Abstract
Women with breast cancer who receive adjuvant therapy are at risk for developing therapy-related myelodysplastic syndrome (MDS) or AML (tMDS/AML). Patients with tMDS/AML are often referred for consideration of allogeneic hematopoietic SCT (HSCT). However, the outcomes of HSCT in such patients have not been well described. We report a retrospective study of all women who were treated with HSCT for MDS or AML at our institution between 1991 and 2008. We compared the transplantation outcomes for 24 women with a history of breast cancer with those for 271 women with de novo disease. Three-year OS and disease-free survival (DFS) for patients with a history of breast cancer were 41 and 45%, respectively. The cumulative incidences of tMDS/AML relapse and non-relapse mortality (NRM) were 38 and 17%, respectively. Those outcomes were very similar to those of patients with de novo disease. In multivariable analyses, a history of breast cancer had no impact on OS, DFS, relapse or NRM. A significant proportion of women with tAML/MDS after breast cancer treatment experience DFS after HSCT, similar to that of patients with de novo MDS or AML. This justifies consideration of HSCT for selected patients in this setting.
Keywords: therapy-related disease, myelodysplastic syndromes, acute myelogenous leukemia, SCT
Introduction
It is well established that radiotherapy1,2 and chemotherapy (specifically alkylating agents3–5 and topoisomerase II inhibitors6) may lead to the development of therapy-related myelodysplastic syndrome or AML (tMDS/AML).7 Patients with breast cancer who receive adjuvant therapy most often receive one or several of the above treatments. Standard adjuvant regimens in the United States often include an alkylator (CY) and an anthracycline (doxorubicin); many patients also receive a taxane. Moreover, some women treated with mastectomy and lumpectomy receive adjuvant radiotherapy. These patients are therefore at risk for developing tMDS/AML. Indeed, the risk of developing leukemia has been shown to be elevated in breast cancer survivors in both long-term follow-up of clinical trials8,9 and epidemiologic studies,10,11 with a 10–year cumulative risk of 1–1.5% in follow-up of prospective studies. Furthermore, many patients treated in the 1990s received auto-SCT for their breast cancer, which has also been associated with an increased risk of tMDS/AML (ranging from 1 to 24% in various series12). Together, the above considerations highlight the importance of tMDS/AML for past and future patients treated for breast cancer.
Several studies have shown that patients with tMDS or AML have a dismal outcome, markedly inferior compared with patients with de novo disease.13–15 Those patients often harbor cytogenetic abnormalities that confer an adverse prognosis in the setting of de novo disease,7,16–23 and which also worsen the prognosis of therapy-related disease.13,15,18,22 Moreover, previous leukemogenic therapy appears to confer a worse prognosis than de novo disease even after accounting for karyotype.13,15 Given the poor prognosis of patients with tMDS/AML, allogeneic hematopoietic SCT (HSCT) is often performed in eligible patients. Unfortunately, there are no prospective data to inform this decision. Moreover, the specific outcomes of HSCT for patients with breast cancer therapy-related disease have not been well described. This information could be useful for those patients when deciding whether or not to pursue HSCT. The only published series on the topic included 11 patients who underwent allogeneic transplantation, which precluded analysis of prognostic factors. Moreover, the outcomes of those patients were not compared with those of patients with de novo disease. We therefore undertook this retrospective review of patients who received an allograft at our institution for breast cancer therapy-related disease, and compared their outcome with that of a cohort of women transplanted for de novo MDS or AML.
Materials and methods
Patients
We reviewed the medical records of all adult female patients with AML or MDS who received a first HSCT at the Dana-Farber/Brigham and Women’s Hospital transplant program between January 1991 and June 2008 and on whom follow-up was available for at least 6 months (for survivors). The diagnostic specimens were reviewed by expert hematopathologists at Brigham and Women’s Hospital. Patients with AML who had a previous diagnosis of MDS, as well as patients in the previously designated refractory anemia with excess blasts in transformation, were categorized as having AML arising from MDS. Patients who received an umbilical cord graft were excluded from this analysis. Patients with a previous diagnosis of breast cancer who had received radiotherapy or chemotherapy containing an alkylating agent or a topoisomerase II inhibitor, and whose date of first leukemogenic treatment was at least 1 year before the diagnosis of MDS/AML, were considered to have therapy-related disease.
