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Annals of Surgical Oncology 9:738-744 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Therapy-Induced Leukemias and Myelodysplastic Syndromes After Breast Cancer Treatment: An Underemphasized Clinical Problem

Christopher B. Weldon, MD, PhD, Bernard M. Jaffe, MD and Marc J. Kahn, MD

From the Departments of Pharmacology (CBW), Surgery (CBW, BMJ), and Medicine (MJK), The Tulane Cancer Center (CBW, BMJ, MJK), New Orleans, Louisiana.

Correspondence: Address correspondence and reprint requests to: Bernard M. Jaffe, MD, Department of Surgery, Tulane University School of Medicine, 1430 Tulane Avenue, SL-22, New Orleans, LA 70112; Fax: 504-584-3793; E-mail: bjaffe{at}tulane.edu

Key Words: Secondary leukemias • Myelodysplastic syndromes • Breast cancer • Chemotherapy


   INTRODUCTION
TOP
 INTRODUCTION
CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
With the advent of multidisciplinary oncologic therapeutic regimens, cancers are being treated with greater effectiveness, as measured by increases in both disease-free and actuarial survival rates. The application of all of these treatment arms into a single, focused therapeutic attack has allowed patients to live far longer than was thought possible 30 years ago. However, for some patients, oncologic treatment (and resultant success) has come with a price, namely, therapy-induced malignancies.1–3 Although this is an important clinical problem, it is an underemphasized and underreported phenomenon in the literature. By using a typical case report to put this problem in perspective, this article reviews the frequency and mechanism of secondary malignancies after therapy for breast cancer.


   CASE REPORT
TOP
 INTRODUCTION
 CASE REPORT
DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
A 56-year-old woman presented to Tulane University Medical Center with extreme fatigue and gum diastasis. Twenty-seven months earlier, she had been diagnosed with infiltrating ductal breast cancer (T2N1M0). The patient detected a mass in the superior outer quadrant of her left breast while showering, and subsequent mammographic studies confirmed the existence of a suspicious lesion. At the time of biopsy, pathologic evaluation confirmed that this lesion was malignant, and the patient then underwent a formal lumpectomy with axillary node dissection. Phenotypically, the tumor was found to be 3.5 cm in diameter, was estrogen receptor (ER) and progesterone receptor positive, was diploid with a low S phase, and expressed Her2/neu in normal quantities. Two of 14 axillary nodes were positive for cancer. Adjuvant therapy consisted of six cycles of chemotherapy containing cyclophosphamide, methotrexate, and fluorouracil, in addition to radiation and tamoxifen.

The patient remained disease free for more than 2 years while continuing on a daily regimen of tamoxifen. Routine physical examinations and annual mammograms remained unremarkable. Several weeks before admission, she noted increased dyspnea on exertion and gum diastasis, initially believed to be secondary to periodontal disease. She also reported an episode of chest pain while gardening. A routine complete blood count was remarkable for a hemoglobin of 6 g/dl, a hematocrit of 18%, and platelet count of 27 x 109/L. Her leukocyte count was 56 x 109/L, and 80% of the leukocytes were myeloblasts. Subsequent analysis confirmed the diagnosis of acute myelogenous leukemia (AML) (French-American-British [FAB] classification M2). Cytogenetics were remarkable for the presence of a clone of cells having trisomy of chromosome 8. The patient did not go into remission, and she died as a result of this disease process.


   DISCUSSION
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
This case is a stereotypical presentation of a patient with therapy-induced malignancy, or secondary malignancy, which has been a concern of cancer therapeutic regimens since cancer treatments first began. Patients receiving immunosuppression for solid organ transplants are at increased risk for lymphoma.4 Reports of radiation-induced leukemias occurring in patients treated for Hodgkin’s disease with total body irradiation are another well-documented phenomenon,5 but reports of radiation-induced solid tumors exist as well.6

Most known chemotherapeutic agents and regimens have been documented to induce both solid and nonsolid tumors after treatment.7 The incidence of chemotherapeutic-induced malignancies will probably increase as well, in light of the greater prevalence of adjuvant and therapeutic chemotherapy combined with subsequent bone marrow transplantation in the treatment of many malignancies. Currently, 10% to 20% of all new cases of AML and myelodysplastic syndrome (MDS) diagnosed annually are secondary to therapeutic regimens.8 Secondary AML and MDS tend to appear with a mean latency of 5 years after therapy. Surveillance has consisted of monitoring routine blood counts periodically for the first 5 years after treatment for breast cancer, but there are no data to suggest that early detection of secondary AML or MDS significantly improves the prognosis of this devastating consequence of therapy. Thus, therapy-induced leukemias and myelodysplastic syndromes both deserve serious consideration. This review article is organized to provide data on secondary malignancies induced by chemotherapy, hormonal manipulation, radiotherapy, and bone marrow transplantation.


