Tumor cell contamination of peripheral blood stem cell transplants and bone marrow in high-risk breast cancer patients

Summary:The aim of this study was to determine whether the detection of CTC in the apheresis product contribute significantly to treatment failure of patients with highrisk breast carcinoma treated with high-dose chemotherapy (HDC) and stem cell transplantation (SCT). Patients were with stage II and III adenocarcinoma of the breast with у10 axillary lymph nodes affected after primary surgery (у10 N+) who had received HDC with SCT. We analyzed retrospectively the presence of CTC as assessed by immunocytochemistry (ICC) in the apheresis products obtained after standard adjuvant chemotherapy. We compared the clinical outcome of patients who received HDC and SCT with or without CTC-positive apheresis. One hundred and twenty-seven apheresis products samples were obtained from 51 patients. Fourteen (27.4%) of these samples were CTC positive. After a median follow-up of 4.6 years, 20 patients have relapsed, 14 died from progression of their disease and 30 patients remain alive and free of progression. For the whole group of patients the 5 year probabilities of DFS and OS were 60% (IC 95%, 47-75%) and 71% (IC 95%, 55-83%), respectively. However, the 5 year probabilities of DFS were 23% (IC 95%, 0-46) and 75% (IC 95%, 60-89) for patients with CTC positive and negative, respectively. The 5 year probabilities of OS were 42% (IC 95%, 15-68) and 83% (IC 95%, 70-95) for patients with CTC positive and negative, respectively. Both univariate and multivariate analysis showed that the presence of CTC in the apheresis product was the only prognostic factor associated with a higher incidence of clinically overt disease relapse (P = 0.002) and shorter survival (P = 0.003). The presence of cytokeratin-positive metastatic cells in the apheresis product increases the risk of relapse after HDC and SCT in patients with stage II and III adeno- High-dose chemotherapy (HDC) with stem cell transplantation (STC) has been extensively used to treat women with breast cancer based on phase II studies suggesting a clinical benefit in some groups of patients with metastatic, 1-6 and high-risk breast cancer (HRBC). 7-11 However, preliminary results from most 12,13 but not all 14 phase III trials in HRBC patients, suggest no benefit for HDC over conventional treatment. Until the results from currently ongoing phase III trials determine the role of this therapy in patients with breast cancer, identification of new prognostic factors associated with an increased risk of relapse after HDC and SCT may help to define better which patients may benefit from this approach. A number of recent studies have implicated the presence of micrometastatic breast cancer cells in the bone marrow (BM) as an important and independent prognostic factor for relapse after standard chemotherapy. [15][16][17][18][19] Some studies have suggested a relation between the presence of CTC in the apheresis and relapse after HDC and SCT while other studies, mainly in patients with metastatic disease, have not been able to demonstrate such a relationship. [20][21][22] The aim of our s...

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prognostic significance of the immunocytochemical detection of contaminating tumor cells (CTC) in apheresis products of patients with high-risk breast cancer treated with high-dose chemotherapy and stem cell transplantation

Solano

Badia

Lluch

et al. 2001

“…6 Although the prognostic significance of tumor cells in PBPC collections requires further evaluation, a trend of higher relapse rates in breast cancer patients receiving tumor cell positive PBPC collections has been reported. 7 High-dose chemotherapy with hematopoietic rescue appears promising in the treatment of breast cancer, 10,11 but the presence of contaminating tumor cells in the reinfused hematopoietic cell product remains a concern. Retrovirally mediated gene marking techniques and retrospective clinical trials have demonstrated in patients with acute myelogenous leukemia, neuroblastoma, B cell lymphoma, chronic lymphocytic leukemia, or chronic myelogenous leukemia that reinfusion of contaminating tumor cells present in the BM harvest can contribute to disease relapse in the BM itself or in extramedullary sites.…”

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confidence: 99%

“…[1][2][3][4] The presence of tumor cells in the BM has been shown to be predictive of relapse in early stage [5][6][7] and advanced stage 8,9 breast cancer patients. In addition, the number of tumor cells identified in the BM has been correlated with shorter disease-free and overall survival.…”

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confidence: 99%

Ex vivo expansion of bone marrow from breast cancer patients: reduction in tumor cell content through passive purging

Lundell

Vredenburgh

Tyer

et al. 1998

Summary:High-dose chemotherapy (HDC) with hematopoietic support appears promising in the treatment of breast cancer, although reinfusion of contaminating tumor cells may contribute to disease relapse. Ex vivo expansion may reduce tumor cell content through use of a small inoculum volume and by passive purging during culture. We assessed the ex vivo expansion potential of tumor cell positive bone marrow (BM) from breast cancer patients and the effect of ex vivo expansion on tumor cell content. Cryopreserved/thawed mononuclear cell (C/T MNC) BM harvests with known tumor cell contamination (n = 7) were assessed for tumor cells preand post-expansion using immunocytochemical (ICC) staining. Pre-expansion inoculum samples contained a range of 6-2128 tumor cells per 5.0 × 10 6 nucleated cells. Ex vivo expansion resulted in fold expansions of 6.67 and 11.37 for total cells and CFU-GM, respectively. Tumor cells were undetectable in four of the seven postexpansion samples and were reduced in the remaining three samples. The data demonstrate passive purging of breast cancer cells during ex vivo expansion, with hematopoietic progenitor cell expansion comparable to that of normal BM. Reduction in tumor cell number contained in the small volume culture inoculum combined with passive purging during the ex vivo expansion process suggest a potential 2-4+ log reduction in tumor cell content in the reinfused cell product. Keywords: bone marrow transplantation; ex vivo expansion; tumor cell contamination Immunologic techniques have revealed tumor cell infiltration of the BM in as many as 48% of early stage breast cancer patients at the time of diagnosis. [1][2][3][4] The presence of tumor cells in the BM has been shown to be predictive of relapse in early stage 5-7 and advanced stage 8,9 breast cancer patients. In addition, the number of tumor cells identified in the BM has been correlated with shorter disease-free and overall survival. 6 Although the prognostic significance of tumor cells in PBPC collections requires further evaluation,

“…Firstly, ifosfamide can be incorporated into chemotherapy regimens to mobilize PBPCs. [8][9][10][11][12][13][14] Secondly, ifosfamide has some potential 428 advantages over cyclophosphamide. Pre-clinical studies have demonstrated that the unique structural properties of ifosfamide may have a beneficial anti-tumor activity; ifosfamide is an analogue of cyclophosphamide with translocation of a chlorethyl group which provides a more effective DNA cross-linking distance between two independent functional alkylating moieties.…”

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confidence: 99%

Ifosfamide in combination with paclitaxel or doxorubicin: regimens which effectively mobilize peripheral blood progenitor cells while demonstrating anti-tumor activity in patients with metastatic breast cancer

Prince

Gardyn

Millward

et al. 1999

Summary:For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients.