Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500

Abstract

Purpose: Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS).

Patients and methods: Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2).

Results: Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001).

Conclusion: This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy.

Trial registration: ClinicalTrials.gov NCT00382018.

Fig 1.

CONSORT diagram of patient entry in the study and distribution. In all, 624 patients with metastatic breast cancer were screened for circulating tumor cells (CTCs) before starting first-line chemotherapy. Of these, treatment failed to reduce CTCs to less than five per 7.5 mL of whole blood after one cycle of chemotherapy for 123 patients, and they were randomly assigned to continue receiving that therapy or switch to alternative chemotherapy.

Fig 2.

Overall survival (OS) and progression-free survival (PFS) in patients with metastatic breast cancer for whom therapy failed to reduce circulating tumor cells (CTCs) within 3 weeks of starting first-line chemotherapy; patients were randomly assigned to continue receiving the initial chemotherapy or to switch to an alternative chemotherapy. Outcomes for the primary objective that tested the primary outcome (OS) and the secondary outcome (PFS) are shown. (A) OS and (B) PFS for patients who had increased CTCs (five or more CTCs per 7.5 mL of whole blood) at baseline and for whom therapy failed to reduce CTCs to less than five CTCs per 7.5 mL of whole blood at first follow-up (approximately 21 days after first dose of chemotherapy). Patients were randomly assigned to maintain the original chemotherapy (arm C1) or to switch to an alternative chemotherapy (arm C2). Choice of original and alternative chemotherapy was at physician's discretion. OS and PFS were calculated from the time of random assignment. The Cox model for both outcomes showed no evidence of violating the proportional hazards assumption (OS P = .92; PFS P = .27). Three patients in arm C2 were judged as progressing on day 22 and were excluded from the PFS analysis but were included in the OS analysis. The progression data were not available at the time of random assignment.

Fig 3.

Overall survival (OS) in patients with metastatic breast cancer according to circulating tumor cell (CTC) levels at baseline or first follow-up. Outcomes for the second primary objective that tested the prognostic ability of baseline and follow-up CTC levels by using the primary outcome (OS) are shown. An unplanned analysis of differences by disease subtype is also shown. (A) OS for all patients was determined from trial entry for patients with CTC levels of less than five CTCs per 7.5 mL of whole blood (WB) at baseline (arm A), for patients with CTC levels of five or more CTCs per 7.5 mL WB at baseline but less than five CTCs per 7.5 mL WB at first follow-up (21 days after first dose of chemotherapy; arm B), and for patients with CTC levels of five or more CTCs per 7.5 mL WB at baseline and five or more CTCs per 7.5 mL WB at first follow-up (21 days after first dose of chemotherapy; arm C). (B-D) OS within biologic subgroups. OS for patients with (B) hormone receptor–positive and HER2-negative disease, (C) triple-negative disease (hormone receptor negative and HER2 negative), and (D) HER2-positive disease.

Fig A1.

SWOG Protocol S0500 study schema.