Originally published as JCO Early Release 10.1200/JCO.2007.12.0832 on July 30 2007

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Acute Myeloid Leukemia After Adjuvant Breast Cancer Therapy in Older Women: Understanding Risk

Debra A. Patt, Zhigang Duan, Shenying Fang, Gabriel N. Hortobagyi, Sharon H. Giordano

From the Departments of Medical Oncology and Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Sharon Giordano, MD, MPH, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 1354, Houston, TX 77030; e-mail: sgiordan{at}mdanderson.org

	ABSTRACT

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Purpose The purpose of this study was to determine the risk of developing acute myeloid leukemia (AML) after adjuvant chemotherapy for breast cancer in older women.

Patients and Methods Data from the Surveillance, Epidemiology, and End Results-Medicare linked database were used for women diagnosed with nonmetastatic breast cancer from 1992 to 2002. The primary end point was a claim with an inpatient or outpatient diagnosis of AML (International Classification of Diseases ninth revision, codes 205 to 208), comparing patients treated with and without adjuvant chemotherapy, and by differing chemotherapy regimens. The cumulative hazard of AML was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to determine factors independently associated with the development of AML.

Results In this observational study, there were 64,715 patients: 10,130 received adjuvant chemotherapy and 54,585 did not. The median patient age was 75.6 years (range, 66 to 104 years). The mean follow-up was 54.8 months (range, 13 to 144 months). The absolute risk of developing AML at 10 years after any adjuvant chemotherapy for breast cancer was 1.8% versus 1.2% for women who had not received chemotherapy. The adjusted hazard ratio for AML with adjuvant chemotherapy versus none was 1.53 (95% CI, 1.14 to 2.06). Granulocyte colony-stimulating factor (G-CSF) within the first year of diagnosis did not convey a significantly increased risk of AML (hazard ratio, 1.14; 95% CI, 0.67 to 1.92).

Conclusion There is a small but real increase in AML after adjuvant chemotherapy for breast cancer in older women. This study may underestimate the true incidence because myelodysplastic syndrome cannot be identified through claims. G-CSF use within the first year of diagnosis does not convey an increased risk of AML in older women.

	INTRODUCTION

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Adjuvant chemotherapy is an important part of breast cancer therapy because it improves survival among women with high-risk breast cancer.¹ For older women, the benefits of chemotherapy are less certain because few clinical trials have included substantial numbers of women older than 70. However, a recent observational study suggests that chemotherapy can improve survival among older women with lymph node–positive, estrogen receptor–negative disease.² Oncologists are also now more likely to treat older patients with adjuvant chemotherapy than in the past.³ With the increasing use of chemotherapy in older women, it has become critical to understand the late effects of therapy in this group.

Certain cytotoxic drugs increase the risk of developing a secondary malignancy. Specifically, secondary leukemias, and myelodysplastic syndrome (MDS) can occur as a result of treatment with alkylating agents and topoisomerase II reactive drugs. Myeloid leukemias that are related to alkylating agents typically develop 5 to 7 years after initial cancer treatment; are frequently associated with MDS; are often classified under the French-American-British classification system as M1 or M2; can have abnormalities in chromosomes 5 or 7; and have a poor prognosis.⁴ Myeloid leukemias that are associated with a topoisomerase II reactive drug typically occur within 5 years of therapy, are not associated with MDS, and are frequently associated with a 11q23 cytogenetic abnormality.⁴

Because the risk of acute myeloid leukemia (AML) increases with age, older patients are under-represented in clinical trials, and most previous studies of secondary AML were not based on currently used adjuvant regimens, we proposed to evaluate risk and predictors of AML in older women with breast cancer.

	PATIENTS AND METHODS

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Data Source
We used the merged Surveillance, Epidemiology, and End Results (SEER)-Medicare database for our analysis. The SEER database program is a population-based tumor registry sponsored by the National Cancer Institute consisting of individual tumor registries that collect information on all newly diagnosed cancer cases that occur in persons residing in SEER participating areas. Over the years of this study, the SEER database included between 14% and 25% of the United States population. The SEER registry routinely collects information on patient demographics, tumor characteristics, stage at diagnosis, date of diagnosis, treatment within 4 months of diagnosis, and date and cause of death. The Medicare program is administered by the Centers for Medicare and Medicaid services, formerly the Health Care Financing Administration, and is the primary insurer for 97% of the US population 65 years and older.⁵ Through Medicare claims data, chemotherapy use, growth factor use, and patient comorbidities can be ascertained. Under an agreement between the National Cancer Institute and the Centers for Medicare and Medicaid services, SEER subjects who are eligible for Medicare have been linked to their Medicare records, using the method described by Potosky et al.⁵

Study Population
The study population included women age 66 years or older who were diagnosed with stage I to III (American Joint Committee on Cancer modified third edition) breast cancer between 1992 and 2002 and who underwent surgical resection for their tumors. Patients who were excluded were: those who were 65 years old because they would not have claims data from the year before diagnosis, and thus a comorbidity score could not be calculated; women with a previous cancer or unstaged disease; those without full coverage of both Medicare A and B for 1 year before and 1 year after diagnosis; and women who belonged to a health maintenance organization because their claims data would be incomplete.

