We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3–64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.
Management of metastatic breast cancer remains a challenge despite advances in treatment and better understanding of the biological and molecular basis of the disease during the past two decades. Use of high-dose chemotherapy for metastatic breast cancer, first proposed in the 1980s, was based on dose–response concepts.1, 2 Autologous hematopoietic cell transplantation (HCT) was used to rescue the bone marrow from the myelotoxic effects of high-dose chemotherapy. Of eight randomized phase III studies comparing conventional chemotherapy with autologous HCT,3, 4, 5, 6, 7, 8, 9, 10, 11 seven suggested that high-dose therapy leads to improved progression-free or event-free survival; however, none of these seven studies have been published in the peer-reviewed literature.3, 4, 5, 8, 9, 10, 11 One published phase III trial showed no advantage of autologous HCT over conventional therapy in terms of either progression-free survival (PFS) or overall survival.6, 7 Disease recurrence remained a major problem even among those who initially achieved a complete response to high-dose therapy. Incomplete disease eradication or contamination of the autologous stem-cell product by malignant cells may contribute to disease recurrence.
Allogeneic HCT for metastatic breast cancer has two potential advantages over autologous HCT—a cancer-free graft and immune-mediated graft-vs-tumor (GVT) effects from the donor's cells. GVT effects against leukemias and lymphomas are well established.12, 13, 14, 15, 16, 17 In the 1980s, spontaneous GVT effects against solid tumors after allogeneic HCT, even with reduced-intensity conditioning (RIC) regimens, were documented in murine models.18 Since the first small studies were published in the 1990s,19, 20, 21, 22, 23 interest has increased in harnessing the potentially beneficial GVT effects of allogeneic HCT for the treatment of metastatic breast cancer.
To avoid the high treatment-related morbidity and mortality associated with the use of traditional myeloablative conditioning, RIC regimens, with or without the use of donor lymphocyte infusion (DLI) after the transplant were developed.24, 25, 26, 27, 28 With RIC regimens, the goal is the induction of immune GVT effects rather than chemotherapy-mediated cytoreduction. Clinical responses suggesting a GVT effect have been described, but none of the studies have included more than 20 patients with metastatic breast cancer. We analyzed the outcomes of patients given allogeneic HCT for treatment of metastatic breast cancer reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) or the European Group for Blood and Marrow Transplantation (EBMT). The objectives were to describe the features and outcomes of these patients, to compare toxicity and outcome after traditional myeloablative conditioning vs RIC and to explore whether allogeneic HCT induces a GVT effect.
Patients and methods
Center for International Blood and Marrow Transplant Research
The CIBMTR is a voluntary working group of more than 500 transplantation centers worldwide that contribute detailed data on consecutive HCTs to the Statistical Center at the Medical College of Wisconsin in Milwaukee. Participating centers are required to register all transplantations consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally, with yearly follow-up.
The CIBMTR collects data at two levels: Registration and Research. Registration data include disease type, age, sex, pretransplant disease stage and chemotherapy-responsiveness, date of diagnosis, graft type (bone marrow- and/or blood-derived stem cells), high-dose conditioning regimen, post-transplant disease progression and survival, development of a new malignancy and cause of death. Research data are collected on subsets of registered patients and include comprehensive pre- and post-transplant clinical information.
European Group for Blood and Marrow Transplantation
The EBMT was founded in 1974 and consists of more than 400 transplant groups in Europe and other countries reporting all their HCTs by the Med A form, similar to the registration form used by CIBMTR. The completeness of reporting is checked by an annual survey and site visits. The EBMT is composed of 21 Working Parties each focusing on major disease groups or HCT complications. All patients with metastatic breast cancer registered with the allogeneic HCT subcommittee of the Solid Tumors Working Party for transplants performed between 1992 and 2000 were included in this study. The data for this study were obtained by collecting Med A information and additional disease-specific information.
For this study, the CIBMTR and EBMT centers also completed supplemental data forms regarding the withdrawal of immunosuppression or DLI and response (if any) to these maneuvers. Data were reviewed to eliminate overlapping reporting of patients between CIBMTR and EBMT teams.
