Japanese Journal of Clinical Oncology Advance Access published online on July 10, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn057
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© The Author (2008). Published by Oxford University Press. All rights reserved
Therapy-Related Acute Promyelocytic Leukemia Caused by Hormonal Therapy and Radiation in a Patient with Recurrent Breast Cancer
1 Breast and Medical Oncology Division
2 Hematology Division, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Chikako Shimizu, Breast and Medical Oncology Division, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. E-mail: cshimizu{at}ncc.go.jp
Received January 31, 2008; accepted June 10, 2008
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Abstract |
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We report a patient with therapy-related acute promyelocytic leukemia (APL) that may have been caused by regional radiation or hormonal therapy after surgery. A 36-year-old Japanese woman developed right breast cancer and underwent breast-conserving surgery and regional radiation to the right breast without adjuvant systemic therapy because she wished to preserve her fertility. Two years later, she developed multiple bone metastases of breast cancer and received hormonal therapy. During the second line hormonal therapy, she developed APL and received induction and consolidation chemotherapy with all-trans retinoic acid (ATRA) and a combination of anthracycline and cytarabine. After she achieved a complete remission (CR) of the APL, her bone metastases of breast cancer progressed. She received weekly paclitaxel treatments and her bone marrow function recovered. However, 9 months later, her APL relapsed; she achieved a second CR after undergoing ATRA therapy again. This patient is thought to be a rare case of secondary leukemia, since the leukemia might have been caused by hormonal therapy and regional radiation without chemotherapy.
Key Words: secondary leukemia • tamoxifen • all-trans retinoic acid • breast-conserving surgery • radiation
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INTRODUCTION |
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Chemotherapy and radiotherapy can induce secondary myelodysplastic syndrome and leukemia in patients with malignancies, and the incidences of secondary myelodysplastic syndrome and leukemia have increased (1). Systemic treatment and radiation therapy have contributed to the long-term survival of breast cancer patients, but these modalities simultaneously have the potential to cause secondary hematological malignancies. Although secondary hematological malignancies caused by chemotherapy in patients with breast cancer are quite common (2–7), the cause-relationship of hormonal agents to hematological malignancies remains controversial (8–11). We present a case of therapy-related acute promyelocytic leukemia (tAPL) that may have been caused by regional radiation or hormonal therapy after breast-conserving surgery.
Case report
A 36-year-old female noticed a mass in her right breast and was referred to our hospital for further examination in June 2002. She was diagnosed as having stage IIA, right breast cancer and underwent a lumpectomy in August 2002. A pathological examination revealed invasive ductal carcinoma, grade 3, with no lymph node metastases. The tumor was positive for hormone-receptor and negative for HER2 over-expression. As she wished to preserve her fertility, she received neither adjuvant chemotherapy nor hormonal therapy. She received radiotherapy to her right breast (50 Gy given in 25 fractions). In January 2004, her breast cancer relapsed with multiple bone metastases and she received hormonal therapy with a gonadotropin-releasing hormone analog and tamoxifen. In April 2005, she started second-line hormonal therapy with medroxyprogesterone acetate (MPA) because of the progression of the bone metastases. In January 2006, she was emergently admitted to our hospital for fever, tender cervical lymph nodes and gingival bleeding. Her laboratory test results are shown in Table 1. A picture of a bone marrow smear is shown in Fig. 1. A cytogenetic analysis showed t(15;17), and both fluorescence in situ hybridization (FISH) and reverse transcription–polymerase chain reaction (RT–PCR) detected PML-RAR
fusion DNA and its transcript, respectively. Based on these results, a diagnosis of acute promyelocytic leukemia (APL) was made. Therefore, tAPL caused by her treatment for breast cancer was suspected. She underwent induction therapy with all-trans retinoic acid (ATRA) for 60 days. Her clinical course is shown in Fig. 2. After the induction therapy, a bone marrow aspiration showed a hematological complete remission (CR). She then underwent consolidation therapy with mitoxantrone, cytarabine and daunorubicin. After the second course of consolidation therapy, a bone marrow aspiration revealed both cytogenetic and molecular CR. She continued receiving MPA during her treatment for APL. However, after the second cycle of consolidation therapy, bone marrow invasion developed. She was treated with weekly paclitaxel (PTX) from July 2006. Although no radiographical changes were seen on a bone scintigraphy, her complete blood count improved. Because of the peripheral edema caused by PTX, she did not receive further therapy for breast cancer after 18 cycles of weekly PTX except for bisphosphonate.
