Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells

Abstract

Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part because of contamination of MPB by circulating tumor cells. CD34(+)Thy-1(+) selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study to determine feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between December 1996 and February 1998, and underwent HDCT followed by rescue with CD34(+)Thy-1(+) HSC isolated from autologous MPB. More than 12 years after the end of the study, 23% (5 of 22) of HSC recipients are alive, and 18% (4 of 22) are free of recurrence with normal hematopoietic function. Median progression-free survival (PFS) was 16 months, and median overall survival (OS) was 60 months. Retrospective comparison with 74 patients transplanted between February 1995 and June 1999 with the identical HDCT regimen but rescue with unmanipulated MPB indicated that 9% of patients are alive, and 7% are without disease. Median PFS was 10 months, and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- to 14-year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced-stage breast cancer patients.

Figure 1

Comparison of fold depletion of cancer cells from MPB using CD34 with and without Thy-1 as positive selecting markers for high-speed cell sorting (FACS) as compared with CD34 magnetic bead selection alone. MPB products were purposefully contaminated with tumor cells and the selected products were analyzed by an immunoflouresence (IFM) assay for breast cancer.

Figure 2

Progression-free survival (A) and overall survival (B) in patients undergoing HCT with purified HSC (n=22; grey) versus unmanipulated mobilized peripheral blood (black).

Figure 3

Overall survival of 22 recipients of purified HSC (grey) as compared to the cohort given MPB, subdivided into patients with [A] estrogen receptor (ER)-positive and ER-negative breast cancer; [B] relapsed breast cancer or patients with newly diagnosed metastatic disease undergoing auto-HCT as part of their upfront treatment; [C] visceral metastasis versus bone, but no visceral metastasis versus local recurrence versus exclusively lymph node disease; [D] complete response (CR), partial response (PR) or stable or progressive disease (SD/PD).