New blood test for treating malignant melanoma: liquid biopsy could complement radiological diagnostics

Treatment with immune checkpoint inhibitors has significantly improved the survival rate of people with advanced-stage malignant melanoma. However, whether patients respond to the therapy can only be checked by radiological imaging around three months after the start of therapy. A relatively new blood test - the liquid biopsy - can provide information on whether the tumor is receding at a much earlier stage. In a study, researchers from Tübingen were able to show that liquid biopsy can supplement complex radiological diagnostics for skin cancer.

Immune checkpoint inhibitors (ICI) are antibodies that strengthen the body's own immune system in the fight against cancer. Since the approval of ICI for the treatment of advanced malignant melanoma, the ten-year survival rate of patients has more than doubled. Not only inoperable metastases can be treated with ICI. For a few years now, ICIs have also been used after the surgical removal of high-risk melanomas or metastases. The risk of recurrence of the disease (relapse) can thus be minimized.
However, ICIs can cause serious health problems as a side effect. This is because the natural brake on the immune system is released, allowing immune cells to attack the body's own tissue or healthy organs. As only around one in two patients responds to the therapy, it is important to recognize as early as possible who the therapy is working for and who is not. In order to determine whether and how the cancer is developing, staging diagnostics are carried out using whole-body computed tomography (CT) or PET-CT. In contrast to conventional whole-body CT, PET-CT can provide additional information about the metabolic activity of the tumor tissue. ICIs need time to develop their full effect. Doctors therefore only know whether the tumor tissue is responding to the therapy around three months after the start of treatment.

Liquid biopsy shows amount of tumor DNA in the blood

In parallel to staging diagnostics, researchers from Tübingen, including those from the German Cancer Consortium (DKTK), have therefore carried out a study to monitor tumors using a new method known as liquid biopsy - a blood test that can be used to detect and evaluate tumor DNA circulating in the body. Liquid biopsy is already routinely performed for breast and lung cancer. Liquid biopsy is currently only used for black skin cancer in individual cases and is not reimbursed by statutory health insurance companies in routine care. However, liquid biopsy is becoming increasingly relevant. “In contrast to PET-CT, it is significantly cheaper and can be repeated several times in a short space of time, for example every month. Just a few weeks after starting treatment with ICI, the test shows whether the amount of tumor DNA in the blood is decreasing or increasing,” explains Prof. Dr. Andrea Forschner, Head of the Melanoma Outpatient Clinic at the University Dermatology Clinic in Tübingen. Together with Dr. Christopher Schroeder from the Institute of Medical Genetics and Applied Genomics, Forschner conducted a study to investigate whether liquid biopsy indicates that patients are responding to ICI. “We wanted to know how reliably the liquid biopsy indicates that the therapy is working - or that recurrences can be detected,” explains Forschner. New bioinformatic analysis methods, developed in the group of Prof. Dr. Stephan Ossowski from the Institute of Medical Genetics and Applied Genomics, make it possible to identify the smallest amounts of tumor DNA in blood plasma.

Blood test could complement PET-CT for melanoma

Half of advanced metastatic melanoma patients with inoperable metastases live longer than ten years after diagnosis thanks to ICI therapy. There are now some patients in whom all metastases have even disappeared. “The radiation exposure from radiological diagnostics should therefore be kept as low as possible in order to minimize the risk of long-term consequential damage,” emphasizes melanoma researcher Forschner. The results of the study have now been published in the journal Nature Communications.
In the study, the research team used a new liquid biopsy procedure, which was carried out on 87 melanoma patients every few weeks. This involved examining not just a single genetic change in the tumor in the blood test, but up to 30 different ones. “With the new method, it was possible to detect even very small amounts of tumor DNA in the blood, which is particularly important for the regular monitoring of possible recurrences,” explains Schroeder. The results of the liquid biopsies were compared with those of the PET-CT.

Liquid biopsy to be financed by health insurance companies

“We were able to show that a regular liquid biopsy can tell us earlier than PET-CT whether a patient is responding to ICI or not,” explains Forschner. In particular, patients who do not respond to ICI therapy but develop side effects could be switched to other therapies earlier. All tumor-free patients in whom the development of a recurrence was monitored remained negative in both the liquid biopsy and PET-CT during the study period, which indicates the high reliability of the liquid biopsy. In future, these patients could be spared the need for closely timed radiological diagnostics thanks to the blood test, and radiological diagnostics could be offered at an early stage in the case of abnormal liquid biopsies.

The study team is currently working on testing monitoring using liquid biopsy in further studies so that it can be used for all melanoma patients in the future. In addition, monitoring would have to be reimbursed by health insurance companies. Currently, apart from individual cases, funding is only possible through research funds. The study was refinanced by funding from the Immuno-Oncology Foundation.

Original publication: Tumour-informed liquid biopsies to monitor advanced melanoma patients under immune checkpoint inhibition. Schroeder, C., Gatidis, S., Kelemen, O. et al.  Nat Commun 15, 8750 (2024).

Source: DKTK