Minimal Residual Disease Testing
By Priyanka Varma
Oct. 27th, 2022
Minimal Residual Disease (MRD) is the tumor burden which remains post treatment of the cancer that cannot be identified by traditional diagnostic methods like imaging or conventional blood tests and can be an occult stage of cancer progression[1, 2, 3]. This likely gives rise to systemic metastatic recurrences .
A test to detect MRD can help ascertain if the patient is in full remission or at a risk of relapse, to diagnose cancer progression or recurrence, before there is clinical, biological, or radiographic evidence of the same, as well as for monitoring response to treatment by stratifying risk, avoiding unnecessary investigations and employ alternate management plans .
MRD testing can be done by PCR based assays or PCR based multigene panels, or often in combination with flow cytometry and Next Generation Sequencing (NGS) . MRD can be detected from circulating tumor cells, disseminated tumor cells, or micro metastasis in bone marrow and circulating tumor DNA .
The pathology behind MRD testing by disseminated tumor cell is explained with the quiescent dormant cells getting awakened from the state of dormancy, being disseminated, and re-entering the circulation to metastasize. They are resistant to therapy owing to non or slow proliferation and can be a potential cause for disease relapse versus senescent dormant cells which have irreversibly stopped proliferating. Several intrinsic and extrinsic factors can influence this process.
There are several biomarkers utilized for MRD testing like circulating tumor cells, disseminated tumor cells, ctDNA, miRNA etc. ctDNA has been utilized for MRD testing in colorectal cancer, for instance, with a sensitivity of 87.5% to detect relapses at or before detection by radiographic imaging. ctDNA detection methods either employ enrichment using EpCAM or cell size and density [5, 7]. miRNA like miR-128-3p and miR-181b-5p have also been used as MRD biomarkers in pediatric precursor-B cell Acute Lymphoblastic Leukemia patients.
Besides being utilized currently in testing for Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Multiple Myeloma, Lymphoma, MRD testing is also utilized in the management of Colorectal Cancer and other solid tumors like Lung Cancer, Breast Cancer, Bladder Cancer, Esophageal Cancer, among others [5, 8, 9, 10, 11].
1. Minimal Residual Disease (MRD): Testing, Results & More (healthline.com)
2. Young Kwang Chae, Michael S. Oh, Detection of Minimal Residual Disease Using ctDNA in Lung Cancer: Current Evidence and Future Directions, Journal of Thoracic Oncology, Volume 14, Issue1,2019, Pages 16-24, ISSN 1556-0864,https://doi.org/10.1016/j.jtho.2018.09.022.
3. Pantel, K., Alix-Panabières, C. Liquid biopsy and minimal residual disease — latest advances and implications for cure. Nat Rev Clin Oncol 16,409–424 (2019). https://doi.org/10.1038/s41571-019-0187-3
4. Parsons, Heather A., et al. "Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer." Clinical Cancer Research 26.11(2020): 2556-2564.
5. LCD- MolDX: Minimal Residual Disease Testing for Cancer (L38822) (cms.gov)
6. Hantel A, Stock W, Kosuri S. Molecular Minimal Residual Disease Testing in Acute Myeloid Leukemia: A Review for the Practicing Clinician. Clin Lymphoma Myeloma Leuk. 2018 Oct;18(10):636-647. doi: 10.1016/j.clml.2018.06.017. Epub 2018 Jun27. PMID: 30006258.
7. Biomarkers detecting minimal residual disease in solid tumors: what do they mean in the clinical management of patients? Nigel P Murray Biomarkers in Medicine 2019 13:18, 1535-1538 Biomarkers detecting minimal residual disease in solid tumors: what do they mean in the clinical management of patients? | Biomarkers in Medicine (futuremedicine.com)
8. Rzepiel, A., Kutszegi, N., Gézsi, A. et al. Circulating microRNAs as minimal residual disease biomarkers in childhood acute lymphoblastic leukemia. J Transl Med 17,372 (2019). https://doi.org/10.1186/s12967-019-2114-x
9. Zhong L, Jin X, Xu Z, Zeng M, Chen D, He Y, Zhang J, Jiang T, Chen J. Circulating miR-451a levels as a potential biomarker to predict the prognosis of patients with multiple myeloma. Oncol Lett. 2020 Nov;20(5):263. doi: 10.3892/ol.2020.12126. Epub 2020 Sep 21. PMID:32989397; PMCID: PMC7517596.
10. Bliss S.A., Sinha G., Sandiford O.A., Williams L.M., Engelberth D.J., Guiro K., Isenalumhe L.L., Greco S.J., Ayer S., Bryan M., et al. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res. 2016;76:5832–5844.doi: 10.1158/0008-5472.CAN-16-1092.
11. Dutta S., Warshall C., Bandyopadhyay C., Dutta D., Chandran B. Interactions between exosomes from breast cancer cells and primary mammary epithelial cells leads to generation of reactive oxygen species which induce DNA damage response, stabilization of p53 and autophagy in epithelial cells. PLoS ONE. 2014;9:e97580. doi: 10.1371/journal.pone.0097580.