Detection of myeloid malignancies through cfDNA profiling in patients with advanced stage cancer

      Background: Clonal hematopoiesis (CH) is frequently incidentally found in liquid biopsy and may reveal a risk situation for developing myeloid malignancy or uncover occult hematologic disease.
      Material and methods: Adult patients with treatment-naïve or pre-treated advanced solid cancer enrolled in the Gustave Roussy Cancer Profiling study (STING, NCT04932525) underwent at least one liquid biopsy with next-generation sequencing of cfDNA performed by FoundationOne Liquid CDx. The Gustave Roussy Molecular Tumor Board reviewed molecular reports. Potential CH alterations were registered, and patients referred to hematology consultation in case of identified mutation in JAK2 or MPL, irrespective of the variant allele frequency (VAF), or mutation with VAF ≥10% in at least one gene between DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, U2AF1. On the contrary, mutations in TP53 were discussed on a case-by-case basis, excluding cases with somatic alteration identified by tumor tissue testing. Objective of the study was to determine the diagnostic rate of myeloid malignancies following the incidental finding of high-risk CH via liquid biopsy for cfDNA detection.
      Results: Between March and October 2021, 1416 patients underwent at least one liquid biopsy. Overall, 113 patients (8%) met the identified criteria and carried at least one CH mutation considered at high-risk for developing myeloid hematologic disorders (JAK2 = 27, MPL =3, DNMT3A = 32, TET2 = 19, ASXL1 = 18, IDH1 =4, IDH2 =3, SF3B1 =5, U2AF1 = 2). Indication for hematology consultation followed in 45 cases, taking into account also patient’s and cancer disease’s characteristics. Five out of these selected patients had a confirmed diagnosis of malignant myeloid disorder: one chronic myelomonocytic leukemia, two myelodysplastic syndrome, two essential thrombocythemia.
      Conclusions: Incidental finding of CH via liquid biopsy may trigger additional hematological tests revealing risk for developing myeloid malignancy or uncovering occult disease. This attitude should follow a multidisciplinary case-by-base evaluation.
      Conflict of interest:
      Other Substantive Relationships: No conflict of interest related to this study.