Cytogenetics was classified according to the MRC scheme for patients with AML,20 and according to our previously proposed22 and validated24 classification scheme for MDS or AML arising from MDS (wherein patients with abnormalities of chromosome 7 or complex karyotypes are considered adverse, and all others are intermediate). The derivation cohort for this scheme overlaps in part with the present cohort, but the validation cohort is completely independent.
Institutional review board approval was obtained from the Office for the Protection of Research Subjects (OPRS) at the Dana-Farber/Harvard Cancer Center, in accordance with the principles of the Declaration of Helsinki.
Transplantation
Patients were transplanted under several treatment and investigational protocols over the period covered by this study. Myeloablative conditioning regimens consisted for most patients of CY (3600 mg/m2 or 120 mg/kg) plus TBI (1400 cGy in 7 fractions), or BU (12.8mg/kg intravenously) plus CY (3600mg/m2). Reduced-intensity regimens consisted of fludarabine (120mg/m2) plus i.v. low-dose BU (3.2mg/kg) with or without anti-thymocyte globulin. Patients received BM or PBSCs from matched or mismatched, related or unrelated donors. Acute GVHD was graded according to the modified consensus scale.25 Supportive care for all patients consisted of Pneumocystis jiroveci prophylaxis and VZV/HSV prophylaxis.
Statistics
Patient baseline characteristics were reported descriptively, and compared using Fisher’s exact test or Wilcoxon rank-sum test. OS and disease-free survival (DFS) were calculated using the Kaplan–Meier method. OS was defined as the time from stem cell infusion to death from any cause. Patients who were alive or lost to follow-up were censored at the time they were last seen alive. DFS was defined as the time from stem cell infusion to disease relapse or progression or death from any cause, whichever occurred first. ‘Disease’ for this purpose always refers to MDS/AML, not to the primary breast cancer. Patients who were alive without disease relapse or progression were censored at the time last seen alive and PFS. The log-rank test was used for comparisons of Kaplan–Meier curves. Cumulative incidence curves for non-relapse death and relapse with or without death were constructed reflecting time to relapse and time to non-relapse death as competing risks. Time to relapse and time to non-relapse death were measured from the date of stem cell infusion. Competing risks analysis was also used to determine the cumulative incidence of GVHD, considering death without GVHD as a competing risk. The difference between cumulative incidence curves in the presence of a competing risk was tested using Gray’s method.26 Specifically, patients with a history of breast cancer were compared with patients with de novo MDS/AML with respect to OS, DFS, relapse and non-relapse mortality (NRM). Potential prognostic factors for OS, DFS, relapse and non-relapse death were examined in the proportional hazards model as well as in the competing risks regression model.27 Interaction terms including interaction with time were examined in the proportional hazards regression model. Proportional hazards assumption for each variable of interest was tested by graphical and numerical methods. All calculations were performed using SAS 9.2 (SAS Institute Inc., Cary, NC, USA), and R (version 2.5.1).
Results
Patient characteristics
Among the 334 women who were treated with HSCT during the study period, 24 had a prior diagnosis of breast cancer for which they received leukemogenic therapy. Their transplantation outcome was analyzed and compared with that of the 271 women with de novo disease (excluding 39 patients with disease related to therapy for primary diagnoses other than breast cancer). The baseline characteristics of both groups are presented and compared in Table 1. Most patients with a history of breast cancer had received alkylators (88%), topoisomerase II inhibitors (79%) or radiation (71%). Only four (17%) had received a prior autograft. The median time between the first leukemogenic treatment and the diagnosis of MDS/AML was 4 years. Compared with patients with de novo disease (DN group), patients with breast cancer therapy-related disease (BC group) were older (median age 51 vs 46, P=0.004). They more frequently had a diagnosis of MDS (42 vs 15%, P=0.003), especially low-risk MDS (33 vs 8%). They also more frequently had adverse cytogenetics (46 vs 18%, P=0.003). Fewer of them received grafts from matched related donors (21 vs 51%, P=0.005), and fewer had ablative conditioning (58 vs 80%, P=0.022). The groups were otherwise comparable with respect to baseline characteristics. Among all women transplanted before 2004, 5% had a history of breast cancer and receipt of prior leukemogenic therapy, compared with 12% among those transplanted in or after 2004 (P=0.084).
Table 1.
