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).
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.
Department of Cytogenetics, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA. slovak@signaturegenomics.com
Marilyn L
ML
Slovak
Victoria
V
Bedell
Danika
D
Lew
Kathy S
KS
Albain
Georgiana K
GK
Ellis
Robert B
RB
Livingston
Silvana
S
Martino
Edith A
EA
Perez
Gabriel N
GN
Hortobagyi
Dorie
D
Sher
Wendy
W
Stock
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006410:Hematopoiesis / Q000187:drug effects* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D053842:Microsatellite Instability / Q000187:drug effects; D008875:Middle Aged; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D004317:Doxorubicin; D003520:Cyclophosphamide