Breast Cancer

Bone Marrow Transplantation (2003) 32, 151–155. doi:10.1038/sj.bmt.1704120

Syngeneic hematopoietic stem cell transplantation for women with metastatic breast cancer

J D Rizzo1, S Williams2, J T Wu1, A L Pecora3, H M Lazarus4, B Bolwell5, K K Fields6, R P Gale7, G Elfenbein8, M M Horowitz1 and K H Antman9

  1. 1International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI, USA
  2. 2Hematology-Oncology Associates of Illinois, Chicago, IL, USA
  3. 3The Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA
  4. 4Case Western Reserve University, Cleveland, OH, USA
  5. 5Cleveland Clinic, Cleveland, OH, USA
  6. 6H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  7. 7Center for Advanced Studies in Leukemia, Los Angeles, CA, USA
  8. 8Roger Williams Medical Center, Providence, RI, USA
  9. 9Columbia University, New York, NY, USA

Correspondence: JD Rizzo, International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

Received 14 October 2002; Accepted 26 November 2002.

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Abstract

Metastatic breast cancer has been a common indication for autologous hematopoietic stem cell transplantation (HSCT). Previous reports indicate 3-year survival and progression-free survival (PFS) rates after autotransplant to be about 30 and 15%, respectively. Most deaths are from recurrent disease. One potential cause for high relapse rates is graft contamination with tumor. We describe 14 women with metastatic breast cancer transplanted between 1991 and 1998 with hematopoietic cells from identical twins. Median age was 41 y (range 34–50). Most women (12 of 14) were treated with mastectomy, and all received anthracycline–based regimens in their pretransplant course; nine women also received a taxane, seven radiotherapy and three hormonal therapy. Four women were in complete remission (one CR, three CRU) at transplant, five were in partial remission, two had stable disease and two had progressive disease. Eight women have died, one of treatment-related causes and seven of progressive breast cancer. Three–year survival was 48% (21–71%) and 3–year PFS was 21% (5–45%). Although the number of patients is small, outcomes for women transplanted with syngeneic grafts are similar to those of women receiving autologous grafts. This suggests that residual cancer in the patient is the major contributor to relapse after transplantation for breast cancer.

Keywords:

breast cancer, syngeneic, hematopoietic stem cell transplantation

Metastatic breast cancer has a uniformly poor prognosis with median survival of about 2 years with standard chemotherapy regimens. Over the past 10 years, many investigators have studied the role of high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) support in this disease. Observational studies suggest a small advantage for HSCT compared to traditional chemotherapy for women with metastatic disease;1 however, one published randomized clinical trial (N=187 evaluated patients) did not confirm this benefit.2 Likewise, other small, randomized trials, comparing high-dose with conventional therapy, have described equivocal results.3,4,5,6 These studies, thus far presented as abstracts with relatively short follow-up, have shown small improvements in progression-free survival (PFS), without improvement in overall survival. One study suggests that overall survival is improved with a strategy that delays HSCT until first recurrence.3 Previous reports from the Autologous Blood and Marrow Transplant Registry (ABMTR) indicate 3-year probabilities of survival and PFS of 31% (95% confidence interval (CI), 28–34%) and 13% (95% CI: 10–16%), respectively, after autologous transplantation for metastatic breast cancer.7 Published randomized trials comparing high-dose with conventional dose therapy for women with stage II/III breast cancer do not demonstrate a survival benefit with high-dose therapy at the present time.8,9 Despite transplantation, most women with metastatic breast cancer eventually relapse and die of their disease. There are two potential reasons for recurrence: (1) the disease is resistant to high-dose therapy and consequently, remains and regrows; and (2) reinfusion of breast cancer cells with the autologous graft leads to growth of new tumor implants. Increased risk of relapse in women with metastatic breast cancer has been associated with tumor cell contamination of the stem cell product.10,11,12 No gene marking studies in breast cancer are available to suggest that residual tumor cells actually participate in the relapse. Investigators have studied methods of purging breast cancer cells from autografts but, to date, there is no evidence of superior survival after purged vs unpurged grafts.13 The issue is complicated by the fact that patients with resistant disease may be more likely to have contaminated grafts and uncertainty regarding the efficiency of cancer cell removal with current purging methods. Only with cells from a healthy donor can one be sure that that the graft is uncontaminated with breast cancer cells.

The goal of this study was to describe the outcomes of women receiving syngeneic (identical twin) HSCT after high-dose therapy for metastatic breast cancer. Outcomes of syngeneic transplantation may provide insight regarding the primary source of relapse in women failing high-dose therapy–the stem cell infusion or residual disease in the host.

