Annals of Oncology Advance Access published online on July 22, 2008
Annals of Oncology, doi:10.1093/annonc/mdn530
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Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers
1 Department of Translational Research Laboratory, Queensland Institute of Medical Research, Brisbane
2 Department of Viertel Cancer Centre, The Cancer Council Queensland, Brisbane
3 Department of Cancer Medicine, Western Australian Institute for Medical Research, Perth, Australia
Correspondence to: Dr G. Beadle, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Herston, Queensland 4029, Australia. Tel: +617-3870-4255; Fax: +617-3870-4305; E-mail: geoffBe{at}qimr.edu.au
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Abstract |
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Background: Clinical trials frequently report acute myeloid leukemia (AML) as a complication of adjuvant chemotherapy for breast cancer (BC).
Patients and methods: This retrospective population-based study investigated AML risk after a prior BC diagnosis and compared the results with women after a prior diagnosis of hematological malignancies (HM), other cancers combined (OCC), and the age-matched Australian female population.
Results: Women with a prior BC diagnosis had 2.56 times the risk of developing AML compared with the Australian female population (P < 0.001). AML risk was also elevated after prior HM and OCC diagnoses (4.73, P < 0.001, and 1.70, P < 0.001, respectively). Although the incidence of AML rose sharply with age in all cohorts, the age-specific relative risk was highest in the 30- to 49-age-group and decreased with increasing age. AML risk increased with the duration of follow-up but there was no change of risk during the 23 years of this study.
Conclusion: AML risk was elevated after a prior diagnosis of BC but there was no evidence of an increasing risk of AML after a BC diagnosis or, in any of the other cancer cohorts, during this era of expansion of the evidence base for more intensive treatments.
acute myeloid leukemia, all cancers, breast cancer, epidemiology, hematological malignancies
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introduction |
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Adjuvant chemotherapy improves survival rates in operable breast cancer (BC) but treatment-induced acute myeloid leukemia (AML) is now widely regarded as an important concern for survivors. Numerous studies have reported an increased risk of AML after treatment of BC [1–7] and support for this association has been strengthened by signature chromosomal aberrations [8–12] and evidence of a dose–response relationship [5, 7] after exposure to alklyating and topoisomerase II-targeted agents. In addition, radiation treatment, with or without chemotherapy [5, 13–15], and granulocyte colony-stimulating growth factors [5, 16] have been reported to be associated with an increased risk of AML in BC survivors. However, the collaborative meta-analysis of adjuvant chemotherapy and hormonal therapy trials reported no evidence of excess AML mortality in women treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF)-based chemotherapy versus controls or anthracycline versus CMF-based chemotherapy [17]. These discrepant findings underscore the need to quantify AML risk after a diagnosis of BC so that plausible contributing factors such as variations in treatment outside of trials, disease co-susceptibility and changing patterns of risk over time can be interpreted in numerical context.
In order to investigate whether survivors of BC in Australia have an increased risk of AML, this population-based study compares their risk with survivors of hematological malignancies (HM), where an elevated AML risk has also been reported [18–20], and other cancers combined (OCC), where early reports of increased AML risk attributed to single-agent alkylating drugs [21, 22] have not been supported by the results of recent clinical trials of newer chemotherapy regimens. Changing trends in absolute and relative risks are compared with the age-matched Australian female population aged 30 years and older from 1982 to 2004, an era of rapid expansion of both the evidence base and the usage of chemotherapy in BC.
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methods |
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female BC cohort
This study was conducted as a retrospective cohort study. The primary cohort consisted of all women in Australia with BC diagnosed from 1 January 1982 (the date mandatory national registration of cancer started in Australia) to 31 December 2004 (the latest year currently available). Data on women diagnosed with invasive BC (ICD-10 code C50) were obtained from the National Cancer Statistics Clearing House (NCSCH), which is maintained by the Australian Institute of Health and Welfare (AIHW). The NCSCH receives data from individual state and territory (population-based) cancer registries on all cancers diagnosed in residents of Australia (except non-melanoma skin cancer).
