Skip to main content

Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy


Therapy-related acute leukemias (t-ALs) represent approximately 10–20% of all acute leukemias, are frequently resistant to chemotherapy, and are associated with guarded outcomes. The national comprehensive cancer network data suggest that t-AL cases are diagnosed at increasing rates in breast cancer patients treated with chemotherapeutic agents targeting topoisomerase II. Two cases of BRCA1-mutated ovarian and breast carcinoma who developed therapy-related APL and ALL, respectively, following topoisomerase II-directed therapy were characterized. Genomic characterization of therapy-related acute promyelocytic leukemia (t-APL) revealed a unique RARA intron 2 breakpoint (Chr17: 40347487) at 3′-end of RARA corroborating breakpoint clustering in t-APL following topoisomerase II inhibition. Both cases of this series harbored germline BRCA1 mutations. The germline BRCA1 mutation in patient with t-APL was detected in exon 8 (HGVS nucleotide: c.512dupT). This mutation in t-APL is extremely rare. Interestingly, t-ALL patient in this series had a BRCA1 mutation (HGVS nucleotide: c.68_69delAG; BIC designation: 187delAG) identical to a previously reported case after the treatment of same primary disease. It is unlikely that two breast cancer patients with identical BRCA1 mutation receiving topoisomerase II-targeted agents for the primary disease developed t-AL by chance. This report highlights the development of t-AL in BRAC1-mutated hereditary breast and ovarian cancer patients and warrants further studies on functional consequences of topoisomerase inhibition in this setting.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–32.

    CAS  Article  Google Scholar 

  2. 2.

    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. 2005;23(18):4179–91.

    CAS  Article  Google Scholar 

  3. 3.

    Martin MG, Welch JS, Luo J, Ellis MJ, Graubert TA, Walter MJ. Therapy related acute myeloid leukemia in breast cancer survivors, a population-based study. Breast Cancer Res Treat. 2009;118(3):593–8.

    Article  Google Scholar 

  4. 4.

    Curtis RE, Boice JD Jr, Stovall M, et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med. 1992;326(26):1745–51.

    CAS  Article  Google Scholar 

  5. 5.

    Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001–2007. Blood. 2012;119(1):34–433.

    CAS  Article  Google Scholar 

  6. 6.

    Aguilera DG, Vaklavas C, Tsimberidou AM, Wen S, Medeiros LJ, Corey SJ. Pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia: the MD Anderson Cancer Center experience. J Pediatr Hematol Oncol. 2009;31(11):803–11.

    Article  Google Scholar 

  7. 7.

    Wolff AC, Blackford AL, Visvanathan K, et al. Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience. J Clin Oncol. 2015;33(4):340–8.

    Article  Google Scholar 

  8. 8.

    Rosenstock AS, Niu J, Giordano SH, Zhao H, Wolff AC, Chavez-MacGregor M. Acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy: A population-based study among older breast cancer patients. Cancer. 2018;124(5):899–906.

    CAS  Article  Google Scholar 

  9. 9.

    Mistry AR, Felix CA, Whitmarsh RJ, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352(15):1529–38.

    CAS  Article  Google Scholar 

  10. 10.

    Hasan SK, Mays AN, Ottone T, et al. Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008;112(8):3383–90.

    CAS  Article  Google Scholar 

  11. 11.

    Hasan SK, Ottone T, Schlenk RF, et al. Analysis of t(15;17) chromosomal breakpoint sequences in therapy-related versus de novo acute promyelocytic leukemia: association of DNA breaks with specific DNA motifs at PML and RARA loci. Genes Chromosom Cancer. 2010;49(8):726–32.

    CAS  Article  Google Scholar 

  12. 12.

    Lo-Coco F, Hasan SK, Montesinos P, Sanz MA. Biology and management of therapy-related acute promyelocytic leukemia. Curr Opin Oncol. 2013;25(6):695–700.

    CAS  Article  Google Scholar 

  13. 13.

    Hasan SK, Barba G, Metzler M, et al. Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23). Genes Chromosom Cancer. 2014;53(3):248–54.

    CAS  Article  Google Scholar 

  14. 14.

    Ottone T, Hasan SK, Montefusco E, et al. Identification of a potential "hotspot" DNA region in the RUNX1 gene targeted by mitoxantrone in therapy-related acute myeloid leukemia with t(16;21) translocation. Genes Chromosom Cancer. 2009;48(3):213–21.

    CAS  Article  Google Scholar 

  15. 15.

    Churpek JE, Marquez R, Neistadt B, et al. Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer. 2016;122(2):304–11.

    CAS  Article  Google Scholar 

  16. 16.

    Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111(9):4477–89.

    Article  Google Scholar 

  17. 17.

    van Dongen JJ, Macintyre EA, Gabert JA, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(12):1901–28.

    Article  Google Scholar 

  18. 18.

    Gabert J, Beillard E, van der Velden VH, et al. Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia. 2003;17(12):2318–57.

    CAS  Article  Google Scholar 

  19. 19.

    Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–21.

    CAS  Article  Google Scholar 

  20. 20.

    Mannan AU, Singh J, Lakshmikeshava R, et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. J Hum Genet. 2016;61(6):515–22.

    CAS  Article  Google Scholar 

  21. 21.

    Rosenthal E, Moyes K, Arnell C, Evans B, Wenstrup RJ. Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry. Breast Cancer Res Treat. 2015;149(1):223–7.

    CAS  Article  Google Scholar 

  22. 22.

    Thompson D, Easton DF. Breast Cancer Linkage C. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94(18):1358–65.

    CAS  Article  Google Scholar 

  23. 23.

    Cole M, Strair R. Acute myelogenous leukemia and myelodysplasia secondary to breast cancer treatment: case studies and literature review. Am J Med Sci. 2010;339(1):36–40.

    Article  Google Scholar 

  24. 24.

    Morton LM, Dores GM, Tucker MA, et al. Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975–2008. Blood. 2013;121(15):2996–3004.

    CAS  Article  Google Scholar 

  25. 25.

    Xie Y, Jiang Y, Yang XB, et al. Response of BRCA1-mutated gallbladder cancer to olaparib: A case report. World J Gastroenterol. 2016;22(46):10254–9.

    Article  Google Scholar 

Download references


The authors are grateful to Professor Richard Larson (University of Chicago) for critical reading of the manuscript. SKH was supported by a grant from ICMR, New Delhi (Ref # 56/7/2019_HAE-BMS).

Author information




BB, RK, and SKH conducted experiments, data acquisition, and data analyses. TG, VT, AB, and NP contributed to patients’ samples, processing and real-time PCR. DS is responsible for cytogenetics; PK and RS contributed to genetic screening of BRCA1. SG and PGS provided clinical data. SKH designed the study and wrote this paper.

Corresponding author

Correspondence to Syed K. Hasan.

Ethics declarations

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

Both the patients provided written informed consent in accordance with the Declaration of Helsinki, and the Ethics Committee of Tata Memorial Centre, Mumbai (TMC-IEC III) DCGI registration number: IECIII: ECR/149/Inst/MH/2013 approved this study (IEC reference number 219/2019 dated 24/05/2019).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bagal, B., Kumar, R., Gaur, T. et al. Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy. Med Oncol 37, 48 (2020).

Download citation


  • Therapy-related leukemia
  • Germline BRCA1
  • Breast cancer
  • Topoisomerase II