Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients

Abstract

Background: To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC).

Methods: CTCBL and CTC1C status was determined as negative (-) or positive (+) for < 5 or ≥ 5 CTCs/7.5 ml blood using CellSearch™ (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2-3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS.

Results: 133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5-3.2) and 2.9 (0.5-4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7-6.1] vs. 7.8 [6.4-9.2]; OS 10.4 [7.9-15.0] vs. 27.2 [22.3-29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6-6.0] vs. 8.5 [6.6-10.4]; OS 7.7 [6.4-13.9] vs. 30.6 [22.6-not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, ≥ 3rd-line therapy, and triple-negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, ≥ 3rd-line therapy, and triple-negative receptor status).

Conclusions: CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC.

Trial registration: Not applicable.

Figure 1

Flow of patients through the study. Of 403 consecutive patients assessed for eligibility, 10 (2.5%) were excluded from the study because essential data items were not available (no clinical data: 1 patient; no CTC_BL data: 9 patients). Of the 393 patients included in the study, 192 had no CTC_1C counts and were therefore excluded from further analysis for the following reasons. During the initial phase of the study, i.e. the first 100 patients, CTC_1C status was routinely determined only in CTC_BL+ patients, resulting in 64 CTC_1C- patients without CTC_1C counts. Of the remaining 128 patients without CTC_1C counts, 12 were excluded because blood samples were not obtained within the predefined study timeframe of 0.5–3.2 months, 25 did not survive to CTC_1C assessment because they died within the first 3.2 months, and 91 patients who survived beyond 3.2 months after inclusion had no CTC_1C count (41 had not yet proceeded to CTC_1C and 50 were lost to follow-up blood sampling as our center often treats external patients).

Figure 2

Progression-free survival and overall survival by CTC status. PFS (left) and OS (right) by CTC status at baseline (top) and after the first cycle of a new line of systemic therapy (bottom) in 356 patients with MBC.

Figure 3

Progression-free survival and overall survival by CTC_KIN. PFS (left) and OS (right) stratified by change in CTC status (CTC_KIN) from baseline to completion of the first treatment cycle.