Women who were <30 years of age were excluded from the study because the small numbers (<1% of all female BC cases) would create unstable estimates. Follow-up began with the first recorded BC. Subsequent diagnoses of BC were not considered in this analysis.
other female cancer cohorts
For comparison purposes, we constructed three additional cohorts of female cancer patients aged 
30 years at diagnosis: other HM (ICD-O-2: C81–C97, excluding C92.0), OCC (excluding BC and HM) (ICD-O-2: C00–C54, C51–C80, C97) and all prior cancers, excluding AML. Data for these three additional cohorts were also obtained from the NCSCH and the inclusion criteria were the same as for the BC cohort. To maintain the independence of the different cancer cohorts, patients who were included in more than one cohort were excluded from the study.
female population comparison group
The comparison group was the female population of Australia aged 30 years. Estimated resident population data, and the Australian AML incidence data, were also sourced from the NCSCH.
analysis
Person-years at risk were accumulated for each woman in each of the four cohorts. Women, entered each cohort when they were diagnosed with cancer and left the cohort when they died, were diagnosed with AML (ICD-0-2 code C92.0) or at 31 December 2004, whichever came first. Only those cases of AML that were diagnosed after a prior cancer diagnosis were considered in the analysis. Outcome measures were split by period of diagnosis (1982–1990 and 1991–2004) and age at diagnosis (30–49, 50–69, 70 years).
The directly age-standardized incidence rate (ASR), with the 95% confidence interval (CI), was calculated for AML for each calendar year in each cohort by summing the age-specific incidence rates (number of cases of AML as the numerator and person-years at risk as the denominator). Rates were standardized to the Australian 2001 population and expressed as per 100 000 population. Poisson regression models were used to assess changes in the ASR between the two time periods. In these models, the log of the population variable was used as the offset variable, and the period effect was adjusted for age-group (entered as indicator variables). In separate analyses, age-group was entered as an ordinal variable to test for trends in incidence rates across age-groups.
Population AML incidence rates for females for each 5-year age-group and calendar year were obtained using the population comparison group. The expected number of AML diagnoses was calculated by applying the 5-year age- and year-specific incidence rate for AML among women in Australia to the age- and year-specific person-years at risk among the respective cancer cohorts.
The indirectly age-standardized incidence ratio (SIR) was calculated for AML diagnoses as the ratio of the observed number of AML diagnoses among the respective cancer cohorts to the expected number of incident AML cases, multiplied by 100. A Poisson distribution was assumed when calculating 95% CIs for these SIR estimates. An SIR of 100 indicated no difference between the risk of AML diagnosis for the respective cancer cohorts compared with the Australian female population. Poisson regression models were also used to assess whether the SIR estimates had changed over time. In these models, the counts and population for both the cancer cohort and the comparison group were included in the model, along with an indicator variable for group (cancer versus comparison) and time period. A statistically significant interaction between group and time period was interpreted as a significant change in the SIR over time.
Kaplan–Meier survival curves were used to assess differences in the time to diagnosis of AML among the cancer cohorts. Members of the cohort who were not diagnosed with AML before the end of the study period were censored. Log-rank tests were used to test for equality of survival curves across the cancer-specific cohorts (BC, HM and OCC).
Data extractions and analyses were conducted using SAS (SAS Institute Inc., Cary, NC) and Stata (StataCorp, TX). Initial data extraction was conducted by AIHW. The relevant programming codes for the ASR and SIR calculations were sent electronically to AIHW staff who submitted the programs and then returned the aggregated results. This ensured that no potentially identifying information was released outside the AIHW. As a result, the AIHW ethics committee waived the requirement for ethics committee approval for this study.
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results |
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In Australia from 1 January 1982 to 31 December 2004, there were 183 123 women diagnosed with BC who met the criteria for inclusion (Table 1). Of these, 158 (0.09%) were subsequently diagnosed with AML. Similarly, of 45 265 eligible women diagnosed with HM, 57 (0.13%) developed AML, and of 424 160 women diagnosed with OCC, 192 (0.05%) developed AML. From 1982 to 2004, there was a total of 4836 women diagnosed with AML in Australia and 407 (8.4%) had been previously diagnosed with a different cancer.