All women who underwent an allogeneic transplant for metastatic breast cancer between 1992 and 2000 and for whom comprehensive data collection forms were submitted to the CIBMTR or to the Allogeneic HCT Subcommittee of the Solid Tumors Working Party of the EBMT were included. Demographic characteristics and survival of the study population were similar to all allogeneic HCT recipients with metastatic breast cancer registered with the CIBMTR during the same time period.
Patients who had had prior autologous HCT were included, except for patients who underwent a planned sequential autologous-allogeneic approach. Patients who received a planned sequential autologous-allogeneic HCT were excluded. Information on patients who received such a tandem HCT approach was recently reported.29
The conditioning regimens used in allogeneic HCT for metastatic breast cancer were divided into myeloablative group and RIC group. The criteria of the division were based on the dose of chemotherapeutic agent in each regimen suggested by the second EBMT workshop.30
The end points in this study were transplant-related mortality (TRM), breast cancer progression or relapse, PFS and overall survival. Acute and chronic GVHD and tumor response to immune manipulation after transplantation were described. TRM was defined as death without progression of breast cancer; relapse or progression were treated as competing events. Disease progression was defined as clinical recurrence (after a complete response) or progression of disease at any site, as determined by the treating physician at the transplant center. Because patients who had a transplant during the study period had been evaluated for radiographic disease response before the RECIST criteria were in common use, all responses represent the traditional World Health Organization criteria.31 For analyses of PFS, treatment failures were defined as clinical disease relapse or progression at any site or death from any cause; data on patients who were alive and without disease progression were censored at the time of last follow-up. For analyses of overall survival, failure was death from any cause; data were censored at last follow-up for surviving patients.
Patient-, disease- and transplant-related characteristics of patients in the myeloablative and RIC cohorts were compared by using the χ2-test for categorical variables and the Kruskal–Wallis test for continuous variables. Univariate probabilities of overall survival and PFS were calculated by using Kaplan–Meier estimates; the log rank test was used for univariate comparisons. Probabilities of acute and chronic GVHD, TRM and disease relapse or progression were calculated by using cumulative incidence estimates to accommodate competing risks.32 TRM and disease relapse (or progression) were treated as competing events. Patients who received DLI were censored for incidence of GVHD at the date of DLI.
Because the number of patients was relatively small, analyses were limited to comparison of outcomes in the presence or absence of GVHD with adjustment for conditioning intensity. Cox proportional hazards regression was used to examine whether acute or chronic GVHD and DLI affected outcomes. We used a time-dependent covariate to model the potential effects of GVHD or DLI, in which patients were considered as having GVHD or DLI only after the onset time of GVHD or after the date of receiving DLI, respectively. Time to development of acute GVHD and any GVHD were each tested in the models, with nearly identical results. Because nearly all patients who developed chronic GVHD had preceding acute GVHD, we chose to present results for acute GVHD. The assumption of proportional hazards regression was tested by using a time-dependent covariate. Interactions between myeloablative vs RIC and covariate factors were tested with the likelihood ratio test.
Data were provided from 15 transplant centers for 66 women who received allogeneic HCT for metastatic breast cancer between 1992 and 2000 (Table 1). Median follow-up time for survivors was 40 months (range, 3–64 months). Median patient age at the time of transplantation was 41 years (range, 25–60 years). Slightly less than half of the patients (41%) had a Karnofsky performance score of less than 80 before transplantation. A total of 37 patients (56%) had hormone-receptor–positive disease; information on HER-2/neu status was not available. A total of 31 patients (47%) had responsive disease before HCT; 17 patients (26%) had progressive disease before transplantation. The median number of prior regimens (not including autologous HCT) was 2 (range, 1–6). The median number of sites of metastatic disease at the time of transplantation was 2 (range, 0–5). A total of 17 patients (26%) had undergone prior autologous HCT. Traditional myeloablative conditioning regimens were used for 39 patients (59%) and RIC regimens for 27 patients (41%). Most patients received transplants from an HLA-identical sibling; two received cells from an unrelated donor. Peripheral blood stem cells were used for 92% of the patients. Prophylaxis for GVHD is shown in Table 1. Patient and disease characteristics were similar between these two groups (Table 1) except for Karnofsky score (⩾80 in 74% of the myeloablative group vs only 37% in the RIC group) and having had one or more prior autologous transplants (8% of the myeloablative group vs 52% of the RIC group).
