The Impact of Oncologic Therapy on Clonal Hematopoiesis and Therapy-Related MDS
EvansMDS Young Investigator Award
My career goal is to become a physician scientist and principal investigator with a clinical and research focus on early cancer detection and prevention using computational genetic and epidemiologic methods. In the next five years, I want to focus on therapy-related leukemia genomics and how clonal hematopoiesis (CH) can be used to both understand the biology of myelodysplastic syndrome (MDS) and to predict risk of therapy-related MDS (tMDS). Characterization of how pre-malignant mutations in the blood, CH, relates to future leukemia risk represents a first step towards the use of non-invasive genomic-based testing to detect pre-malignant states. With the increasing sensitivity of genomic assays, genomic-based screening programs can be used to detect pre-malignant lesions for solid tumors. This has the advantage of informing not only on likelihood of an occult malignancy but also providing insight into the disease biology.
Roughly 10-20% of myelodysplastic syndrome is accounted for by therapy-related MDS (t-MDS). t-MDS is highly treatment resistant, with a 5-year survival of only 10%. Given the increasing rates of both cancer incidence and cancer survivorship, the number of cancer survivors in the U.S. is projected to approach 18 million by 2022. The incidence of t-MDS is expected to rise in parallel. Although t-MDS is known to be linked to specific subclasses of chemotherapy, it is not well established which patient populations are at sufficient risk of t-MDS to warrant intervention. t-MDS was traditionally thought to develop from the mutagenic effects of oncologic therapy but recent studies show that cancer-initiating mutations driving t-MDS can often be detected prior to therapy. Genomic studies in healthy populations have shown that the acquisition of somatic mutations in leukemia-associated genes in blood cells can also be detected in people without any apparent hematologic disease, referred to as clonal hematopoiesis (CH). We and others have shown that CH is frequently observed (~20%) in solid tumor patients, is associated with prior exposure to oncologic therapy, and confers a substantially increased risk of subsequent hematological malignancy. Identifying the specific oncologic regimens associated with CH, and its genetic features that lead to high risk for t-MDS, would inform the development of prevention strategies for t-MDS. However, the relationship between exposure to specific therapeutic agents and the development and progression of CH to t-MDS is not established. Many solid tumor patients undergo genetic sequencing of tumor and blood samples (representing a constitutional control) for standard clinical care. I ascertained detailed clinical, treatment and outcome data for over 17,500 cancer patients with blood sequencing data. My preliminary analysis shows that exposure to specific oncologic therapies is highly associated with CH. I define subsets of patients at high risk of t-MDS on the basis of genetic characteristics of their CH as well as clinical features. I hypothesize that CH is promoted by exposure to specific oncologic therapies and that a combination of CH and clinical factors are associated with t-MDS risk. Identification of patient subgroups at high risk of t-MDS would inform the development of prevention protocols to avoid or minimize exposure to t-MDS-associated therapies.