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directly ASRs per 100 000 person-years
The ASR of AML among women with any prior cancer diagnosis was 10.0 cases per 100 000 woman-years (95% CI = 9.0–11.3). The ASR of AML for the BC cohort was 11.97 (95% CI = 9.7–15.0), for the HM cohort 29.28 (95% CI = 20.4–41.9) and for the OCC cohort 7.59 (95% CI = 6.4–9.0). The AML annual incidence rate among all eligible Australian females from 1982 to 2004 was 4.08 per 100 000 population (95% CI = 4.0–4.2).
The ASR of AML among Australian women increased only slightly from 3.98 during 1982–1990 to 4.13 during 1991–2004 (P = 0.199) (Figure 1, Table 2). There were nonsignificant increases of AML incidence rates among the BC cohort between the two time periods (ASR 10.23 and 13.39, respectively; P = 0.382), the HM cohort (28.74 and 29.78, respectively; P = 0.506) and the all cancer cohort (9.72 and 10.3, respectively; P = 0.850). There was a slight, nonsignificant decrease in AML incidence rates in the OCC cohort (8.47 and 6.61, respectively; P = 0.202) (Figure 1, Table 2).
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Among all Australian women, the incidence rate of AML per 100 000 population increased sharply with age (test for trend: P < 0.001) (Figure 2, Table 2). Similar age-specific incidence patterns were observed among most of the cancer cohorts (test for trend: P < 0.001), with the exception of the HM cohort (test for trend: P = 0.650), where rates of AML peaked in the 50- to 69-year age-group.
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indirectly SIRs per 100 000 person-years
Women in each of the cancer cohorts had a greater risk of subsequently being diagnosed with AML compared with the general Australian female population, with all calculated SIR estimates being significantly >100 (Table 2, Figure 3). Women diagnosed with BC were
2.6 times more likely (SIR = 256, P < 0.001) to be diagnosed with AML than was expected, on the basis of the Australian female AML rates. This was similar to the increased risk for all women with a prior cancer diagnosis (SIR = 218, P < 0.001). Women with a prior HM had 4.7 times the risk of being diagnosed with AML (SIR = 472, P < 0.001) and women in the OCC group had 1.7 times the risk (SIR = 170, P < 0.001) expected on the basis of the Australian female population.
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There was no evidence that the increased risk of AML after a prior BC diagnosis changed between 1982–1990 and 1991–2004 (interaction between ‘group’ and period: P = 0.763) nor for the HM and all cancer cohorts (interaction between ‘group’ and period for HM: P = 0.835; all prior cancers: P = 0.345). There was some evidence that the SIR had decreased between the two time periods for the OCC cohort (SIR = 201 versus 148 in 1982–1990 and 1991–2004, respectively; P = 0.050).
From 1982 to 2004, the AML risk for BC survivors (relative to the comparison population) was highest in the 30- to 49-year-old age-group and decreased with age (Table 2, Figure 4). Similar patterns were identified for the each of the four cancer cohorts.
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time to AML diagnosis among the cancer cohorts
Figure 5 records the time to AML diagnosis for all women with a prior cancer diagnosis as well as the BC, HM and OCC cohorts. The 5-year risk of being diagnosed with AML after a BC diagnosis was 0.07%. The 5-year risk was the same (0.07%) for the entire cohort and the respective figures after a diagnosis of HM and OCC were 0.16% and 0.05%, respectively. There was no evidence that the AML risk for the entire cancer cohort plateaued with increasing time after diagnosis.