   CHEMOTHERAPY-INDUCED AML/MDS
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
The three primary classes of chemotherapeutic agents used in the treatment of breast cancer—alkylating agents, topoisomerase inhibitors, and taxanes—have all been shown to induce AML/MDS after therapy. The best-characterized class of chemotherapeutic agents used in breast cancer treatment is the alkylating agents, a diverse group of drugs that are the oldest known oncologic chemotherapeutic drugs in use today.9 Covalent linkage of the active moiety of the alkylating agent to an electrophilic region of DNA produces DNA adducts, including single and double strand breaks, that induce lethality.10 The precise cytotoxic mechanism is not fully understood, but it is believed to interfere with and block DNA replication, with unabated protein and RNA production.10 This resultant decrease in DNA replication, combined with altered protein and RNA production, leads to an imbalance in the formation of intracellular macromolecules and induces an irreversible cellular death signal. Alkylating agents can also be described as radiomimetic, secondary to their ability to induce cytotoxic effects in a similar fashion to radiotherapy.11

Alkylating agents are categorized into five classes: the nitrogen mustard compounds, the nitrosoureas, the tetrazine compounds, the aziridines, and other miscellaneous agents. The majority of alkylating agents have been shown to be leukemogenic,2 but the best-characterized and most potent leukemogenic agents are the nitrogen mustard compounds. The secondary AML/MDS that they produce can be characterized by specific clinical and cytogenetic measures.

Melphalan is the nitrogen mustard alkylating agent that demonstrates the greatest leukemogenic potential; as a result, its clinical ubiquity has declined considerably in favor of less toxic drugs. One such agent is cyclophosphamide, which is now the most common alkylating and chemotherapeutic agent used in the treatment of breast cancer.

The 10-year incidence of secondary AML/MDS after the administration of one of these agents is roughly 1.5%.8 The cumulative risk increases by .25% to 1% for the first 8 years after treatment.2,5,12–25 Ultimately, the relative leukemic risk of these compounds decreases to that of the general population by 10 years after treatment.8 The leukemic potential of cyclophosphamide has been shown to be far less than that of melphalan. Curtis et al.26 demonstrated a 10-fold difference (3.1 vs. 31.4) in the relative risk of acquiring secondary AML/MDS in patients treated with cyclophosphamide versus melphalan, respectively.

Various treatment factors have been noted to increase or contribute to the likelihood of acquiring secondary AML/MDS, including cumulative dose, length of treatment, and the age of the patient. Patients treated with melphalan with a dose >350 mg have a 133-fold increase in the relative risk of developing AML/MDS compared with those treated with <350 mg; patients treated for <15 months of total therapy also have a decreased relative risk for acquiring AML/MDS.26 A similar situation is found with cyclophosphamide. With cumulative doses of >20 g, the relative risk is 5.7-fold greater than those individuals treated with <20 g.26

Regardless of the specific alkylating agent used, the leukemia induced after treatment with these agents can be characterized according to the latency to onset after initial therapy, clinical presentation, phenotypic expression according to the FAB classification of hematological malignancies, prognosis, and cytogenetic abnormalities (Table 1). Classically, these agents have a long latency period from 1 to 20 years after treatment before the onset of leukemia, with 4 to 6 years being the average.27 Patients typically present with a myelodysplastic syndrome or preleukemic phase, and then they ultimately develop a clinical leukemia.28 The induced leukemia is generally described as an M1 (myeloblastic leukemia without maturation) or M2 (myeloblastic leukemia with maturation)8 or, rarely, as an M6 (erythroleukemia) or M7 (megakaryocytic leukemia),29 according to the FAB classification.30–33 The prognosis after diagnosis is especially poor because of the scarcity of successful treatment regimens.34,35


View this table:
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  		TABLE 1. Comparison of alkylating agent–and topoisomerase II inhibitor–induced secondary leukemias and myelodysplastic syndromes
 