Chemotherapy use and regimens were identified as previously described.² Chemotherapy was classified as adjuvant if the first claim was within 6 months of diagnosis. Granulocyte colony-stimulating factor (G-CSF) use was defined by Health Care Procedure Coding System codes of J1440 or J1441 within 12 months of diagnosis. Patients were considered to have received adjuvant radiotherapy if so identified in SEER. The primary outcome was development of AML, defined by the following International Classification of Diseases ninth revision codes: 205.0 to 205.9, 206.0, 206.2, 206.8, 206.9, 207.0, 207.2, 208.0, 208.2, 208.8, 208.9.

Data Analysis
Patient characteristics were compared between those patients who did and did not receive adjuvant chemotherapy using the ² test for categoric variables and the t test for continuous variables. Time-to-event curves for the development of AML were calculated using the Kaplan-Meier method. Patients were censored at time of death, Medicare ineligibility, or receipt of care through a health maintenance organization. Cox proportional hazard models were used to calculate the hazard of AML. The first model compared patients who did and did not receive adjuvant chemotherapy, adjusting for age at diagnosis (66 to 70, 71 to 75, 76 to 80, 81+), year of diagnosis (1992 to 2002), race (white, black, other), SEER region, stage (I, II, III), grade (1, 2, 3, unknown), estrogen status (positive, negative, unknown), radiation (yes, no, unknown), Charlson comorbidity index (0, 1, 2+),⁶ and type of surgery (mastectomy, breast conserving surgery). To evaluate the effect of different chemotherapy regimens, additional Cox models were performed, which included only the patients who received adjuvant chemotherapy. When assessing hazard by chemotherapy type, the Cox models also included chemotherapy type and G-CSF use within the first year of diagnosis, in addition to the covariates in the previous model. Follow-up in Medicare claims was available through December 2003.

All P values presented are two sided. Statistical analyses were performed using SAS software version 8.02 (SAS Institute, Cary, NC).

This research was reviewed by our institutional review board and was determined to be exempt in accordance with the code of federal regulations category 4 because the SEER-Medicare data are completely deidentified.

	RESULTS

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Of the 64,715 patients included in this study, 10,130 received adjuvant chemotherapy and 54,585 did not. Mean follow-up time for all patients was 54.8 months (range, 13 to 144 months). Median age at diagnosis was 75.6 years overall (range, 66 to 104 years): 71.5 years among patients who received adjuvant chemotherapy and 76.4 years for patients who were not treated with adjuvant chemotherapy. Patient characteristics differed significantly between the two groups (Table 1). Patients who were treated with chemotherapy were significantly younger, were diagnosed more recently, were more likely to be black, and had lower comorbidity scores. As expected, patients who received chemotherapy had more advanced stage disease, larger tumors, more nodal involvement, and more estrogen receptor–negative disease.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative hazard of acute myeloid leukemia (AML) by adjuvant chemotherapy use among patients with stage I-III breast cancer (N = 64,715).

	DISCUSSION

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In this population-based study of nearly 65,000 women older than 65, adjuvant chemotherapy was associated with a significantly increased risk of the development of AML. To our knowledge this is the first study of this size to evaluate the risk of AML in older women treated with more modern treatment practice. While older women treated with adjuvant chemotherapy had more than a 50% increase in risk of AML, the absolute increase in risk at 10 years was low (1.8% among chemotherapy treated patients v 1.2% among patients who did not receive chemotherapy). Interestingly, we were not able to appreciate any significant differences in risk of AML by differing chemotherapy regimens. In particular, the addition of a taxane to anthracycline-based regimens did not confer an increase in risk of leukemia.