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Patients and methods

Data collection

The IBMTR is a voluntary working group of more than 400 transplantation centers worldwide that contribute detailed data on allogeneic and syngeneic HSCT recipients to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee. Participating centers are required to register all transplants consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally, with yearly follow-up. Computerized checks for errors, physicians' review of submitted data and on–site audits of participating centers ensure the quality of the data.

The IBMTR collects data at two levels: registration and research. Registration data include disease type, age, gender, 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. Requests for data on progression or death for registered patients are at yearly intervals. All teams contribute registration data. Research data are collected on subsets of registered patients, including comprehensive pre-transplant and post-transplant clinical information such as tumor size and pathology, sites of disease, hormone receptor status, all cancer treatments before and after transplant, clinical status (including cardiac, pulmonary, renal and liver function) before and after transplant, doses of high-dose therapy, blood or marrow graft treatment and sites of post-transplant progression. Response is reported in the usual categories of complete response, partial response, stable or progressive disease. Owing to the difficulties of evaluating response of bony lesions in breast cancer, an additional category of 'complete response with exception of bone scan abnormalities of unknown significance' (CRU) can be reported for patients having response to therapy at nonbone disease sites without changes in bony lesions.

Patients

In total, 22 women receiving HSCT from identical twins between 1991 and 1998 for metastatic breast cancer were registered with the IBMTR. Detailed (Research) information regarding disease and transplant was available for 14 of these patients. Demographics and survival rates were similar in the Registration and Research databases.

Endpoints

Survival was the primary outcome of interest. Death from any cause was considered an event; survivors were censored at the time of last contact. PFS was defined as survival without recurrence or progression of breast cancer. Recurrence or progression of breast cancer and death from any cause were considered events. Women surviving without recurrence or progression were censored at date of last contact.

Statistical analysis

Descriptive tables of patient, disease and transplant characteristics are presented. Continuous variables are reported as medians with ranges; categorical variables are reported as absolute numbers and percent of total patients. Survival curves for overall survival and PFS were calculated using the Kaplan–Meier estimator.14 Cumulative incidence rates were computed for treatment-related mortality and recurrence/progression.15,16

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Results

In total, 14 women received syngeneic stem cell transplantation for metastatic breast cancer between 1991 and 1998, and were reported to the ABMTR by 13 centers. Of these, 12 women were followed more than 1 year and nine were followed more than 2 years. The median follow-up of survivors is 40 (30–58) months.

Patient-, disease- and transplantation-related characteristics of the 14 women are presented in Table 1. The median age was 41 years, with a range of 34–50 years. In all, 86% of women had a Karnofsky performance score of 90% or better pretransplant. Most women were initially diagnosed with stage II/III breast cancer; 57% of women had estrogen receptor/progesterone receptor (ER/PR) positive tumors. Most women (86%) had three or fewer chemotherapy regimens pretransplant. Two women received one chemotherapy regimen, five received two, five received three, one received four and one received five regimens before proceeding to the high-dose therapy. Nine received a taxane and seven received radiation therapy at some point before transplant. In total 20% had more than three sites of metastases at some point in their illness. Nine women (64%) had disease sensitive to chemotherapy at the time of transplantation, four women were in complete remission (CR — 1 patient) or CR with bone scan abnormalities of uncertain significance (CRU — three patients). Half of the women received cyclophosphamide and thiotepa with or without platinum as their conditioning regimen. Five received peripheral blood stem cells as the graft source. Six women received tamoxifen after transplantation; four of these women were hormone receptor positive before transplantation. One woman had a planned second syngeneic transplant as part of sequential therapy.


Outcomes are shown in Table 2 and Figure 1. Four of 10 women with disease present at transplant experienced improvement in response to the transplant procedure. One person transplanted with progressive disease developed a complete response, as did another woman with stable disease at transplant. One woman with a partial response to pretransplant therapy had a complete response, and one woman with stable disease had a partial response. Six of 14 women had either no response or progressed after HSCT. The patient with CR at the time of transplant continues to be free of breast cancer. The patient with stable disease, who developed CRU after transplant had a second syngeneic transplant (day 120) as a planned sequential transplant, and remains in CRU more than 3 years after the second transplant. All three women with CRU at transplant have progressed between 6 and 17 months after transplant.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Overall and PFS for women receiving syngeneic HSCT for metastatic breast cancer.