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discussion |
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Clinical trials routinely report AML as a complication of adjuvant chemotherapy for BC but there is little information available on the risk in non-trial use of chemotherapy. The purpose of this population-based study was to investigate the magnitude of AML risk after a diagnosis of BC and to compare this risk with other cancer survivors and the non-cancer population. The results show that AML risk was higher for BC survivors than for the non-cancer population and was a continuing risk for long-term survivors. Overall, women with a prior BC diagnosis were
2.6 times more likely to develop AML than the total Australian female population. Survivors of HM and OCC also had elevated risks of AML compared with the total Australian female population. Although other population-based studies have reported an increased risk of AML after a prior diagnosis of BC and HM [1, 14, 20], our findings of an elevated risk in OCC and a continuing risk over time for all cancer cohorts indicate that AML is a clinically relevant concern that extends across a broad spectrum of cancer survivors. In order to investigate the nature of this relationship further, we examined AML risk after BC taking into account both the changing evidence base for adjuvant chemotherapy during the time of this study and the age of the patients, and compared the results with the AML risk in the HM, OCC and non-cancer populations. The evidence base for adjuvant chemotherapy in BC increased significantly during the 23 years of this study as the sequential results of clinical trials demonstrated incremental survival benefits [17]. During this time, there was a marked expansion of oncology services in Australia as well as an evolution of adjuvant chemotherapy use in BC characterized by the introduction of more active agents, more widespread use in good prognosis subsets, higher dose intensity, use of growth factor support and integration with radiation treatment. In order to investigate the potential impact of these changing patterns of practice on AML risk, we compared ASRs and SIRs between the eras 1982–1990 and 1991–2004. This cut-off was selected because adjuvant chemotherapy for BC in Australia during the 1980s was characterized by CMF-based regimens and minimal use of anthracyclines. If anthracycline-based chemotherapy were significantly leukemogenic, then AML risk would be expected to rise in the later years of this study. However, the ASRs and SIRs changed little in the BC cohort between 1981–1990 and 1991–2004 and were similar to the nonsignificant increase of AML observed in the whole Australian female population.
An assessment of AML risk after a prior HM and OCC diagnosis also needs to be considered in the context of changing patterns of treatment and the background population risk. Chemotherapy is central to the successful outcomes for HM but, despite the highest risk of AML in this cohort, the ASRs and SIRs remained stable between 1982–1990 and 1991–2004. Possible explanations for this finding include disease co-susceptibility or a treatment substitution effect. For example, a shift from higher risk alkylating agents such as melphalan and chlorambucil [23, 24] to lower risk cyclophosphamide could be offset by a higher dose of chemotherapy, more widespread use of anthracyclines, the introduction of growth factor support and, in the later years of this study, transplantation. Similarly, while the slight decrease of ASRs and SIRs in OCC cohort cannot be explained in the absence of both treatment details and a breakdown of AML risk according to prior cancer site, it is possible that the single-agent alkylating therapies, which were used for some solid tumors in the 1970s and early 1980s [25, 26], have been replaced by newer, less leukemogenic regimens.
The AIHW is a population-based registry and does not record treatment details. Inferences about AML causality after a prior cancer diagnosis therefore need to be interpreted with caution. However, there was no evidence of an increased AML risk after a BC diagnosis with increasing use of CMF-based chemotherapy during the 1980s or the addition of doxorubicin and epirubicin to adjuvant programs of chemotherapy in BC during the 1990s and early 2000s, respectively. Although there is concern about the leukemogenic risk of cyclophosphamide, this alkylating agent is reported to be less leukemogenic than melphalan [14], and several adjuvant chemotherapy studies have failed to demonstrate an increased risk of AML after CMF-based therapy [3, 27, 28]. Epirubicin has also been reported as a leukemogenic agent [7, 29] but most of the time frame of the current study antedates the use of epirubicin as an approved drug in adjuvant chemotherapy regimens for BC in Australia. Reports of the leukemogenic effect of mitozantrone [1, 30] are unlikely to be relevant in this study because mitozantrone has never qualified for reimbursement as adjuvant chemotherapy for BC in Australia. While the negative findings of our study could be attributed to lower usage of more potentially leukemogenic agents, the results are consistent with the findings of the collaborative meta-analysis which failed to document increased AML mortality in women randomized to adjuvant CMF and anthracycline-based chemotherapy.