The precise mechanism by which alkylating agents induce leukemias is unclear, but it is possibly related to chromosomal damage that produces mutations or translocations of genes that are important for cellular growth and differentiation. These specific DNA alterations are thought to lead to a survival advantage for a pluripotent cell that eventually leads to clonal expansion of this malignant clone. Cytogenetic abnormalities seen with alkylating agent therapy are generally deletion or loss of all or part of chromosomes 5 and 7,16,36 particularly in the regions of the long arm of chromosome 5 (5q31–33), where a multitude of genes—including granulocyte-macrophage colony-stimulating factor; interleukin-3, -4, -5, and -9; interferon regulatory factor-1; early growth response-1; CDC25C; and the FMS oncogene—are located and are thought to play an active role in hematopoiesis.27,29 Although the precise mechanism of leukemogenicity remains to be determined definitively, alkylating agents are not the only therapeutic culprits known to induce AML/MDS. In fact, the topoisomerase inhibitors—the epipodophyllotoxins (etoposide and teniposide), the anthracyclines (doxorubicin), and the camptothecins (topotecan)—are a broad category of agents that have been shown to induce a distinctive form of secondary AML/MDS.

As a class, the topoisomerase inhibitors are a diverse group of drugs that function to disrupt and block the progression of a cell through its normal cell cycle. In essence, these agents serve to induce cytotoxicity by binding to and preventing topoisomerases from performing their normal and vital cellular functions. These insults lead to cellular death, or the cells may attempt to repair the induced nucleic acid deficits and escape the onslaught of apoptotic processes. The classes of agents involved target both type I and type II topoisomerases, but only recently have the type I–targeting agents been used in clinical practice. The type I agents—camptothecins—are irreversible agents that function by binding to the topoisomerase I/DNA complex after the initial single-stranded DNA break. Once this occurs, there is no resealing of the ligated single DNA strand, and this scenario induces an irreversible double-stranded DNA break. Once the double stranded break occurs, the cell is marked for apoptotic induction or repair, if possible.

The major type II topoisomerase inhibitors in clinical use consist of the epipodophyllotoxins and the anthracyclines. These agents, like the camptothecins, are cell cycle specific, functioning primarily in G2 and S phases.37,38 They function to interrupt the re-ligation process of the topoisomerase II enzyme after initiating a double-stranded DNA break.39 However, this process is reversible. The anthracyclines, a class of agents consisting of synthetic (idarubicin and epirubicin) and natural (daunorubicin and doxorubicin) drugs, are the most active drugs in the treatment of breast cancer.40,41 In addition to inducing a covalent linkage between the topoisomerase II enzyme and DNA,42,43 they also are known as DNA intercalators that independently function to block transcription.44 Another proposed mechanism for their cytotoxic effects rests on their ability to undergo iron- and enzymatic-catalyzed reduction reactions that result in the production of reactive oxygen species, which, in turn, induce cytotoxicity.45 Among these agents, doxorubicin has been used extensively in both the primary and adjuvant treatment of breast cancer.

Teniposide and etoposide are members of a second class of topoisomerase II inhibitors whose use as adjuvant agents in the treatment of breast cancer has grown considerably in the last 15 years. Their mechanism of action and cellular target are similar to those of the anthracycline compounds discussed previously. Although these topoisomerase II inhibitors are effective chemotherapeutic agents, they can induce the occurrence of a distinctive secondary leukemia.

The leukemia induced by topoisomerase II inhibitors is a clinical entity distinct from that of the alkylating agent-induced leukemia discussed previously.46–48 The cumulative risk of secondary AML/MDS after epipodophyllotoxin therapy has ranged from .7% to 9.1%, depending on the dose, route of administration, and concomitant use of other agents.49–51 Typically, these agents promote the formation of a secondary leukemia that has a short latency period of roughly 12 to 36 months (median) and a range of 6 to 54 months.29 As with the alkylating agents, the precise mechanism for leukemogenesis is not known. The leukemia induced has no preleukemic phase, and it is phenotypically categorized as a M4 (myelomonocytic leukemia) or M5 (monocytic leukemia).29 Genotypically, this leukemia is markedly different as well. The classic cytogenetic abnormality induced in this leukemic derivative is found on the long arm of chromosome 11 (11q23 locus)52,53 and specifically in a 9-kilobase region where more than 21 different translocation products have been identified. The significance of this genomic location rests on the fact that it is the location of the MLL (mixed-lineage or myeloid-lymphoid leukemia) gene,53 shown to be central in the regulation of many genes involved in differentiation and hematopoiesis.53,54 Specifically, it is thought that this gene controls the regulation of homeobox genes that are responsible for transcription factors that regulate hematopoiesis. Any possible translocations in this region would most likely give rise to one or several chimeric proteins that would disrupt normal transcriptional processes, leading to the formation of leukemia. Other genetic lesions have also been described, including the 21q22 translocation,55,56 but these insults are yet to be described in detail.