Baseline characteristics of the patients
| Variable | Breast cancer patients N (%)a |
De novo patients N (%)a |
P-value |
|---|---|---|---|
| Number of patients | 24 | 271 | |
| Age (years) (median, range) | 51 (38–62) | 46 (18–71) | 0.004 |
| Disease | |||
| MDS | 10 (42) | 41 (15) | 0.003 |
| Low riskb | 8 (33) | 24 (9) | |
| High riskb | 2 (8) | 17 (6) | |
| AML arising from MDS | 1 (4) | 42 (15) | NS (>0.05) |
| AML | 13 (54) | 188 (69) | NS (>0.05) |
| Prior treatment | |||
| Alkylating agent(s) | 21 (88) | ||
| Topoisomerase II inhibitor | 19 (79) | ||
| Radiation | 17 (71) | ||
| ASCT | 4 (17) | ||
| Time to AML/MDS diagnosisc (years) (median, range) | 4 (1–19) | ||
| Stage at HSCT | |||
| Early | 20 (83) | 195 (72) | NS (>0.05) |
| Untreatedd | 10 (42) | 43 (16) | |
| CR1 | 8 (33) | 92 (34) | |
| CR > 1 | 2 (8) | 60 (22) | |
| Advanced | 4 (17) | 76 (28) | NS (>0.05) |
| Induction failure/PR | 3 (13) | 36 (13) | |
| Relapse | 1 (4) | 40 (15) | |
| Cytogeneticse | |||
| Not available | 2 (8) | 25 (9) | NS (>0.05) |
| Favorable | 2 (8) | 23 (8) | NS (>0.05) |
| Intermediate | 9 (38) | 174 (64) | 0.015 |
| Adverse | 11 (46) | 49 (18) | 0.003 |
| Donor match | |||
| MRD | 5 (21) | 138 (51) | 0.005 |
| Non-MRD | 19 (79) | 133 (49) | |
| Matched URD | 14 (58) | 105 (39) | |
| MMRD | 2 (8) | 5 (2) | |
| MMURD | 3 (13) | 23 (8) | |
| Graft source | |||
| PB | 18 (75) | 153 (56) | NS (>0.05) |
| BM | 6 (25) | 118 (44) | |
| Conditioning | |||
| Conventional | 14 (58) | 216 (80) | 0.022 |
| Reduced intensity | 10 (42) | 55 (20) | |
| GVHD prophylaxis | |||
| CnI/MTX | 7 (29) | 105 (39) | NS (>0.05) |
| CnI/Siro +/− MTX | 11 (46) | 87 (32) | NS (>0.05) |
| T-cell depletion | 4 (17) | 73 (27) | NS (>0.05) |
| Other | 2 (8) | 6 (2) | NS (>0.05) |
| CMV serostatusf | |||
| Recipient or donor + | 17 (71) | 178 (66) | NS (>0.05) |
| Gender of donorg | |||
| Male | 11 (46) | 128 (47) | NS (>0.05) |
| Year of HSCT (median, range) | 2004 (1991–2008) | 2002 (1991–2008) | NS (>0.05) |
| Months of follow-up (median, range) | 36 (13–94) | 32 (6–161) | NS (>0.05) |
Abbreviations: CnI=calcineurin inhibitor (CYA or tacrolimus); CR41=CR beyond first; CR1=first CR; HSCT=allogeneic hematopoietic SCT; MDS=myelodysplastic syndrome; MMRD=mismatched related donor; MMURD=mismatched unrelated donor; MRD=matched related donor; PB=peripheral blood; siro=sirolimus; URD=unrelated donor.
Percentages may not add to 100 because of rounding.
Low-risk MDS includes refractory anemia with or without ringed sideroblasts, refractory cytopenias with multilineage dysplasia, and chronic myelomonocytic leukemia; high-risk MDS includes refractory anemia with excess blasts (RAEB-1 and RAEB-2).
From the time of first leukemogenic treatment.
All of the 6 untreated breast cancer patients had MDS; 39 of the de novo untreated patients had MDS and 5 had AML arising from MDS.
See Materials and methods section for classification details.
CMV serostatus was unavailable for seven patients with de novo disease.
Data were unavailable for two patients with de novo disease.
Transplantation outcomes for breast cancer patients
Median follow-up for survivors in the BC group was 34 months. The estimated 3-year OS and DFS were 41% (95% confidence interval (95% CI), 20–61%) and 45% (95% CI, 25–64%), respectively (Figure 1a). We performed univariate analyses for OS and DFS testing all of the factors in Table 1. As the year of transplantation was a significant factor associated with outcome, we stratified the analyses by year of transplantation (before or after 2004, which was the median year of HSCT in this group). The only significant factor for OS was cytogenetics (P=0.011). Cytogenetics was also significant for DFS (P=0.019), as was graft source (adverse for BM graft compared with peripheral blood, P=0.019).
