The onset and progression of malignancy is the result of a combination of genetic, lifestyle, and environmental factors. Some people are more likely to develop thyroid cancer because they carry certain genetic mutations, and they may also use these mutations as “targets” for targeted therapy (targeted therapy). Genetic testing can help find these targets.
Differentiated cancers
What are the common genetic mutations?
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and the one with the lowest “density” of mutations. The BRAF V600E mutation is the most common, occurring in 28% to 77% of papillary carcinoma patients, with an average of about 45%, followed by the RAS mutation, which accounts for about 15%.
For follicular thyroid carcinoma (FTC), RAS gene mutations are frequently present, but there is no specific type of mutation.
Note: The full name of BRAF is v-raf murine sarcoma viral oncogene homologue B1, and the full name of RAS is rat sarcoma viral oncogene homolog.
Which patients need genetic testing?
If you have had a fine needle aspiration (FNA) biopsy of a thyroid nodule and did not get a definitive diagnosis, your doctor may recommend genetic testing to help evaluate for malignancy before surgery.
For postoperative evaluation, studies have found that BRAF mutations alone do not predict long-term outcome; however, the combination of TRET (telomerase reverse transcriptase) mutations often suggests poor outcome.
The combined detection of mutations and recombination (BRAF, RAS, RET/PTC, PAX8/PPAR y) may further improve diagnostic sensitivity.
What is the use of testing for genetic mutations?
The presence of a specific gene mutation means that cancer cells may have unique behaviors and treatments may be different. For example, papillary cancers with a BRAF mutation are more likely to have lymph node metastases, are more likely to recur after surgery, and are poorly treated with radioactive iodine (RAI). In contrast, papillary cancers with RAS mutations are less likely to have vascular invasion and regional lymph node metastases, and are sensitive to RAI therapy.
For most post-operative patients, if these mutation types are identified, it can help doctors better understand the disease and guide review in a more targeted way.
For some patients who are too advanced for surgery, or RAI therapy has not worked, targeted therapy may be tried. Sorafenib (trade name Doxorubicin) and levatinib (trade name Lenvima) can be used for advanced iodine-refractory differentiated cancers, of which sorafenib has been marketed in China and entered medical insurance. A variety of other drugs are in clinical trials in China and abroad.
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Lowly differentiated/undifferentiated carcinoma
Anaplastic thyroid cancer (ATC) is prone to widespread systemic metastasis, is insensitive to RAI therapy, and is the most difficult problem to treat with traditional chemotherapy and radiation.
The most important feature of this type of cancer is the presence of complex genetic mutations: 27% of cases were found to have RAS mutations, 25% had BRAF mutations, 11% had PTEN mutations, and 12% had PIK3CA mutations, and this complexity may also explain its high malignancy. Unfortunately, there are no suitable targeted drugs available.
In these patients, if surgery is not possible, chemotherapy is currently the mainstay, either paclitaxel, or in combination with carboplatin or doxorubicin.
Medullary carcinoma
Medullary thyroid cancer (MTC) is sporadic (about 75% of cases) and hereditary (about 25% of cases). Sporadic cases are not inherited, and none of the children’s families will develop the disease, whereas hereditary cases may occur in multiple patients within a family.
95% of hereditary cases and 70% of sporadic cases are caused by mutations in the RET gene, with about 70% of these being mutations at the M918T locus.
Doctors recommend that all children of MTC patients be screened by having blood drawn for tumor marker [(carcinoembryonic antigen, CEA) and serum calcitonin (CT)] levels. If these two indicators are found to be abnormal, the doctor will usually recommend genetic testing.
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Two targeted drugs, Vandetanib (trade name Caprelsa) and Cabozantinib (trade name Cometriq), are already available in the US for MTC treatment, but not yet in China.
Both drugs have prolonged patient survival in clinical trials, but they have multiple targets and do not specifically target RET mutations, which can lead to toxicities such as diarrhea, skin reactions on the hands and feet, fatigue, and hypertension at high doses.
Co-written by Dr. Xiaoke Zheng, Cancer Hospital, Fudan University