Graft-vs-host disease and immune manipulation
The cumulative incidence of grade II-IV acute GVHD at 100 days was 44% after myeloablative conditioning and 34% after RIC (Table 2). The cumulative incidence of chronic GVHD at 1 year was much higher in the myeloablative group (36%) than in the RIC group (8%) (Table 2). Chimerism data were not available to confirm long-term engraftment in the RIC group. A total of 33 patients (50%) received additional immune manipulation (withdrawal of immunosuppression, administration of DLI or both) for disease control within 60 days after transplantation. Six patients (18%) had significant disease response and three other patients (9%) had minor response or stable disease (Table 3).
Survival, treatment-related mortality, response and relapse
Overall survival rates after myeloablative conditioning were 51% at 1 year and 25% at 2 years vs 26% at 1 year and 15% at 2 years after RIC (Table 2, Figure 1). The cumulative incidence of TRM at 100 days was 26% in the myeloablative group and 7% for the RIC group (Table 2, Figure 2). Among patients not in complete response at transplantation, the overall response rate (complete or partial response) after HCT was 31% in the myeloablative group (three complete responses and nine partial responses) and 29% in the RIC group (two complete responses and six partial responses) (Table 3). A total of 6 of the 33 patients (18%) who received immune manipulation for disease control had a complete (n=1) or partial (n=5) response; 3 others (9%) had stable disease (Table 3). The cumulative incidence of disease relapse or progression in the myeloablative group was 44% at 1 year and 62% at 2 years; corresponding incidences in the RIC group were 76 and 84% (Table 2, Figure 3). Probabilities of PFS in the myeloablative group were 23% at 1 year and 5% at 2 years; corresponding probabilities of PFS in the RIC group were 8 and 0% (Table 2).
Analysis of conditioning vs graft-vs-host disease
The presence of acute GVHD was associated with a significantly increased risk of TRM (P=0.03) for recipients of myeloablative HCT compared to those who did not develop acute GVHD. The risk of TRM associated with aGVHD was also increased but not statistically significant for RIC recipients (Table 4). In Cox time-dependent analysis, women treated with RIC regimens who developed acute GVHD had a lower risk of progression relative to those who did not develop acute GVHD (relative risk 0.33: P=0.03). For patients given myeloablative regimens, no difference in risk of relapse was found between those who developed acute GVHD and those who did not. For patients who developed acute GVHD, the risk of progression was similar for women given RIC and for women given myeloablative regimens. However, for those who did not develop acute GVHD, the risk of progression in patients who received myeloablative regimens was significantly decreased compared to those received RIC regimens (relative risk 0.14: P⩽0.0001).
Among women given a myeloablative conditioning regimen, the development of acute GVHD was associated with an increased risk of treatment failure (progression/relapse or death) (relative risk 2.04: P=0.03) (Table 4). In contrast, for women treated with RIC regimens, there was a decreased risk of treatment failure associated with development of acute GVHD (relative risk 0.51: P=0.12). This risk was not, however, statistically significant. As was true in the models for relapse, no significant difference in the risk of treatment failure was found between myeloablative and RIC approaches when acute GVHD developed, but for patients who did not develop acute GVHD, those who received myeloablative regimens had less treatment failure than those received RIC regimens. Neither GVHD nor intensity of conditioning was associated with overall survival in bivariate analysis.
Published clinical studies have suggested that allogeneic HCT can produce a GVT effect in metastatic breast cancer.24, 25, 26, 27, 28 However, those studies included very small numbers of patients. This retrospective registry study suggests that allogeneic HCT can produce a GVT effect in metastatic breast cancer, as evidenced by tumor response after post-transplant immune manipulation and the association of acute GVHD with reduced risk of disease progression. These findings are consistent with a graft-vs-malignancy effect in hematologic malignancies.