AML rates increased markedly with increasing age of the BC and OCC cohorts in this study as well as in the non-cancer population. Despite this pattern, SIR's were highest in the 30- to 49-year age-group for all cancer cohorts and decreased with increasing age (from >500 in the youngest group to 200 in the oldest group). These findings support the notion that treatment could be contributing to AML in younger women since adjuvant chemotherapy is more widely administered in this group. However, the absolute excess number of cases was small. For example, in the 30- to 49-year age-group, there were 25 more cases of AML in the BC cohort than was expected in 49 333 women followed for 380 788 person-years. For the age-group 70 years and older, the impact of chemotherapy on elevated AML risk is less certain. Adjuvant chemotherapy is difficult to administer in older age-groups and, historically, age 70 has been considered as the cut-off point for the safe administration of chemotherapy in clinical practice and most clinical trials. For example, a survey of trials sponsored by the National Cancer Institute from 1997 to 2000 reported underrepresentation of women with early-stage BC aged 65 years and older and that few trials entered patients 70 years [31]. In another study of adjuvant chemotherapy use from 1991 to 1999, data sourced from the Surveillance, Epidemiology and End-Results, Medicare-linked database reported that 11% of women aged 70–79 years were treated with adjuvant chemotherapy for BC [32]. Key limitations to the administration of optimal doses of adjuvant chemotherapy in this age-group are the elevated risk of anthracycline-induced cardiomyopathy and myelosuppression. In Australia, granulocyte colony-stimulating growth factor support in conjunction with adjuvant chemotherapy for BC was not reimbursed as primary prophylaxis during the time of this study although it has been reimbursed since 1995 after a prior episode of febrile neutropenia. It seems unlikely, therefore, that the elevated ASRs and SIRs in the BC group aged 70 years in our study are the result of adjuvant chemotherapy.
The time to diagnosis curves in our study also support the possibility of differing etiologies of age-related AML in cancer survivors. The actuarial risk of AML rose in all cohorts throughout the time of this study, including the OCC cohort with the lowest ASRs and SIRs. Although treatment-related AML has been reported within the first several years after chemotherapy for BC [14, 21] and other malignancies [33], the results of our study show no evidence of a short-term peak incidence and emphasize that long-term follow-up is necessary in BC and other cancer survivors to assess whether the risk of AML continues to be higher than that of the age-matched non-cancer population. AML is a result of acquired, nonrandom somatic mutations in hematopoietic progenitor cells. These mutations are found in the majority of cases, with higher frequencies in leukemia attributed to chemotherapy and advancing age [34, 35]. Reports of a short time course to myelodysplastic syndrome and AML, and a recent study of granulocyte colony-stimulating growth factor use in BC [16] support the possibility that treatment accelerates molecular events predestined to progress to AML. Disease co-susceptibility is also a plausible explanation in the HM cohort. The cumulative risk of AML was by far the highest in this cohort but ASRs and SIRs changed minimally between 1982–1990 and 1991–2004 despite the trend to more intensive treatment, increasing use of granulocyte colony-stimulating factor and transplantation during the later time frame of this study.
Important limitations of our study are the inability to document myelodysplastic syndrome or treatment details. However, a strength of this study is long-term follow-up, and the finding of only a small number of excess cases of AML in the BC cohort provides reassurance that AML risk is not increasing disproportionately to the population trend of AML incidence in Australian women aged 30 years. On-going vigilance is nevertheless warranted since the full impact of more extensive treatment of cancer generally, and adjuvant chemotherapy in BC particularly, means that treatment-induced AML could become an increasing problem for long-term survivors in the future. An important part of future surveillance needs to consider population-based studies in order to place the risk of AML in cancer survivors into numerical context and to provide a reference point for the interpretation of AML as a treatment complication reported by clinical trials.
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Cancer Council Queensland.
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The authors thank staff at the Australian Institute of Health and Welfare who have extracted data from the National Cancer Statistics Clearing House. The Cancer Council Queensland had no role in the interpretation of the data or the decision to submit the article for publication.
Received for publication June 18, 2008. Accepted for publication June 23, 2008.
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