Screening for clonal hematopoiesis as a predictive marker for development of t-AML following adjuvant therapy for breast cancer (S0012)

Abstract

11051 Background: A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related acute myeloid leukemia (t-AML). To evaluate and possibly identify patients (pts) at high risk for development of t-AML, the Southwest Oncology Group asked whether dose-intensive adjuvant regimens for high risk breast cancer pts induced genetic damage to hematopoietic stem cells (HSC), defined by the emergence of clonal hematopoiesis, an early marker of HSC damage. Methods: 274 pts consented to the clonal hematopoiesis study objective of S0012, a randomized clinical trial of standard doxorubicin and cyclophosphamide followed by weekly paclitaxel (arm 1, 129 pts) vs. weekly doxorubicin and daily oral cyclophosphamide plus G-CSF followed by weekly paclitaxel (arm 2, 145 pts) as neoadjuvant therapy for inflammatory and locally advanced breast cancer. Two different clonality assays were used: the HUMARA (HUMan Androgen Receptor) Assay to estimate the incidence of early genetic damage by clonal proliferation and microsatellite instability (MSI) testing at 5 loci (Bat 26, Bat 40, APC, Mfd, D2S123), common ‘hotspots‘ in t-AML, to screen for loss of heterozygosity or defective DNA mismatch repair mechanisms. Blood samples were evaluated prior to treatment and at 6 and 12 mos post-surgery for emergence of clonal hematopoiesis. Results: Of the 274 pts enrolled, follow-up clonal hematopoiesis samples were available for 195 pts; 96 pts on arm 1 and 99 pts on arm 2. Both HUMARA and MSI results were negative for clonal hematopoiesis in 96% of samples analyzed. In 14 cases, the HUMARA assay suggested that a clonal population was present, but MSI analysis was negative. No cases were HUMARA+/MSI+. With a median follow-up of 19.6 mos, only one pt has developed t-AML 3 yr 5 mos post randomization. Her clonal hematopoiesis test samples at 6 and 12 mos following treatment were negative. Conclusions: Clonal hematopoiesis assays performed within the first year following neoadjuvant therapy and surgery on S0012 failed to identify an emerging clonal HSC population. Longer clinical follow-up will be necessary to define the positive predictive value of detecting clonal hematopoiesis in the 14 HUMARA+/MSI- cases as a harbinger of t-AML. No significant financial relationships to disclose.