The most direct evidence of the existence of a GVT effect is disease response associated with immune manipulations such as DLI.28 In this study, nine patients (27%) who underwent additional immune manipulation after transplantation showed disease response or stable disease (Table 3).
Indirect evidence of a GVT effect comes from the observation of disease control in combination with acute GVHD when an RIC regimen was used (Table 4). Disease progression was observed more frequently among those who received RIC regimens and did not develop acute GVHD compared to those patients who received RIC regimens and developed acute GVHD. For women treated with conventional high-dose conditioning, those who developed acute GVHD were at significantly higher risk of TRM and did not experience better disease control than women without acute GVHD. This suggests that an immune-mediated GVT effect associated with acute GVHD in patients given RIC regimens played a role in disease control. The effect of GVHD on recurrence may represent a minor antigen specific alloimmune effect rather than a tumor-specific response for breast cancer. Further research with larger numbers of patients is required to determine whether GVT effect occurs without GVHD or if it could be separated in a clinically meaningful fashion from GVHD.
One explanation for the above findings is that most of the patients (79%) in the myeloablative group had stable or responsive disease before transplantation, and they also had had fewer prior treatments (median, 2) than did the patients in the RIC group, though these differences were not statistically significant. This suggests that most of the patients in the myeloablative group had relatively chemosensitive disease. Therefore, the immune-mediated GVT effect may not play a major role in decreasing risk of progression in patients with relatively chemosensitive disease who received myeloablative regimens. However, the increased TRM in the myeloablative group may offset the benefit associated with development of GVHD. Therefore, development of acute GVHD was associated with increased treatment failure among those who received a myeloablative regimen.
There are several limitations of this study. First is the heterogeneity of the patient and disease characteristics and transplant approaches. Many patients had poor performance status and nonresponsive disease before the transplant. One fourth of the patients had prior autologous HCT that failed, and at least half had visceral organ involvement. The types of conditioning regimens and GVHD prophylaxis, and the timing and intent of immune manipulation varied across transplant centers. This heterogeneity reflects variation in the eligibility criteria among the different transplant centers and the selection of patients with poor prognosis typical of early investigational studies of high-risk procedures. Although a few characteristics were statistically significantly different between the conditioning approaches (RIC vs ablative), small numbers limited our ability to further adjust for the effects of patient, disease and transplant characteristics on transplant outcome. Data were not available regarding HER-2 expression in these patients. Data were collected from multiple sources, and data regarding tumor responses were not subjected to review outside of the transplant center performing the procedures.
Despite these limitations, our analysis reveals some interesting findings. Our analysis supports an allogeneic GVT effect in metastatic breast cancer that could produce disease response. Whether this can be separated from GVHD is to be determined in future studies. A second finding is the demonstration that the TRM associated with allogeneic HCT when an RIC regimen was used was much lower than the TRM associated with traditional myeloablative regimens. However, more intense conditioning regimens may improve disease control, as shown by the lower relapse or progression rates among patients given myeloablative therapy as compared with those given reduced-intensity therapy.
In murine models, a GVT effect was demonstrated in mice implanted with 4T1 mammary carcinoma cell line and given minor histocompatibility-mismatched DBA/2 spleen cells.33 This direct GVT effect mediated by the alloreactive donor splenocytes in the absence of any anti-carcinoma agents has also been demonstrated by direct inhibition of liver metastases through intraportal inoculation of allogeneic splenocytes but not syngeneic splenocytes.34 Activated allogeneic natural killer splenocytes and allogeneic donor-specific CD8+ cytotoxic T cells with a type 2 cytokine phenotype have also been shown induce a GVT effect against metastatic mammary carcinoma.35, 36 The same murine models of metastatic mammary carcinoma have demonstrated as an effective immunotherapy of metastatic mammary carcinoma by allogeneic HCT after non-myeloablative conditioning.37 Despite these findings, more preclinical studies should be conducted to facilitate targeted adoptive immunotherapy for breast cancer. These studies need to clarify the nature of the GVT effect, including identification of the specific tumor antigens involved in GVT (if any) and identification of methods to promote GVT without GVHD.
