Clonal Hematopoiesis as a Marker of Genetic Damage Following Adjuvant Chemotherapy for Breast Cancer: Pilot Study to Evaluate Incidence

摘要

A serious late complication associated with breast cancer treatment is the increased risk for development of therapy-related hematologic malignancies. The goal of this biologic study is to determine whether dose- intensive adjuvant regimens for breast cancer induce genetic damage to hematopoietic stem cells, defined by the emergence of clonal hematopoiesis. Clonal hematopoiesis has been proposed as an early marker of. hematopoietic stem cell damage, preceding the acquisition of critical, recurring genetic alterations associated with the development of therapy-related myelodysplastic syndromes and acute leukemia. Clonal hematopoiesis is being evaluated by two different methods, the X-linked HUMARA clonality and microsatellite instability assays. Positive clones will be further analyzed for MLL and RAS alterations. Study accomplishments to date: (a) Clonal hematopoiesis biological protocols (S9719 and S0012) written and approved for study by DOD, CTEP and CTSU; (b) clonality assays developed and standardized; (c) S9719 biologic study incorporated into S0012 , new clinical treatment protocol on 12/l5/2001, due to the early closure of the companion clinical protocol, S9623; (d) as of October 15, 2004 504 samples have been submitted for study, including 29 patients registered to 5 S9719 (completed) and 168 patients registered to S0012; (e) to increase assay sensitivity, the manual. HUMASA method was modified to the ABI- 3100 automated platform and a similar revision is in progress for the MSI assay; and (f) the amendment to add paclitaxel, and eliminate estrogen receptor status and offer clonal hematopoiesis testing was made mandatory in 2003, substantially increasing patient accrual.