Photo by Juan D. Alfonso
Blood sample collection
Scientists from the Dana-Farber Cancer Institute and the Broad Institute in Boston, Massachusetts, have shown that in multiple myeloma (MM), liquid biopsies provide similar genetic information as tumor biopsies.
Unlike tumor biopsies, liquid biopsies are noninvasive and, in the future, may offer a cost-effective way of following disease state, disease progression, and response to treatment.
The scientists used cell-free DNA (cfDNA) from 107 patients, circulating tumor cells (CTCs) from 56 patients, and compared their genomic profiling with bone marrow biopsies from 9 patients with MM.
The researchers used a two-step approach using the 2 kinds of liquid biopsies—CTCs and cfDNA. They first used “ultra-low pass” whole genome sequencing, which was a rapid and cost-effective method to identify blood samples with tumor DNA of at least 5%-10% (tumor fraction).
These samples were then subject to whole-exome sequencing (WES), which analyzes protein-coding sequence of the genome.
The researchers found genetic alterations in MM such as copy number alterations (1p, 13q deletions or 11q gain) and somatic single nucleotide variations (SSNVs), among others, which they observed in matched cfDNA, CTCs, and tumor DNA (tDNA) from tumor biopsies.
The liquid biopsies also captured the clonal heterogeneity characteristic of MM—99% of clonal mutations present in tDNA were also seen in cfDNA or CTCs, and 94% of mutations present in cfDNA or CTCs were seen in tDNA.
In addition, CTCs or cfDNA samples with higher tumor purity uncovered more mutations than were seen in tDNA.
“[The] combination of CTCs and cfDNA was able to detect almost all clonal mutations identified in the bone marrow biopsy sample and defined other subclones that were not identified in the bone marrow,” the scientists noted.
This increased sensitivity was “potentially due to the limitation of sampling site of the bone marrow,” they pointed out.
The scientists also showed that the tumor fraction in cfDNA and enriched CTCs correlated with disease progression from MGUS (monoclonal gammopathy of undetermined significance) and SMM (smoldering MM), to overt MM.
The scientists also evaluated liquid biopsies to determine response to treatment.
For example, a patient who responded to carfilzomib, lenalidomide, and dexamethasone, had a decreased cfDNA tumor fraction—from 22% to 2%.
Another patient who progressed on daratumumab over a period of 2 months showed an increase in tumor fraction—from 11% to 46%.
CTCs and cfDNA captured the mutational landscape of MM and provided a non-invasive profiling of tumor evolution. The liquid biopsy approach may be used as a novel biomarker for disease progression and response to therapy, the scientists suggest.
"Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding,” said co-senior author Irene Ghobrial, MD, “because this means that routine genetic profiling of patient tumors from blood would be feasible."
"Our ultimate goal is to eventually use all the samples to monitor disease progression," added Jihye Park, PhD, researcher in the Ghobrial lab and co-first author on the paper.
Currently, bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of MM.
However, due to their invasive nature and associated costs, they are not done at every visit. Liquid biopsies are an attractive way forward.
Nevertheless, before they can be used in the clinical management of patients with MM, these results need to be confirmed in larger prospective studies.
The investigators reported their findings in Nature Communications.