Figure 1.
Survival and relapse for patients with breast cancer therapy-related disease. (a) OS and DFS; (b) Cumulative incidence of relapse and of non-relapse mortality.
In the BC group, the estimated 3-year cumulative incidence of disease relapse was 38% (95% CI, 18–58%), and the estimated 3-year cumulative incidence of NRM was 17% (95% CI, 1–33%) (Figure 1b). There were no relapse or NRM events after 16 months from transplantation (although three patients who had relapsed within the first 16 months died at a later time). There were also no longterm survivors among patients who relapsed.
With respect to other transplantation outcomes, the 100-day cumulative incidences of grade 2–4 and grade 3–4 acute GVHD were 30 and 9%, respectively, whereas the 2-year cumulative incidence of chronic GVHD was 54%. No patient had a relapse of breast cancer during the follow-up of this study. One patient was diagnosed with endometrial cancer. One patient suffered from late graft failure with autologous recovery 9 months after a reduced-intensity transplantation; she remains alive without relapse at last follow-up, 13 months from transplantation.
Comparison with patients with de novo disease
Figures 2a and b compare the OS and DFS, respectively, between patients in the BC group and patients in the DN group. Three-year OS was 41% in both groups (P=0.5); 3-year DFS was 45% in the BC group vs 36% in the DN group (P=0.6). Three-year cumulative incidence of relapse was 38% in both groups (P=0.7); 3-year NRM was 17% in the BC group vs 26% in the DN group (P=0.3).
Figure 2.
Comparison of patients with breast cancer therapy-related disease and patients with de novo disease. (a) OS; (b) DFS.
We built multivariable models for OS and DFS on the entire cohort of patients, including the 24 patients in the BC group and the 271 patients in the DN group (Table 2). The analyses were stratified by time period of transplantation, as well as age and GVHD prophylaxis regimen (as these variables, although not significantly associated with outcome, did not meet the proportional hazards assumption). A history of breast cancer was not a significant factor for OS (hazard ratio (HR)=0.7, P=0.3) or DFS (HR=0.9, P=0.8). Advanced stage was associated with inferior OS (HR=1.5, P=0.023) (where early stage refers to untreated MDS or AML in CR, and advanced stage to induction failure/PR or active relapse). In the DFS model, there was a significant interaction between disease stage and conditioning intensity. We therefore examined each of the four categories of disease stage and conditioning intensity individually. Compared with patients with early stage disease (regardless of conditioning intensity), patients receiving myeloablative conditioning for advanced stage disease had significantly inferior DFS (HR=1.5, P=0.048), as did patients receiving reduced intensity conditioning for advanced stage disease (HR=4.3, P=0.0003) (Table 2). The other significant factor for OS was cytogenetics (HR for adverse cytogenetics compared with intermediate 1.6, P=0.014; HR for favorable cytogenetics 0.3, P=0.002), which was also significant for DFS (HR for adverse cytogenetics 1.8, P=0.004; for favorable cytogenetics 0.3, P=0.004). Similarly, in multivariable competing risks regression models, a history of breast cancer was not a significant factor for relapse (HR=1.0, P=0.9) or NRM (HR=0.6, P=0.4).
Table 2.
Multivariable analyses for OS and disease-free survival
| Variable | HR | P-value |
|---|---|---|
| Overall survival | ||
| Breast cancer history (vs not) | 0.7 | 0.2 |
| Disease | ||
| AML vs MDSa | 1.2 | 0.3 |
| Stageb | ||
| Advanced vs early | 1.5 | 0.023 |
| Cytogenetics | ||
| Favorable vs intermediate | 0.3 | 0.002 |
| Adverse vs intermediate | 1.6 | 0.021 |
| Donor HLA match | ||
| Non-MRD vs MRD | 1.4 | 0.082 |
| Conditioning | ||
| RIC vs full intensity | 1.4 | 0.3 |
| Graft source | ||
| BM vs PB | 1.0 | 1.0 |
| CMV serostatus | ||
| Donor or rec+vs both− | 1.0 | 0.9 |
| Donor | ||
| Female vs male | 0.8 | 0.2 |
| Disease-free survival | ||
| Breast cancer history (vs not) | 0.9 | 0.8 |
| Disease | ||
| AML vs MDSa | 1.1 | 0.7 |
| Stage and conditioningb,c | ||
| Advanced stage and full intensity | 1.5 | 0.048 |
| Advanced stage and RIC | 4.3 | 0.0003 |
| Cytogenetics | ||
| Favorable vs intermediate | 0.3 | 0.003 |
| Adverse vs intermediate | 1.8 | 0.004 |
| Donor HLA match | ||
| Non-MRD vs MRD | 1.4 | 0.089 |
| Graft source | ||
| BM vs PB | 1.0 | 0.9 |
| CMV serostatus | ||
| Donor or rec+ vs both − | 1.0 | 0.9 |
| Donor | ||
| Male vs female | 0.8 | 0.14 |
Abbreviations: HR=hazard ratio; Ref=reference group; RIC=reduced intensity conditioning; rec= recipient; +=positive; −=negative; other abbreviations are described in Table 1.