Full figure and legend (16K)


Six women are alive at 24 months or more after HSCT; two of them are free of disease. There was only one treatment-related death, in a woman who died from interstitial pneumonitis at 68 days post-transplant after a partial response to high-dose therapy. Breast cancer was reported as the primary cause of death in the other seven women who died. Probabilities of survival and PFS at 3 years were 48% (95% CI: 21–71%) and 21% (95% CI: 5–45%), respectively.

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Discussion

We briefly describe the outcomes of 14 women with metastatic breast cancer who received syngeneic HSCT. Treatment-related mortality was low; one patient of 14 died from interstitial pneumonitis within the first 100 days after transplantation. This treatment-related mortality rate does not appear to be substantially different from the 1 to 5% treatment-related mortality rates reported for patients receiving autologous transplantation.8,17

Probabilities of survival and PFS at 3 years in this group of women were 48 and 21%. A previous analysis from the ABMTR reports 3-year survival and PFS of 31% (95% CI: 28–34%) and 13% (95% CI: 10–16%) for women with metastatic breast cancer receiving autologous HSCT.7 Outcomes of the transplant arm from a randomized trial are similar, with 3-year probability of survival of 32% and PFS of 6%.2 Although the overall survival appears longer among women receiving syngeneic transplantation, these estimates are based on small numbers of patients that may not be directly comparable. Additionally, there appears to be no difference in the probability of PFS at 3 years.

Survival in women transplanted with stem cells obtained from twins appears to be similar to published results for women with metastatic breast cancer transplanted with CD34-selected autologous stem cells. With a median follow-up of only 16 months, Negrin et al18 report a probability of survival and PFS at 2 years of 60 and 41%, respectively, in women with metastatic breast cancer treated with CD34-selected autografts. The survival and PFS appear similar to the twin transplant patients reported in this study (64 and 28%, Table 2), after considering the differences in length of follow-up between the two studies.

Speculation continues as to whether one of the sources of failure after autologous HSCT is clonogenic breast cancer cells in the stem cell reinfusion product. These data, from a small group of patients, do not support the hypothesis that contamination of the stem cell product by tumor cells is a major contributor to relapse or progression after transplantation for metastatic breast cancer. Relapse in these women after high-dose therapy appears to occur from endogenous breast cancer. Future trials of HSCT in metastatic breast cancer might focus on better eradication of disease pretransplant or taking advantage of the post-transplant minimal residual disease state to effectively deliver novel therapies, including immunotherapy.

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References

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Acknowledgements

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; and grants from Abgenix, Inc.; AmCell Corporation; American Cancer Society; American Society of Clinical Oncology; Amgen, Inc.; Anonymous; Aventis Pharmaceuticals; Berlex Laboratories; BioTransplant, Incorporated; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Oncology; Center for Advanced Studies in Leukemia; Cerus Corporation; Chimeric Therapies; Chiron Therapeutics; Eleanor Naylor Dana Charitable Trust; Deborah J. Dearholt Memorial Fund; Empire Blue Cross Blue Shield; Fujisawa Healthcare, Inc.; Gambro BCT, Inc.; Genentech, Inc.; GlaxoSmithKline, Inc.; Human Genome Sciences; ICN Pharmaceuticals, Inc.; IDEC Pharmaceuticals Corporation; IntraBiotics Pharmaceuticals; Kettering Family Foundation; Kirin Brewery Company; Robert J Kleberg, Jr and Helen C Kleberg Foundation; LifeTrac/Allianz; The Liposome Company; Nada and Herbert P Mahler Charities; Market Certitude, LLC; Mayer Ventures; MedImmune, Inc.; Merck & Co., Inc.; Milliman & Robertson, Inc.; Milstein Family Foundation; The Greater Milwaukee Foundation/Elsa Schoeneich Research Fund; NeoRx; Nexell Therapeutics; Novartis Pharmaceuticals; Orphan Medical; Ortho Biotech, Inc.; John Oster Family Foundation; Pfizer US Pharmaceuticals; Pharmacia Corporation; Pharmametrics GmbH; Principal Life Insurance Company; Response Oncology, Inc.; RGK Foundation; Roche Laboratories, Inc.; SangStat; Schering AG; Schering Oncology/Biotech; Stackner Family Foundation; The Starr Foundation; SuperGen, Inc.; TheraTechnologies, Inc.; Unicare Life & Health Insurance; and Wyeth/Genetics Institute. The contents of this article are solely the responsibility of the authors and do not represent the Official views of the National Cancer Institute.

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