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Nine months after she finished PTX, she developed pancytopenia again in August 2007. A bone marrow aspiration revealed the relapse of APL, with positive RT-PCR findings for PML-RAR
, as well as bone marrow invasion of the breast cancer cells. Re-induction therapy with ATRA for 60 days was started again because of her relatively long absence from ATRA exposure. She achieved a second hematological CR and received chemotherapy with mitoxantrone, daunorubicin and idarubicin consolidation therapy. In addition, hormonal therapy with aromatase inhibitor was given because of concerns over the progression of breast cancer. She was discharged from our hospital and remained in molecular CR. |
DISCUSSION |
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The patient received radiation therapy to her right breast after undergoing breast-conserving surgery and tamoxifen treatment after the recurrence of her breast cancer. Generally, the risk of radiation-induced leukemia appears to be related to the volume of the bone marrow included within the radiation field, the total radiation dose and the concomitant use of chemotherapy (1,5,7). A previous study reported that the 5- and 10-year cumulative incidences for leukemia after both breast-conservative surgery and radiation for patients with stages I or II breast cancer were 0.08 and 0.8%, respectively (12), which were very low incidences and did not show a significant association. In the National Surgical Adjuvant Breast and Bowel Project trial, the overall risk of leukemia in patients with breast cancer who received postoperative regional radiation was 1.39% at 10 years (2). Two other large-scale, case-controlled studies demonstrated that breast cancer patients who received postoperative chest wall irradiation had an unremarkable leukemia relative risk of 0.9 [90% confidence intervals (CI), 0.4–1.8] in Germany (11) and 1.2 (90% CI, 0.6–2.1) in Connecticut (13). Although radiation therapy might have induced secondary leukemia in the present patient, this would be a rare case because the patient only received regional radiation without chemotherapy. Alkylating agents and topoisomerase II inhibitors and radiotherapy, which are useful for the treatment of breast cancer, are known to cause secondary leukemia (2–7,14). Whether hormonal therapy is related to secondary leukemia, however, remains uncertain. Yalcin et al. reported that two breast cancer patients receiving tamoxifen developed acute leukemia (8). However, several large retrospective studies have not revealed a significant association between tamoxifen and secondary malignancies, except for endometrial cancer and colorectal cancer (9–11). In Japan, a retrospective study of secondary cancers after tamoxifen treatment in patients with breast cancer also reported that the incidence rate ratio (IRR) for secondary leukemia did not increase, but that the IRR for endometrial cancers and stomach cancers tended to increase (15).
In previous reports, the incidence of patients with tAPL ranged from 1.7 to 5.8% (16–18). One report concluded that the incidence of tAPL had increased in recent years, because 26 patients were reported between 1982 and 1991 and 80 patients were reported between 1992 and 2001 (19). Given that the overall incidence of APL has not increased, these observations suggest that either the number of patients with tAPL has increased or the disease classification of tAPL has become better recognized. Although secondary leukemia is generally considered to have aggressive characteristics and a poor prognosis because of the short duration of response, several retrospective studies have described responses to chemotherapy and the prognosis of secondary APL seem to be similar to that of de novo APL (19–21). Therefore, it is also important to treat patients with tAPL with the same drugs as those used for patients with de novo APL. Recently, ATRA and anthracycline are considered to be key drugs for de novo APL, while a role of cytarabine has not been confirmed (22). Because of this point of view and insufficient recovery of her bone marrow due to the bone metastases of breast cancer cells, we treated her with anthracyclines in consolidation therapy. Beaumont et al. indicated that the survival of tAPL was 59% at 8 years and that the preponderance for primary malignancy of patients with tAPL was breast cancer. The interval between the primary malignancy and secondary leukemia was less than 5 years in most cases (1,5,19). Because metastatic breast cancer patients may achieve long-term survival, the possibility of secondary malignancies should be careful monitored.
In case of this patient, because her complete blood count did not fully recover and a bone marrow biopsy disclosed that bone metastases of breast cancer cells had progressed after the first consolidation chemotherapy for tAPL, the subsequent consolidation chemotherapy for tAPL was interrupted and chemotherapy for breast cancer was forced to start, resulting in a possibly insufficient treatment for tAPL. Considering the palliative nature of the treatment of metastatic breast cancer patients, the priorities and goals of treatment should be carefully considered—with thought given to whether the breast cancer or the secondary malignancy is the life-limiting disease. Even if intensive treatment for tAPL is considered, if the tAPL becomes refractory to induction and consolidation chemotherapy, high-dose chemotherapy supported by hematopoietic stem cell transplantation might not be indicated because of the incurable breast cancer bone metastases.
In conclusion, we have reported a case of tAPL in a patient with breast cancer who had not undergone chemotherapy. Although the present case is thought to be rare, patients should be carefully monitored for secondary malignancies like tAPL. Simultaneously, the possibility that multimodality treatments, including the use of various cytotoxic agents, such as alkylating agents and topoisomerase II inhibitors, may cause secondary malignancies as well as contributing to the long-term survival of patients with breast cancer must be kept in mind. For patients with secondary malignancy and advanced primary disease, the treatment priorities must be carefully considered.
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Acknowledgments |
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We thank Yukio Kobayashi (Hematology Division, National Cancer Center Hospital) and Akiko Maeshima (Pathology Division, National Cancer Center Hospital) for histopathological diagnosis and preparing the figure.
Conflict of interest statement
None declared.
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References |
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