Analyses were stratified by time period of transplantation, as well as age and GVHD prohpylaxis regimens (which did not meet proportional hazards assumption).
Including patients with AML arising from MDS.
Stage is as defined in Table 1.
Early stage (reduced intensity or full-intensity conditioning) is the referent group.
Discussion
In this cohort of 24 women with breast cancer tMDS or AML, HSCT resulted in a 3-year OS and DFS of 41 and 45%, respectively. This compares very favorably with the historical outcomes of patients with therapy-related disease treated with conventional therapy.13–15 Moreover, a history of breast cancer and prior leukemogenic therapy did not have any apparent effect on the outcome of transplantation; indeed, patients with breast cancer had similar OS and DFS, relapse and NRM after HSCT as did a contemporaneous cohort of women who underwent HSCT for de novo MDS or AML in the same time period. Finally, none of the transplanted patients experienced a recurrence of their original breast cancer.
This retrospective study is subject to several important limitations. By its nature, this is a study of patients who proceeded to transplantation, which is a selected subset of all patients with therapy-related disease. It is possible that patients with therapy-related disease may have a lower rate of CR with induction chemotherapy,13,18,28 which would affect their ability to get to HSCT as well as the transplantation’s outcome. It should also be noted that women with breast cancer therapy-related disease in our cohort more frequently had adverse cytogenetics. This is consistent with many published series of patients with tMDS or AML. As cytogenetics is an important determinant of transplantation outcome, it is possible that in a larger group of women with tMDS/AML, the overall HSCT outcomes would be worse than in an unselected group of women with de novo disease. There was also a higher proportion of women with low-risk MDS in the breast cancer group. Although this could have biased the comparison with patients with de novo disease, there was no suggestion of such bias in the multivariable models (which included a term for disease stage). Finally, this study comprises only 24 patients with breast cancer therapy-related disease, which limits our ability to find smaller differences in outcomes between the groups.
In our cohort, the percentage of women with breast cancer therapy-related disease increased in recent years, suggesting that this type of disease may be increasing in incidence. Although the lack of statistical significance and vulnerability to selection bias demand caution in interpreting this finding, one may speculate about the possible explanations. This increase could reflect in a delayed manner the frequent use of ASCT in the treatment of breast cancer from the mid-to-late 1990s. Also, there has been an increase in the use of G-CSF in adjuvant regimens, especially to support ‘dose-dense’ schedules.9,29,30 There has been a suggestion that adjuvant CSF exposure may affect the risk of tMDS/AML;9,29,31 however, the potential role of CSFs in promoting therapy-related disease is poorly defined and controversial, and no increased risk of tMDS/AML was seen in one of the largest trials randomizing women to CSF or not.30 Selection bias could also contribute to this observation, as we cannot assess the numerator of women with treated breast cancer who form the referral base for our transplantation center, and referral patterns could change over time. Furthermore, there is currently interest in anthracycline-free adjuvant chemotherapy regimens32,33 (although such regimens still include leukemogenic agents), which may potentially alter future risk of therapy-related hematologic neoplasms.
Regardless, this study suggests that allo-SCT is a reasonable treatment for selected women with breast cancer tMDS or AML, who may derive a similar benefit from transplantation as patients with de novo disease. It also argues that such patients should be promptly referred to transplantation centers.
Acknowledgements
This work was funded in part by P01 AI 29350 from the National Institute of Allergy and Infectious Diseases. PA is the recipient of a career development award from the Leukemia and Lymphoma Society.
Footnotes
Conflict of interest
The authors declare no conflict of interest.
References
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