Liquid Biopsies for Circulating Tumor DNA Detection May Reveal Occult Hematologic Malignancies in Patients With Solid Tumors

Abstract

PURPOSE High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell–free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525 ) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.

Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients

“…As a result, a tissue profile may falsely show a negative result for an alteration identified in the liquid biopsy. On the other hand, liquid biopsy is recognized as a reliable reflection of tumor heterogeneity and serves as a valuable tool for detecting second occult solid cancers 7 or hematological malignancies 8 .…”

“…Being able to reflect tumor heterogeneity 1 , liquid biopsies are useful for identifying molecular targets, monitoring treatment response 2 and identifying resistance mechanisms 3 – 5 . The use of liquid biopsies raises several questions regarding incidental germline alterations 6 , identification of occult malignancies 7 or detection of hematological malignancies 8 . Additional technical advantages include low invasiveness of blood drawing, the easy repeatability of the analysis or the short turnaround time that ensures early initiation of treatment.…”

Tissue- and liquid-biopsy based NGS profiling in advanced non-small-cell lung cancer in a real-world setting: the IMMINENT study

“…Of note, high-risk clonal hematopoiesis (CH) is often unexpectedly detected in solid tumor patients undergoing plasma cell-free DNA sequencing. These findings could lead to further hematologic diagnostic tests and uncover an occult hematologic malignancy ( 51 ). These insights pose a limitation to our study as we did not evaluate monoclonal components due to data insufficiency and the primary objectives of the study.…”

Clonal Hematopoiesis: Updates and Implications at the Solid Tumor-Immune Interface

“… 72 - 75 As an incidental finding, CH with high-risk mutations can act as a point of referral for further hematologic consultation, helping to reveal occult hematological malignancies. 76 The possibility of CH contaminating or interfering with diagnostic tests warrants consideration from precision oncologists, although knowledge of CH and the utilization of matched blood and/or tissue normal sequencing alongside tumor sequencing can drastically reduce the risk of any adverse consequences for patients.…”