In summary, more preclinical studies will result in deployment of innovative allotransplant approaches that take advantage of GVT effects to control disease while minimizing TRM or development of GVHD. Future studies should only include patients with better performance status and with chemotherapy responsive disease before transplant who may be more likely to benefit from GVT effects. One recent approach is the use of planned tandem autologous/allogeneic RIC transplantation for patients with metastatic breast cancer.29
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Other authors include are Javier Garcia-Conde, Gabriela Rondón, Roger H Herzig, Charles F LeMaistre, Philip L McCarthy, Elizabeth C Reed, Shimon Slavin, Edward A Stadtmauer, Karen H Antman, Richard Childs and Mary M Horowitz.
This was supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; Office of Naval Research; Health Services Research Administration (DHHS); Programme Hospitalier de Recherche Clinique (PHRC2000, France); Deutsche Krebshilfe, Verbund Allogene Stammzelltransplantation und Immuntherapeutische Strategien; Associazione Italiana per la Ricerca sul Cancro, Italy; and grants from AABB, Abbott Laboratories; Aetna; AIG Medical Excess; American Red Cross; Amgen Inc.; Anonymous donation to the Medical College of Wisconsin; AnorMED Inc.; Astellas Pharma US Inc.; Berlex Laboratories Inc.; Biogen IDEC Inc.; Blue Cross and Blue Shield Association; BRT Laboratories Inc.; Celgene Corp.; Cell Therapeutics Inc.; CelMed Biosciences; Chugai Germany; Cubist Pharmaceuticals; Dynal Biotech, LLC; Edwards Lifesciences RMI; Endo Pharmaceuticals Inc.; Enzon Pharmaceuticals Inc.; Gambro BCT Inc.; Genzyme Corporation; GlaxoSmithKline Inc.; Histogenetics Inc.; Human Genome Sciences; Kirin Brewery Company; Ligand Pharmaceuticals Inc.; Medac GmbH Germany; Merck & Co.; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA Inc.; Miltenyi Biotec; National Center for Biotechnology Information; National Leukemia Research Association; National Marrow Donor Program; NeoRx Corporation; Novartis Pharmaceuticals Inc.; Novo Nordisk Pharmaceuticals; Ortho Biotech Inc.; Osiris Therapeutics Inc.; Pall Medical; PDL Bio Pharma Inc.; Pfizer Inc.; Pharmion Corp.; QOL Medical; Roche Laboratories; StemCyte Inc.; Stemco Biomedical; StemSoft Software Inc.; SuperGen Inc.; Sysmex; THERAKOS Inc.; University of Colorado Cord Blood Bank; Valeant Pharmaceuticals; ViaCell Inc.; ViraCor Laboratories; WB Saunders Mosby Churchill; and Wellpoint Inc.; and Zelos Therapeutics Inc.
We thank Christine Wogan and Sandy Sobotka for their excellent help in editing the manuscript.
The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense or any other agency of the US Government.
We also acknowledge the following institutions for contributing transplantation data for this study: Roswell Park Cancer Institute, Buffalo, NY, USA; University of Alabama, Birmingham, AL, USA; MD Anderson Cancer Center, Houston, TX, USA; Loyola University Medical Center, Maywood, IL, USA; Louisiana State University Medical Center, Shreveport, LA, USA; Roger Williams Medical Center, Providence, RI, USA; Richland Memorial Hospital. Columbia, SC, USA; University of California-San Diego, La Jolla, CA, USA; Memorial Medical Center, New Orleans, LA, USA; Blood and Marrow Group of Georgia, Atlanta, GA, USA; Hospital G U Gregorio Maranon, Madrid, Spain; Ruprecht-Karls-Universitaet, Heidelberg, Germany; University of Iowa Hospital and Clinics, Iowa City, IA, USA. Genoa, Italy; Marseille, France; Innsbruck, Austria; Leipzig, Germany; Milan, Italy.
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Ueno, N., Rizzo, J., Demirer, T. et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant 41, 537–545 (2008). https://doi.org/10.1038/sj.bmt.1705940
- allogeneic hematopoietic cell transplantation
- metastatic breast cancer
- graft-versus-tumor effect
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