clinical validity. Elevated CTC was associated with worse PFS (median (m) PFS: 3.3 vs. 5.9 mos; P<0.01). Low, intermediate, and high CTC-ETI were observed in 75 (69%), 6 (6%), and 27 (25%) pts, respectively. CTC-ETI was associated with PFS (logrank P<0.01): pts with low, intermediate, and high CTC-ETI had mPFS of 5.7, 8.5, and 2.8 mos, respectively. In the 96 pts eligible for determination, elevated CTC was associated with RP, (65.6% vs. 42.2%; P=0.05) as was CTC-ETI (P=0.003): 79.2% (95% CI, 57.8% to 92.9%) of pts with high CTC-ETI had RP versus 41.2% (95% CI, 29.4% to 53.8%) with low CTC-ETI; in the small group with intermediate CTC-ETI 1 of 4 pts (25%) had RP. Conclusions: In this multi-institutional, prospective study, CTC-ETI was accurately determined, confirming the previously established analytical validity of the assay, meeting the primary objective of the trial. Elevated CTC and CTC-ETI high compared to low were associated with poor outcomes to ET. CTC-ETI distribution resulted in a small number of patients assigned to the intermediate group, restricting our ability to associate this group with outcomes. These results suggest that CTC-biomarker phenotype and enumeration have clinical validity. CTC-ETI may identify ER+ HER2– MBC pts who are unlikely to benefit from ET and might be better treated with ET in combination with other therapies or proceed to chemotherapy. Further analyses including CTC-ETI at serial time points during ET are planned. Citation Format: Paoletti C, Regan MM, Liu MC, Marcom PK, Hart LL, Smith II JW, Tedesco KL, Amir E, Krop IE, DeMichele AM, Goodwin PJ, Block M, Aung K, Cannell EM, Darga EP, Baratta PJ, Brown ME, McCormack RT, Hayes DF. Circulating tumor cell number and CTC-endocrine therapy index predict clinical outcomes in ER positive metastatic breast cancer patients: Results of the COMETI Phase 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-01.

Abstract Background: Circulating Tumor cells (CTCs) are prognostic at baseline and first follow-up in patients with metastatic breast cancer (MBC). Using the most commonly used assay (CellSearch®), we have previously reported the ability to detect apoptotic vs. non-apoptotic CTCs in patients with MBC. However, there has been concern regarding the performance of the CellSearch® assay in patients with triple negative (TN) MBC. We hypothesized that CellSearch® is an effective assay in patients with TN MBC, and that CTC-apoptosis might further separate prognosis. Therefore, we studied CTCs in patients with TN MBC who participated in a prospective randomized phase II trial testing for activity of tigatuzumab (TIG) in combination with nanoparticle albumin-bound paclitaxel (nab-PAC) conducted by the Translational Breast Cancer Research Consortium (overall results reported by Forero A., et al, ASCO 2013). Methods: Whole blood (WB) was drawn into a CellSave tube at baseline, day 15, and day 29 and CTC counts were determined using the CXC CellSearch® kit. Apoptosis was characterized by staining with a monoclonal antibody that detects a neo-epitope on fragmented cytokeratin (M-30) and independently by visual inspection (nucleic condensation and/or fragmentation, as well as granular cytokeratin). Association between levels of CTCs and CTC-apoptosis with the overall response rate (ORR) and progression free survival (PFS) at baseline, day 15, and day 29 was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Results: Of the 60 patients entered into the trial, 52 were evaluable for CTCs. Of these, 19/52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) had elevated CTCs (≥5CTC/7.5 ml WB) at baseline, day 15, and day 29, respectively. Patients with elevated CTCs at each time point had worse PFS than patients with low or no CTCs. Hazard rates (HR) at baseline, day 15, and day 29 were 2.38 (95% CI: 1.27-4.45, p = 0.007), 2.87 (95% CI: 1.46-5.66, p = 0.002), and 3.40 (95% CI: 1.68-6.89, p = 0.001), respectively. The odds of overall response for those who had elevated CTCs compared to those who did not at baseline, day 15, and day 29, were 0.25 (95% CI: 0.073-0.81, p = 0.024), 0.18 (95% CI: 0.04-0.67, p = 0.014), and 0.06 (95% CI: 0.01-0.28, p = 0.001), respectively. There was no apparent prognostic effect comparing the degree of CTC-apoptosis vs. non-apoptosis. Conclusions: Similar to observations in other intrinsic subgroups, CTCs were detected in a large fraction of TN MBC patients at baseline using CellSearch® assay, and reductions in CTC levels reflected response. In these homogenously prospectively enrolled TN MBC patients, regardless of treatment, CTCs are prognostic at baseline, day 15, and day 29. It does not appear that analysis of CTC-apoptosis is prognostic. Supported by Susan G. Komen for the Cure, Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP), Triple Negative Breast Cancer Foundation, The AVON Foundation, and The Breast Cancer Research Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-04-01.