Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer

Abstract

The increasing number of treatment options for patients with metastatic carcinomas has created a concomitant need for new methods to monitor their use. Ideally, these modalities would be noninvasive, be independent of treatment, and provide quantitative real-time analysis of tumor activity in a variety of carcinomas. Assessment of circulating tumor cells (CTCs) shed into the blood during metastasis may satisfy this need. We developed the CellSearch System to enumerate CTC from 7.5 mL of venous blood. In this review we compare the outcomes from three prospective multicenter studies investigating the use of CTC to monitor patients undergoing treatment for metastatic breast (MBC), colorectal (MCRC), or prostate cancer (MPC) and review the CTC definition used in these studies. Evaluation of CTC at anytime during the course of disease allows assessment of patient prognosis and is predictive of overall survival.

Figure 1

Images of twenty-four CTC candidates identified by the CellTracks Analyzer II. The images show an overlay of DAPI purple and CK-PE green. No staining was observed in the CD45 APC and FITC channel at the position of the CTC candidates. Six operators trained to review CellSearch CTC data classified objects 1–10, 13–17 as CTC, and discard objects 20–24 as CTC. 1 of 6 operators classified object 11 as a CTC and 5 of 6 operators classified object 12, 18, and 19 as a CTC.

Figure 2

Kaplan Meier Analysis of overall survival before starting a new line of therapy for patients with metastatic breast cancer (a), metastatic colorectal cancer (b), and castration resistant prostate cancer (c). Patients were divided into those with Favorable and Unfavorable CTC. The cutoff value between favorable and unfavorable CTC was ≥5 CTC/7.5 mL blood for breast and prostate cancer and ≥3 CTC/7.5 mL blood for prostate cancer.

Figure 3

Kaplan Meier Analysis of overall survival. Favorable CTCs are indicated with 1 through 4 and Unfavorable CTCs with 5 through 8. (a) Median overall survival of MBC patients with Favorable CTC after 3–5 Weeks (1) (n = 92), 6–8 Weeks (2) (n = 77), 9–14 Weeks (3) (n = 105) and 15–20 Weeks (4) (n = 70) of treatment median was 21.7, 19.1, 20.8, and 20.1 months, respectively. Median overall survival of MBC patients with Unfavorable CTC after 3–5 Weeks (5) (n = 40), 6–8 Weeks (6) (n = 22) 9–14 Weeks (7) (n = 24), and 15–20 Weeks (8) (n = 15) of treatment was 6.2, 6.3, 6.4, and 11.3 months, respectively. (b) Median overall survival of MCRC patients with Favorable CTC after 1–2 Weeks (1) (n = 316), 3–5 Weeks (2) (n = 292), 6–12 Weeks (3) (n = 285), and 13–20 Weeks (4) (n = 172) of treatment was 15.7, 16.4, 15.8, and 14.6 months, respectively. Median overall survival of MCRC patients with Unfavorable CTC after 1–2 Weeks (5) (n = 41) 3–5 Weeks (6) (n = 41), 6–12 Weeks (7) (n = 25), and 13–20 Weeks (8) (n = 21) of treatment median was 6.1, 4.4, 3.3, and 3.3 months, respectively. (c) Median overall survival of MPC patients with Favorable CTC after 2–5 Weeks (1) (n = 123), 6–8 Weeks (2) (n = 110), 9–12 Weeks (3) (n = 100), and 13–20 Weeks (4) (n = 99) of treatment median was 20.7, 19.9, 19.6, and 19.8 months, respectively. Median overall survival of MPC patients with Unfavorable CTC after 2–5 Weeks (5) (n = 80), 6–8 Weeks (6) (n = 53), 9–12 Weeks (7) (n = 49), and 13–20 Weeks (8) (n = 44) of treatment was 9.5, 8.5, 7.6, and 6.7 months, respectively. The cutoff value between favorable and unfavorable CTC was ≥5 CTC/7.5 mL blood for breast and prostate cancer and ≥3 CTC/7.5 mL blood for prostate cancer.

Figure 4

CTC changes after treatment in patients with MBC (a), MCRC (b), and MPC (c). Curves labeled 1 represent patients with CTCs that remain Favorable, labeled 2 CTCs convert from Unfavorable to Favorable, labeled 3 CTCs convert from Favorable to Unfavorable, and labeled 4 CTC remain Unfavorable. (a) After initiation of therapy, CTC in 83 (47%) MBC remained Favorable with median overall survival (OS) of 22.6 months, CTC in 39 (22%) patients remained Unfavorable median OS 4.1 months, CTC in 38 (21%) patients converted to Favorable CTC median OS 19.8 months, and CTC converted to Unfavorable in 17 (10%) patients median OS 10.6 months. (b) CTC in 303 (70%) MCRC remained Favorable median OS 18.6 months, CTC in 24 (6%) patients remained Unfavorable median OS 3.9 months, CTC in 74 (17%) patients converted to Favorable CTC median OS 11.7 months, and CTC converted to Unfavorable in 29 (7%) patients median OS 7.1 months. (c) CTC in 88 (38%) MPC remained Favorable median OS of more than 26 months, CTC in 71 (31%) patients remained Unfavorable median OS 6.8 months, CTC in 45 (20%) patients converted to Favorable CTC median OS 21.3 months, and CTC converted to Unfavorable in 26 (11%) patients median OS 9.3 months. The cutoff value between favorable and unfavorable CTC was ≥5 CTC/7.5 mL blood for breast and prostate cancer and ≥3 CTC/7.5 mL blood for prostate cancer.