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Screening for clonal hematopoiesis as a predictive marker for development of therapy-related myeloid neoplasia (t-MN) following neoadjuvant therapy for breast cancer: a Southwest Oncology Group study (S0012)

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Abstract

A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related myeloid neoplasms (t-MN). To determine whether dose-intensive adjuvant regimens for breast cancer induce genetic damage to hematopoietic stem cells, defined by the emergence of clonal hematopoiesis, and whether detection of clonal hematopoiesis could be used as an early marker for the subsequent development of t-MN, the Southwest Oncology Group designed a pilot clonality investigation to estimate the incidence of clonal hematopoiesis during and shortly after completion of the dose-intensive neoadjuvant regimens for high-risk breast cancer patients. Peripheral blood samples from 274 patients obtained prior to treatment, at time of surgery, and at 6 and 12 months post-surgery were examined by two different clonality assays: the HUMARA (HUMan Androgen Receptor) assay to estimate the incidence of early genetic damage by clonal proliferation, and microsatellite instability (MSI) testing to screen for LOH or defective DNA mismatch repair mechanisms. Clonal hematopoiesis was negative in 93.5% of the samples analyzed. Five patients showed a HUMARA-positive/MSI-negative pattern, and no patients showed a HUMARA-negative/MSI-positive pattern. With a median follow-up of 3.1 years, one patient in our study developed t-AML at 3 years 5 months after randomization. Our results indicate that clonal hematopoiesis assays performed within the 2 years following dose-intensive neoadjuvant therapy failed to identify an emerging clonal hematopoietic stem cell population. Longer clinical follow-up will be necessary to define better the positive predictive value of detecting clonal hematopoiesis in the HUMARA+/MSI− cases.

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Acknowledgments

This investigation was supported in part by a grant from the Department of Defense, DOD # DAMD17-97-1-7088 and in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA58882, CA86780, CA14028, CA20319, CA52654, CA63845, CA379891, CA63844, CA22433, CA35431, CA76448, CA35176, CA58861, CA46441, CA35178, CA67575, CA45808, CA12644, CA11083, CA35192, CA76447, CA46282, CA45560, CA04919, CA45377, CA35090, CA74811, CA95860, CA35281, CA74647, CA76462, CA35128, CA76462, CA46136, and CA35119. The authors also thank Mr. Aaron Theisen for assistance in paper preparation.

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Authors and Affiliations

  1. Department of Cytogenetics, City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA

    Marilyn L. Slovak & Victoria Bedell

  2. Southwest Oncology Group Statistical Center, 1100 Fairview Ave N, M3-C102, P.O. Box 19024, Seattle, WA, 98109-1024, USA

    Danika Lew

  3. Cardinal Bernardin Cancer Center, Loyola University Medical Center, Bldg 112, Rm 109, Maywood, IL, 60153-5589, USA

    Kathy S. Albain

  4. Seattle Cancer Care Alliance, 825 Eastlake Ave E, MS G-3200, Seattle, WA, 98109, USA

    Georgiana K. Ellis

  5. Arizona Cancer Center, Hematology/Oncology Section, University of Arizona, 1515 N Campbell Avenue, P.O. Box 245024, Tucson, AZ, 85724-5024, USA

    Robert B. Livingston

  6. The Angeles Clinic and Research Institute, 2001 Santa Monica Blvd., Suite 560W, Santa Monica, CA, 90404, USA

    Silvana Martino

  7. The Breast Center and Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Road, E8A, Jacksonville, FL, 32224, USA

    Edith A. Perez

  8. Department of Breast Medicine/Oncology - Unit 1354, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, P.O. Box 301439, Houston, TX, 77230-1439, USA

    Gabriel N. Hortobagyi

  9. Section of Hematology/Oncology, University of Chicago Medical Center, 5841 S. Maryland, M/C 2115, Chicago, IL, 60637, USA

    Dorie Sher & Wendy Stock

  10. Signature Genomic Laboratories, 2820 N. Astor St., Spokane, WA, 99207, USA

    Marilyn L. Slovak

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  1. Marilyn L. Slovak
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  2. Victoria Bedell
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Correspondence to Marilyn L. Slovak.

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Slovak, M.L., Bedell, V., Lew, D. et al. Screening for clonal hematopoiesis as a predictive marker for development of therapy-related myeloid neoplasia (t-MN) following neoadjuvant therapy for breast cancer: a Southwest Oncology Group study (S0012). Breast Cancer Res Treat 119, 391–398 (2010). https://doi.org/10.1007/s10549-009-0597-5

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  • DOI: https://doi.org/10.1007/s10549-009-0597-5

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