Our study adds to the previous literature examining AML among breast cancer patients. In 1992, Curtis et al⁷ published a large study evaluating the effects of chemotherapy and radiotherapy in breast cancer. This was a case-control study in a cohort of 82,700 women diagnosed with breast cancer from 1973 to 1985. It demonstrated that patients who received radiotherapy had a relative risk (RR) of 2.4 of developing AML, those who underwent therapy with alkylating agents had a RR of 10, and the risk was 17.4 when the two were used in combination. Though strengths of this study include its size and that it reflects community practice, it provides limited data on older women as the mean patient age was in the 60s. In addition, the chemotherapy regimens employed in the 1970s had some substantial differences from regimens in current use. Many patients in this study were treated with melphalan, which today is rarely used for breast cancer. Also, the cumulative dose of alkylating agent was substantially higher among patients treated in the 1970s, with many patients receiving 12 to 24 months of alkylating agents, as compared with 3 months in current practice. Therefore, this study may not be an accurate representation of the risk conveyed from current practice.

In a study by Praga et al, ⁸ 7,110 patients from 19 randomized trials were treated with epirubicin-containing regimens (and 92% also received regimens containing cyclophosphamide). The 8-year cumulative probability of developing AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). For the majority of patients who received standard doses the probability was lower (0.37%) and for patients who received higher than standard doses risk was much higher (4.97%). However, this study was limited to those patients treated with epirubicin-based chemotherapy and included mostly young women, as the majority of women in the study were younger than 50. The French Adjuvant Study Group published a similar analysis evaluating the incidence of AML.⁹ In this study, which included 3,653 patients of whom 2,603 received adjuvant epirubicin, the risk of developing leukemia was 0.34% at 9 years; however, this may be an underestimate of the true risk because the epirubicin-treated patients were almost 10 years younger that the control group (mean age for epirubicin-treated patients was 49 years).

In a review of six National Surgical Adjuvant Breast and Bowel Project trials, the risk of AML/MDS was increased when compared with similar age-matched controls, although again the mean age of patients included in this study was younger than 50.¹⁰ RR was found to increase based on dose intensity, cumulative dose, G-CSF, and the presence of radiotherapy. In a single institution study from M.D. Anderson Cancer Center (Houston, TX), the risk was higher.¹¹ In this study, the cumulative incidence of AML at 10 years was 1.5% for all patients, 2.5% for patients who received radiotherapy and chemotherapy, and 0.5% for patients who received chemotherapy alone. This study too is limited by the fact that the average patient age was 50 years. More recently, a case-control study evaluating 182 patients with AML or MDS evaluated the risk of various treatment modalities.¹² In this study, mitoxantrone use (RR, 15.6; 95% CI, 7.1 to 34.2), anthracycline use (RR, 2.7; 95% CI, 1.7 to 4.5), and use of G-CSF (RR, 6.3; 95% CI, 1.9 to 21) all conveyed an increased risk for development of MDS or AML.

We also evaluated the risk of leukemia among individuals who received G-CSF within the first year of diagnosis of breast cancer as part of their adjuvant therapy. Our study did not demonstrate an increased risk of AML when G-CSF was used within the first year of breast cancer diagnosis. While there has always been a concern that growth factors could be leukemogenic, G-CSF may simply be an innocent bystander.¹³ For example, the risk of AML could be higher among G-CSF–treated patients either due to an effect of the drug itself or because it was more likely to be given to patients with intrinsic bone marrow disease, which resulted in a requirement for growth factor support.

Hershman et al¹⁴ have recently reported on the use of G-CSF among older women with localized breast cancer. They reported that G-CSF use was associated with an increased risk of AML and MDS (HR, 2.14; 95% CI, 1.12 to 4.08). In contrast, data from the National Marrow Donor Program were published showing that after almost 10,000 patient-years of follow-up, only 20 of 4,015 healthy donors who were exposed to G-CSF for the purpose of peripheral blood stem cell collection have developed cancers.¹⁵ These numbers are comparable with population-based estimates of the incidence of leukemia, and suggest that G-CSF is not causing an increase in risk. While the data from the National Marrow Donor Program are reassuring, potential toxicities of G-CSF need further study.

Our analyses found that adjuvant radiation therapy was not associated with an increased risk of leukemia. These findings are in contrast to many of the studies previously discussed, which showed that radiation therapy does increase the risk of leukemia. One potential explanation for this discrepancy between studies is that radiation therapy might generate greater risk in younger than older patients. Other possible reasons include the decreasing use of fluorouracil, which is a radiosensitizer, changes in radiotherapy techniques, or changes in the sequencing of chemotherapy and radiotherapy.

All of these data are compelling. Women treated with adjuvant chemotherapy for breast cancer are clearly at increased risk for secondary AML. It is important to be able to accurately quantify this risk as we advise our patients on their risk of recurrence and on the potential benefits of therapy. Understanding this risk will allow us to tailor our therapy to maximize benefits and minimize toxicities.

