A liquid biopsy used to monitor progress for patients treated with advanced solid tumors was also found to detect individuals with a high risk of developing myeloid malignancies, according to research by a team of researchers from France.
Specifically, liquid biopsies in this study were used to identify clonal hematopoiesis (CH), or the presence of clones of white blood cells that harbor mutations usually linked to some blood cancers. Discovery of these mutations, sloughed off into the blood from mutated cells, may provide an early screen for myeloid malignancies among patients already treated for advanced solid tumors. Overall, about 8 percent of patients in the study carried at least one CH mutation considered to be a high risk for developing a blood cancer during their lifetime, the researchers found.
"We show that liquid biopsy can be useful to select those patients with solid tumors who may benefit from a personalized hematologic care after the detection on the liquid biopsy of high-risk clonal hematopoiesis," said Marco Tagliamento, a medical oncologist and research fellow with the Gustave Roussy Institute of Oncology in Villejuif, France, who presented the study's results during a press briefing at the 34th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain (Abstract 22).
CH occurs when a mutated hematopoietic stem cell-produced in the bone marrow-churns out cells with the same genetic mutations, leading to myeloid malignancies. Previous studies have shown that the absolute risk of CH progressing to blood cancer is around 1 percent a year, with a 10-fold increase in relative risk. "The message here is that you can use liquid biopsy for the molecular profile in solid tumors and you can get some collateral information that was not for your specific aim," Tagliamento noted.
Added Ruth Plummer, MBE, FMedSci, Professor of Experimental Cancer Medicine at Newcastle University in the UK, and chair of the ENA symposium: "This is well-conducted research that reveals an additional facet to the information gained from liquid biopsies."
Study Details
Liquid biopsies-sometimes referred to as the "holy grail" for cancer diagnostics-have been gaining acceptance as routine assays for the early diagnosis and monitoring for a variety of cancers based on proteins, metabolites, and nucleic acids that are shed by tumor cells into circulating blood. For this study, the research team sought to detect occult myeloid malignancies in the form of CH from patients with solid tumors who underwent a liquid biopsy to molecularly profile their tumor, based on circulating or cell-free DNA in their sera. Patients with treatment-naive or pre-treated tumors were evaluated.
The study's molecular tumor board recommended hematologic evaluation when a CH was detected in genes known to increase risk for blood cancers. These mutated genes included JAK2 or MPL, irrespective of variant allele frequency, or mutation with variant allele frequency of 10 percent or greater in at least one gene between DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1. Mutations in TP53 were to be discussed with patients on a case-by-case basis.
Between March and October 2021, the team took liquid biopsies from 1,416 adult patients with a wide range of treated or treatment-naive solid cancers enrolled in the Gustave Roussy Cancer Profiling study (STING). Some 113 patients, or 8 percent, met the identified criteria of carrying at least one CH mutation considered at high risk for developing a myeloid hematological disorder.
From this list, the Molecular Tumor Board recommended further hematologic evaluation in 45 patients. Taking into consideration patient and disease characteristics, the list was further trimmed to 17 patients who then underwent additional testing. Of these, five patients were subsequently diagnosed with a malignant blood myeloid disorder: one for chronic myelomonocytic leukemia, two for myelodysplastic syndrome, and two for essential thrombocythemia. These patients were referred to a hematologic unit for follow-up and treatment.
"Early detection could prevent complications during anti-cancer treatments-for instance, alterations in blood counts and consequent interruption or delay to treatment," Tagliamento noted. "It could also indicate possible diagnostic and therapeutic pathways for doctors to consider hematological disease."
The research team noted that the Gustave Roussy Molecular Tumor Board provided case-by-case advice on which patients should be referred for further evaluation to reveal actual risk of developing a blood cancer or uncover cases where the disease already is present. They recommended this approach for the future.
"Incidental finding of CH via liquid biopsy may trigger additional hematological tests revealing risk for developing myeloid malignancy or uncovering occult disease," the researchers wrote in their abstract. "This attitude should follow a multidisciplinary case-by-case evaluation."
Plummer, who did not participate in this study, also stressed the importance of evaluating the context for each patient's case before referring for further hematologic tests. Among other things, she noted that only some specific CH mutations are likely to predict a higher risk of blood cancer in the future.
"Cancer patients have much to worry about, and so their doctors need to take into account the patient's clinical situation and their treatment plan," Plummer added. "Patients' anxieties mean that it will not always be appropriate to highlight a potential increased risk of developing an additional blood cancer in later years."
Asked to describe any limitations of his study, Tagliamento said "any limitation of a liquid biopsy depends on the technique being used. In this study, we used a large [next-generation sequencing] panel with more than 300 genes and we were able to go down to 1 percent of threshold of allele frequency, so this sensitivity was good.
"But (the panel) we used is a panel for molecularly profile solid tumors; it is not a panel used to detect hematologic cancer. So, in this panel, some genes that are important to hematology are not included...so we may miss some mutations."
As for next steps, Tagliamento said his team will work to implement and improve the efficiency of the algorithm used to select patients with solid cancers who could benefit from a hematological evaluation.
Warren Froelich is a contributing writer.