BACKGROUND
Medullary thyroid cancer (MTC) is an uncommon form of thyroid cancer. MTC is associated with mutations in the RET proto-oncogene, which is a cancer-associated gene that is normally expressed in cells. It is unclear whether mutations in the RET proto-oncogene cause cancer or are just associated with cancer cells. Mutations in the RET proto-oncogene are seen in the inherited type of MTC. However, about 75% of the cases of MTC are sporadic, meaning they are not inherited. Mutations in the RET proto-oncogene can be found in about half of the sporadic cases and certain mutations are more frequent in more aggressive forms of MTC. Identification of these mutations can help guide treatment by using drugs that target these specific genetic changes in patients with MTC.

Circulating cancer DNA (cDNA) are pieces of DNA shed by cancer cells in the body and found in the blood. Newly developed blood tests, often called liquid biopsy, can now detect these pieces of cDNA, and help make a diagnosis of cancer, inform if the cancer is coming back and guide treatment. It is a way to examine cancer without getting a tissue biopsy. This study examined whether testing for cDNA can be a useful tool in managing patients with MTC, particularly in patients with large amounts of cancer still in the body.

THE FULL ARTICLE TITLE
Ciampi R et al. Liquid biopsy-based RET mutation profiling to guide RET inhibitor treatment in sporadic medullary thyroid carcinoma may be useful in cases with high tumor burden and progressive disease. Thyroid. 2026;36(2):188–194; doi: 10.1177/10507256261416836. PMID: 41578741.

SUMMARY OF THE STUDY
The authors tested the blood of 36 patients with sporadic MTC who received medical care in Pisa, Italy. All the patients had RET mutations identified by testing the cancer tissue. They divided the patients in three groups: patients with progressive disease (PD), patients with stable disease (SD) who are receiving treatment and patients with SD being monitored not on treatment. RET mutations by cDNA were identified in 44 % of the patients (16). All the 16 patients with a RET mutation detected in ctDNA were in the PD group. Patients with detectable mutations by cDNA were more likely to have spread of the cancer outside of the neck, more progression of the cancer and higher levels of MTC markers (calcitonin and CEA). Patients in the SD group were negative for ctDNA testing, whether on treatment or not.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Testing cDNA in patients with MTC helps recognize those patients who are more likely to have large amount of cancer cells in the body, and whose disease is more likely to progress. This offers a non-invasive way to evaluate patients with MTC and help make decisions about when and how to treat. Because only about half of the patients with sporadic MTC have detectable RET mutations by cDNA, tissue testing for the RET mutation is still the initial approach. However, cDNA appears most useful in patients who do not have cancer tissue available for testing and whose cancer is growing. We need more studies to better understand the advantages and disadvantages of this new test.

— Susana Ebner MD

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