Session: 503. Clonal Hematopoiesis: Aging and Inflammation: Poster II
Hematology Disease Topics & Pathways:
HSCs, Adult, Non-Biological, Diseases, Therapies, Adverse Events, Biological Processes, DNA damage, epigenetics, Cell Lineage, Study Population, genomics, Clinically relevant, Myeloid Malignancies, pharmacology, hematopoiesis
Methods. The NET Biobank housed at Roswell Park Comprehensive Cancer Center contains banked serial samples for pts receiving PRRT since its FDA approval in 2018. In this retrospective analysis, we identified pre-PRRT blood samples from 13 pts with NET treated at our institute from 2018-19. Serial samples (post PRRT exposure) were available for 6 of 13 pts. Genomic DNA collected from pts before and after PRRT treatment initiation was analyzed for CH mutations using a custom panel targeting 93 genes. A VAF cut off of 1% was used to define putative CH mutations. Relationships among clinical, laboratory and mutational variables were examined using chi-square test, at a significance level of 0.05.
Results. Pt characteristics (n=13) are shown in Table 1. Median age was 58 years. 70% were men. Only 1/13 pt had prior chemotherapy exposure, and 3/13 had prior RT exposure. The primary location of NETs was small bowel (46%) followed by pancreas (23%) and others (cecal, rectal or unknown - 31%). All pts had stage IV disease. Over half (54%) harbored CH mutations, despite their relatively young age. This prevalence is much higher than previously reported CH prevalence of 25.1% in pts with other solid tumors.1 TET2 (25%) was the most commonly mutated gene, followed by ASXL1 (12.5%), CHEK (12.5%), PPM1D (12.5%) and TP53 (12.5%) which together accounted for 50% of all mutations. Other mutations (DNMT3A, JAK2, DDX41, SRCAP) were less common (Figure 1). DNMT3A mutations (usually most prevalent mutation in cancer cohorts) were uncommon in this cohort and did not occur in the R882 AML/MDS hotspot, previously described in CH. Frameshift mutations and truncations comprised 53.3% of all mutations, and these mutations had higher mean VAFs (6.14%) than single nucleotide variants (1.93%; p = 0.001). This may suggest that frameshift mutations and truncations provide survival advantage to the affected clone. Mutations were more common in smokers than in non-smokers (100% vs 40%, p = 0.067). As expected, mutations were more common in individuals age 61 and above (75% harbored 1 or more mutation) vs only 20% mutation occurrence was noted in age 60 or below (p=0.05).
Conclusion. CH with a distinct mutation profile occurs in NET patients, and in higher prevalence (54%) than observed in other solid tumors (25%). High baseline prevalence of putative CH mutations in NET patients may be an important contributor to heightened risk of MN development after PRRT exposure. Ongoing serial sample evaluation will provide further insights into clonal evolution of the above detected CH mutations after exposure to PRRT. The results regarding clonal evolution may have implications in predicting risk of MN associated with PRRT therapy and influence treatment selection in pts planned for PRRT.
- Coombs CC, Zehir A, Devlin SM, et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 2017;21(3):374-382.e374.
Acknowledgement: Data and samples for this study were provided by the Data Bank and BioRepository (DBBR), which is funded by the National Cancer Institute (P30 CA016056) and is a Roswell Park Cancer Institute Cancer Center Support Grant shared resource.
Disclosures: Iyer: Advanced Accelerator Applications: Consultancy. Guzman: SeqRx: Honoraria; Cellectis: Research Funding. Wang: Astellas: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Pfizer: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy.
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