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A subset of plasma cell-free DNA (cfDNA) known as circulating tumor DNA (ctDNA) continues to gain momentum as a noninvasive biomarker in detecting cancer. A study in the Annals of Oncology describes another potential breakthrough: analyzing cfDNA to identify imbalances in genomewide copy number alterations (CNA) as a means of screening healthy individuals for cancers. Identifying tumors at early stages would offer the possibility of improved survival rates.
Developing a unique genomic profiling method for cfDNA, a team of Belgian and Dutch investigators initially tested the approach in 50,000 asymptomatic pregnant women to identify fetal and maternal chromosomal imbalances. The Genomic Imbalance Profiling from cfDNA SEQuencing (GIPseq) method was able to find eight malignancies by discerning cancer-like CNAs in cfDNA, as well as CNAs in patients with solid and hematological tumors. Armed with these findings, the researchers’ next step was to test GIPseq’s unbiased, noninvasive method in otherwise healthy patients with a high risk of developing cancer.
Collecting cfDNA samples from 1,002 elderly Belgian patients with no prior history of cancer, they used GIPseq to look for chromosomal aberrations that suggested the presence of a malignancy. Six-month clinical analyses took place in cases where aberrations were found, with investigators cataloguing any CNAs present in cfDNA to create a “map” of aberrations found in this aging population.
Overall, 3% of the participants had chromosomal imbalances. Follow-up clinical work unveiled five hematologic malignancies: one stage II Hodgkin lymphoma (HL); one stage II myelodysplastic syndrome with excess blasts, and three non-HL cases of varying stages. “The CNAs detected in cfDNA were tumor-specific,” wrote the investigators, who additionally identified one monoclonal B-cell lymphocytosis in their analysis, indicating a precursor of B-cell malignancy. In 24 additional cases, patients were not diagnosed with cancer either because their aberrant cfDNA profile originated from peripheral blood cells or the origin of aberrations in cfDNA couldn’t be identified.
The results illustrate the GIPseq’s effectiveness in detecting incipient hematologic malignancies and clonal mosaicism with unknown clinical significance in healthy patients, the investigators concluded. “We demonstrate that cfDNA screening detects CNAs, which are not only derived from peripheral blood, but even more from other tissues. Since the clinical relevance of clonal mosaics in other tissues remains unknown, long-term follow-up is warranted.”
Previous research has questioned the clinical utility and validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection, according to a related editorial. What the latest research in the Annals of Oncology suggests is a re-evaluation of this technology may be in order.
“The early detection of malignancies using a blood sample and the prevention of cancer by detecting premalignant states was always a dream of oncologists, which might come true step by step in the next years,” wrote the editorialists. Using whole-genome profiling to detect early cancer in asymptomatic elderly adults is “one step of many further steps to be taken,” they added.