The taxanes, paclitaxel and docetaxel, have also been linked to AML/MDS posttreatment induction. They exert their antitumor effects by interfering with the microtubule assembly. Specifically, the taxanes promote microtubule assembly and inhibit disassembly.57 Cells treated with taxanes are therefore arrested in the G2 and M phases of the cell cycle.58 The taxanes have become commonly used drugs in both the primary and adjuvant treatment of breast cancer. Recently, several cases of secondary AML have been reported after treatment with paclitaxel.59 Interestingly, these cases were associated with a unique cytogenetic aberration at chromosome 16 (inv p13q22), which is associated with a myelomonocytic leukemia with eosinophils (FAB M4EO). This particular cytogenetic abnormality is associated with a favorable outcome.


   HORMONAL THERAPY–INDUCED AML/MDS
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
The primary hormonal agent used in the adjuvant and primary treatment of breast cancer is tamoxifen, which has been under active investigation in both in vivo and in vitro studies since 1966. Pharmacologically, it functions as an agonist, an antagonist, and a partial agonist or competitive inhibitor of the ER,60 and its function is determined by precise cellular context. It is a cell cycle–specific agent that preferentially targets the G2 phase,61 and it is primarily recognized as a cytostatic agent.62 In binding to the ER, tamoxifen induces a conformational change in the ER that prevents optimal binding to the estrogen response elements (EREs) on nuclear DNA.60 By preventing this ER/ERE binding, transcriptional activation of specific genes is hindered, with resultant cellular senescence or quiescence.

Although the side-effect and toxicity profiles of tamoxifen are rather benign in comparison to most oncologic chemotherapeutic agents, it does have the potential to induce endometrial carcinomas.63 There is only anecdotal evidence linking tamoxifen to secondary AML/MDS.64 The two postmenopausal patients reported were treated after surgery for stage I disease with 20 mg of tamoxifen per day. The patients returned 15 and 23 months later with symptoms of leukemia. They were diagnosed with AML and treated. Only one patient survived therapy.


   RADIOTHERAPY-INDUCED AML/MDS
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
Radiotherapy has been a mainstay in both primary and adjuvant breast cancer treatment for more than four decades. Radiation induces its lethal effects through both direct and indirect means.65 The direct effects include rendering the critical cellular component incompetent, thus bringing on cellular demise via necrosis or apoptosis. The indirect means are postulated to be the induction of free radicals via interaction of the radiation with cellular water molecules. These free radicals then induce cellular toxicity via a plethora of different constitutive cellular signaling mechanisms. In addition to these observations, it is well established that radiotherapy is cell cycle specific, inducing its greatest cytotoxic effects during the M and G2 phases,66,67 but it is also capable of inducing cytotoxic effects during the G1 and S phases.68,69 Regardless of whether the lethal lesions induced by radiotherapy are the result of direct or indirect actions in any of the specific cell-cycle phases, they are random events that result in a wide spectrum of outcomes, from outright cellular toxicity via apoptosis, to cellular sterility and terminal differentiation, to cellular survival with no resultant effects.70 The randomness of the effects of radiotherapy poses a serious problem in designing treatment regimens, because both malignant and nonmalignant cells may be killed, may not be killed at all, or may even undergo further or initial malignant oncologic perturbations.70,71 This scenario accounts for the induction of secondary malignancies.