Our study has several limitations. First, cumulative dose and infusion time could not be assessed with our data. Inclusion of this information would have strengthened our analysis because the risk of leukemia has previously been shown to increase with increasing chemotherapy dose. Another limitation of our study was the inability to look at MDS. MDS does not have a unique ICD-09 code in the Medicare database, and thus we were unable to accurately identify incident cases and may have underestimated the true incidence of secondary hematologic malignancy. Time trends in therapy may also have affected our findings. Anthracycline and taxane use both dramatically increased over the time period of this study, and thus patients treated with these regimens may have had less time at risk to develop AML. With longer follow-up, differences could emerge. Finally, because patients could have been diagnosed as recently as 2002 and the Medicare data were available through 2003, some patients had very short follow-up. Thus, the number of cases of AML is likely to increase over the next 10 years of follow-up.

In conclusion, our study demonstrates that adjuvant chemotherapy increases the risk of AML in older women, although the absolute increase in risk is low. Women older than 80 who receive chemotherapy may be at particularly high risk. Decisions regarding adjuvant chemotherapy use in older women must incorporate both short- and long-term risks of chemotherapy as well as potential benefits, so that patients can make informed decisions.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Debra A. Patt, Zhigang Duan, Shenying Fang, Gabriel N. Hortobagyi, Sharon H. Giordano

Financial support: Debra A. Patt, Gabriel N. Hortobagyi, Sharon H. Giordano

Administrative support: Sharon H. Giordano

Provision of study materials or patients: Sharon H. Giordano

Collection and assembly of data: Debra A. Patt, Sharon H. Giordano

Data analysis and interpretation: Debra A. Patt, Zhigang Duan, Shenying Fang, Sharon H. Giordano

Manuscript writing: Debra A. Patt, Zhigang Duan, Shenying Fang, Gabriel N. Hortobagyi, Sharon H. Giordano

Final approval of manuscript: Debra A. Patt, Zhigang Duan, Shenying Fang, Gabriel N. Hortobagyi, Sharon H. Giordano

	NOTES

 
published online ahead of print at www.jco.org on July 30, 2007.

Supported by National Institutes of Health Grant No. 1K07 CA 109064-03 (S.H.G.) and by an American Society of Clinical Oncology 2006 Young Investigator Award (D.A.P.).

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline]

2. Giordano SH, Duan Z, Kuo YF, et al: Use and outcomes of adjuvant chemotherapy in older women with breast cancer J Clin Oncol 24:2750-2756, 2006[Abstract/Free Full Text]

3. Giordano SH, Hortobagyi GN, Kau SW, et al: Breast cancer treatment guidelines in older women. J Clin Oncol 23:783-791, 2005[Abstract/Free Full Text]

4. Pedersen-Bjergaard J, Pedersen M, Roulston D, et al: Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood 86:3542-3552, 1995[Abstract/Free Full Text]

5. Potosky AL, Riley GF, Lubitz JD, et al: Potential for cancer related health services research using a linked Medicare-tumor registry database. Med Care 31:732-748, 1993[Medline]

6. Klabunde CN, Potosky AL, Legler JM, et al: Development of a comorbidity index using physician claims data. J Clin Epidemiol 53:1258-1267, 2000[CrossRef][Medline]

7. Curtis RE, Boice JD Jr, Stovall M, et al: Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 326:1745-1751, 1992[Abstract]

8. Praga C, Bergh J, Bliss J, et al: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: Correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23:4179-4191, 2005[Abstract/Free Full Text]

9. Campone M, Roche H, Kerbrat P, et al: Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group. Ann Oncol 16:1343-1351, 2005[Abstract/Free Full Text]

10. Smith RE: Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome among patients with breast cancer: Review of the literature and the National Surgical Adjuvant Breast and Bowel Project experience. Clin Breast Cancer 4:273-279, 2003[Medline]

11. Diamandidou E, Buzdar AU, Smith TL, et al: Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 14:2722-2730, 1996[Abstract/Free Full Text]

12. Le Deley MC, Suzan F, Cutuli B, et al: Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: Risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol 25:292-300, 2007[Abstract/Free Full Text]

13. Touw IP, Bontenbal M: Granulocyte colony-stimulating factor: Key (f)actor or innocent bystander in the development of secondary myeloid malignancy? J Natl Cancer Inst 99:183-186, 2007[Free Full Text]

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Submitted April 6, 2007; accepted June 11, 2007.

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