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The term Minimal Residual Disease (MRD) has so far been used primarily in leukemias, particularly in chronic myeloid leukemia (CML), to describe the persistence of a very small number, a minimal residual burden, of malignant cells in the blood during treatment.

Several types of leukemia have defined genetic alterations; a classic example is CML, in which the bcr/abl translocation is responsible for disease development and can be detected using polymerase chain reaction (PCR). This small number of cells, detectable at the lower limit of detection, may increase again during the course of the disease, upon discontinuation of therapy, or in the case of therapy resistance, and thus become clinically relevant. Therefore, MRD monitoring is routinely used in CML.

Minimal Residual Disease in Solid Tumors

In the case of solid tumors, it was originally assumed that once a tumor was surgically removed with wide, healthy margins, the patient was cured (Halsted). However, in breast cancer, it became apparent that metastases could still occur even after radical mastectomy. Because such radical procedures were highly burdensome, it was a great relief when it was shown that removing only the malignant lump followed by radiation therapy achieved outcomes comparable to the radical approach. Nevertheless, metastases were also observed in these cases.

Apparently, even after successful cancer surgery, individual viable tumor cells may remain in the body, these are referred to as minimal residual disease. It must be assumed that once tumors have access to the bloodstream, they can release single cells into circulation, often long before the tumor is even detected. Based on this hypothesis, adjuvant chemotherapy was developed (Fisher, Bonadonna) to eliminate these minimal residual cells. Although this led to significant, albeit only moderate, improvements in survival, at the time adjuvant therapy was developed there were no means to detect the presumed residual cells. The moderate improvement in survival might therefore have resulted from overtreatment (no residual cells present) or undertreatment (residual cells not adequately responsive to therapy).

Because solid tumors generally do not exhibit the clear genetic alterations seen in leukemias, and the number of cells shed into the bloodstream is extremely low, detection using PCR is practically impossible.

To address this limitation, preoperative (neoadjuvant) chemotherapy was introduced, allowing assessment of treatment response based on tumor shrinkage. Unexpectedly, breast cancer patients whose tumors responded poorly or not at all to chemotherapy showed better relapse-free survival than those whose tumors responded well to neoadjuvant therapy. Thus, this approach cannot be used universally as a biomarker for therapy monitoring.

Detection of MRD in Solid Tumors

As mentioned, after completion of therapy, the number of tumor cells remaining in the body in solid tumors is usually extremely low. With new technologies, particularly liquid biopsy methods for detecting and analyzing circulating tumor cells (CTCs) or circulating tumor DNA fragments (ctDNA) in blood, there is hope for monitoring minimal residual disease.

Current knowledge suggests that circulating tumor DNA (ctDNA) is less sensitive than detecting circulating epithelial tumor cells (CETCs/CTCs) using the maintrac® method, which can identify very small numbers of viable tumor cells circulating in the blood. Some of these cells can enter a dormant state, during which their numbers remain constant and they evade therapeutic intervention. Others may acquire mutations that make them resistant to therapy, allowing them to proliferate despite treatment, form new tumors, and cause relapse.

This phenomenon is primarily attributed to circulating tumor stem cells (cCSCs) among the circulating tumor cells, which are capable of initiating recurrences.

Clinical Significance of MRD Monitoring with CETCs/CTCs in Breast and Prostate Cancer

An increase in the number of viable circulating tumor cells in solid tumors is associated with a significantly increased risk of recurrence, while a decrease indicates a low or very low recurrence risk. In a study conducted at the University of Jena, breast cancer patients who showed a rise in CETC/CTC numbers during radiotherapy in the first two follow-up years accounted for nearly all observed recurrences, indicating an almost tenfold difference in recurrence risk (Schott et al., 2024) compared to patients whose CETC/CTC numbers declined. Similarly, prostate cancer patients with rising CETC counts during radiotherapy showed a comparably high hazard ratio, whereas those with falling or consistently low cell counts experienced no recurrence at all during the first four years of follow-up (Schott et al., 2025).

Application of MRD Monitoring

Such personalized information can play an important role for patients when deciding which therapies to pursue, especially as, according to the new S3 guidelines, patients are increasingly involved in treatment planning. The physical burden is minimal, since only blood samples are required. However, reimbursement by health insurance providers is currently granted only in specific cases.