Radiotherapy-induced secondary leukemia in breast cancer patients has been evaluated in a multitude of studies that examined radiation as a single modality71–75 and in combination with other therapies, including surgery and chemotherapy.24,26,76,77 They have found relative risk ratios from 076 at 10 years after treatment to 1024 after treatment. Curtis et al.75 found no increase in the relative risk of radiation-induced leukemias with radiotherapy doses >5 Gy, and, in fact, this study further documented that radiation doses of <5 Gy did not decrease the risk of secondary leukemias. However, in a subsequent study, Curtis et al.26 did find a 7-fold greater risk after radiotherapy with doses >9 G. Other studies have documented that combined regimens of radiation and chemotherapy increase the relative risk of secondary leukemias (16.7–17.4) over those of radiotherapy alone (0–2.4).26,76 Several theories have been proposed for these observations, and most deal with the direct radiation exposure of the marrow compartments in the sternum, clavicle, and ribs.71,75 This direct exposure induces nonlethal DNA damage to marrow components that than undergo malignant transformation, resulting in the observed occurrence of leukemia.71 However, this hypothesis has also been refuted because the quantity and the activity of the bone marrow components in the sternum, clavicle, and ribs are not extensive, nor are these regions central foci of hemato- or leukopoiesis.75


   BONE MARROW TRANSPLANTATION–INDUCED AML/MDS
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
SUMMARY AND CONCLUSIONS
 REFERENCES
 
High-dose chemotherapeutic regimens, with or without autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT), have raised concerns about the risk of therapy-induced leukemias. These concerns are heightened with the realization that these modalities are being used in the adjuvant setting as therapies for the patients believed to be at high risk for recurrent disease at the time of definitive diagnosis. The lymphoma literature supports these concerns, for there is a 5-year 9% risk of secondary leukemias after PBSCT for lymphoid malignancies.8 There are only a few reports in the literature that directly explore the issue of secondary leukemias after PBSCT or ABMT for breast cancer,8,78–80 and the crude incidences in these studies have been estimated as .6% to 12%.78–80 However, the authors of these studies uniformly agree that the resultant cases of secondary leukemia after PBSCT/ABMT are probably due to the prior chemotherapy or radiation treatments and are not the results of the ABMT/PBSCT treatment regimen per se.78–80 The basis of these claims is the fact that the latency periods (47–51 months) from the time of the initial diagnosis and treatment are roughly the same as those expected for secondary leukemias caused by initial chemotherapy and radiotherapy.78–80 The median latency for the onset of these secondary leukemias after ABMT/PBSCT is 15 to 30 months,79,80 which is far shorter than the standard times discussed previously. As a result, these authors conclude that the inciting lesions occurred during prior treatment regimens and not from the ABMT/PBSCT therapy.79,80 However, these studies contain small patient populations, and furthermore, long-term studies need to be performed to determine the true incidence and risk posed by ABMT/PBSCT in inciting secondary leukemias.


   SUMMARY AND CONCLUSIONS
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
REFERENCES
 
Two major cooperative groups have published their experience with therapy-related leukemia and myelodysplastic syndromes in breast cancer patients.24,81 The National Surgical Adjuvant breast program reviewed 8483 women with breast cancer and found that leukemia developed in .6% of patients treated surgically, as compared with .77% of those treated with radiotherapy alone and .51% of those receiving L-phenylalanine mustard–containing regimens.29 The Eastern Cooperative Oncology Group reviewed trials involving 2638 patients and found an overall incidence of therapy-related leukemia or myelodysplastic syndromes of .23%.81 These patients received cyclophosphamide rather than L-phenylalanine mustard, as in the previous study.

The treatment of breast cancer remains an evolving science. As creative treatment strategies and new drugs to treat this unfortunately common disease are developed, careful studies must be designed to evaluate all the toxicities of treatment. Although the study of posttherapy leukemias and myelodysplastic syndromes has furthered the understanding of the molecular pathogenesis of cancer, it is imperative that future therapies be designed that do not also induce other malignant diseases.


   Acknowledgments
 
Supported by National Institutes of Health grant 1 T32 CA65436-01A3 (BMJ).


   Footnotes
 
Presented in part at the local chapter of the American College of Surgeons meeting, New Orleans, Louisiana, January 20–21, 2001.

The multidisciplinary approach to the therapy of breast cancer has allowed patients to live longer, but it has also induced a number of leukemias and myelodysplastic syndromes. By using a typical case report to put this underreported clinical problem in perspective, this article reviews the frequency and mechanism of secondary malignancies after therapy for breast cancer.

Received for publication July 6, 2001. Accepted for publication May 8, 2002.


   REFERENCES
TOP
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 CHEMOTHERAPY-INDUCED AML/MDS
 HORMONAL THERAPY-INDUCED AML/MDS
 RADIOTHERAPY-INDUCED AML/MDS
 BONE MARROW TRANSPLANTATION...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 

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