MRD in Solid Tumors
Minimal residual disease (MRD) refers to a small number of cancer cells that can remain in a patient’s body after treatment, potentially leading to relapse. Building on the insights from our previous article, which highlighted the potential of liquid biopsies as a non-invasive alternative to traditional tissue biopsies of solid tumors, this article discusses the specific challenges in MRD detection in solid tumors, highlighting recent advances that are helping to close these hurdles.
Difficulties in MRD Determination of Solid Tumors
Compared to hematologic malignancies, the detection of MRD in solid tumors presents unique challenges, largely due to the fundamental biological differences between these cancers.
Intratumor Heterogeneity
Solid tumors exhibit greater genetic heterogeneity than blood cancers, meaning that mutations can vary widely within different regions of the same tumor [1]. This variability complicates the identification and tracking of tumor-specific mutations, making MRD detection more challenging [2,3]. In contrast, hematologic malignancies originate from blood or bone marrow cells, where established MRD markers, such as clonal immunoglobulin or T-cell receptor rearrangements, are more consistently present across the malignant cell population [4].
ctDNA Release
Unlike blood cancers, which involve circulating cells, solid tumors are confined to specific organs and typically do not release intact tumor cells into the bloodstream. Instead, MRD detection in solid tumors depends on the analysis of circulating tumor DNA (ctDNA), which is released into the blood as tumor cells undergo cell death. ctDNA derived from solid tumors is often present at very low concentrations, particularly in early-stage disease or following surgical intervention, which makes detection significantly more challenging [5,6]. Furthermore, residual cancer cells can enter a dormant state with altered metabolic activity, further hindering the accurate detection of MRD [7,8].
MRD Detection Methods in Solid Tumors
Given the heterogeneity and low abundance of ctDNA in the blood of solid tumor patients, its analysis requires ultrasensitive methods capable of detecting tumor-specific genetic or epigenetic alterations in cell free DNA [8]. To date, several methods have been developed to achieve this level of detection [8–10]. Ultrasensitive targeted approaches, for example, focus on detecting pre-specified cancer-associated mutations with high sensitivity. These methods include the following examples:
- Droplet digital PCR [11,12]: This technique partitions a sample into thousands of nanoliter-sized droplets, performs individual PCR reactions in each droplet, and uses fluorescence-based detection and Poisson statistics to determine the absolute number of target DNA molecules.
- BEAMing [11,13–15]: Stands for beads, emulsion, amplification, and magnetics. This method combines emulsion PCR on magnetic beads with flow cytometry, enabling sensitive, relative quantification of mutant versus wild-type DNA in a highly parallel, single-molecule format.
- Next-generation sequencing (NGS) [16,17]: A high-throughput technology that enables the rapid, parallel sequencing of millions of DNA fragments, allowing comprehensive analysis of genetic mutations, gene expression, and genome-wide variations with high sensitivity and accuracy.
- Refined real-time PCR methods [8]: Several advancements in PCR techniques have made it possible to detect mutations quickly, inexpensively, and with high sensitivity. These include allele-specific PCR (AS-PCR), allele-specific non-extendable primer blocker PCR (AS-NEPB-PCR), co-amplification at lower denaturation temperature (COLD-PCR), and peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamps.
In contrast, untargeted approaches such as whole-exome sequencing (WES) and whole-genome sequencing (WGS) do not rely on pre-specified information about the mutation patterns of the primary tumor, allowing for an unbiased detection of genomic aberrations [8].
Conclusion
Thanks to recent advancements in ctDNA detection, liquid biopsy-based MRD testing is becoming an increasingly powerful tool in personalized treatment of solid tumors, and incorporating MRD analysis into clinical practice holds great potential to refine treatment decisions, lower the risk of recurrence, and ultimately improve patient outcomes.
LIQOMICS & Our Services
LIQOMICS offers ctDNA-based MRD detection in solid tumors for a range of clinical and research applications. Learn more about our services here and contact us to discuss how we can support your needs.
Author: Lisa Baum, PhD, Bioinformatician and Data Scientist, LIQOMICS
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