Treating Thyroid Cancer with Precision Oncology

Avishek Roy

Scientific Liaison Manager
4baseCare

Thyroid cancer is a rare but serious disease and is the most common endocrine malignancy. Every year, more than 567,000 new cases of thyroid cancer are diagnosed throughout the world (and over 41,000 people are estimated to die from the disease per year).Thyroid cancer is typically found as palpable nodules in the thyroid. Despite the favorable prognosis for differentiated thyroid carcinoma, roughly 5–10% of patients will acquire aggressive behavior, develop metastases, and be resistant to treatment strategies such as radioactive iodine for unexplained reasons.

Pozdeyev and colleagues conducted a large-scale analysis to describe the genetic landscape of advanced differentiated and anaplastic thyroid carcinoma (ATC) and identify genetic alterations with significant diagnostic, prognostic, and therapeutic implications. Each thyroid cancer patient may be thought of as an individual with distinct genetic characteristics. It has been proposed that some genetic mutations and polymorphisms found in thyroid cancer should be considered when selecting high-efficacy treatment strategies. Recent research based on genetic profiling of thyroid cancers has resulted in a number of individualized thyroid cancer therapy options.

As understanding of the molecular mechanisms of thyroid cancer expands, molecular markers for diagnosis, prognosis, surveillance, and treatment are becoming increasingly significant. Several mutations and rearrangements in molecular markers including BRAF, VEGF receptors, RET, and RET/PTC, KDR, KIT, PDGFRA, CD274, and JAK2 are now taken into account for therapeutic components such Entrectinib, larotrectinib, vemurafenib, sunitinib, sorafenib, selumetinib, and axitinib.Tyrosine kinase inhibitors (TKIs) such as Entrectinib and larotrectinib target NTRK fusions in medullary thyroid cancer, whereas pralsetinib and selpercatinib target RET mutations in radioactive iodine (RAI)–refractory differentiated thyroid tumours and anaplastic thyroid cancers (ATCs). Dabrafenib and vemurafenib have also shown promise in RAI-resistant papillary thyroid tumors, and a combination of dabrafenib and trametinib has been approved by the FDA.

A brief discussion about mutations in thyroid cancer that can be targeted with precision oncology medicines is as under:

Multi-kinase Inhibitors:
The MAPK/ERK pathway is a protein chain in a cell that transmits a signal from a cell’s surface receptor to the cell’s DNA in the nucleus. The signal begins when a signaling molecule attaches to a cell surface receptor and ends when the nucleus’ DNA expresses a protein and causes a change in the cell.  Many proteins are involved in the pathway, including MAPK (mitogen-activated protein kinases), which communicate the signals. In this pathway, abnormal activation of several tyrosine kinase receptors can lead to cell proliferation, differentiation, survival, and malignancy.The FDA has approved four different drugs targeting the MAPK signaling pathway.

• Lenvatinib: As an oral anti-angiogenic medication that targets the growth of new blood vessels.  Overall, Lenvatinib therapy resulted in the partial or total elimination of resistant thyroid cancer in 65 % of patients. In a comparison trial, they survived an average of 18.3 months without cancer development, compared to 3.6 months for those who were not treated with Lenvatinib.
• Cabozantinib: Cabozantinib is a tyrosine kinase inhibitor that inhibits many biological processes involved in cancer progression including the receptor tyrosine kinase RET as well as MET and VEGFR2. The drug is approved to treat metastatic medullary thyroid cancer, as well as patients with previously treated radioactive iodine-refractory thyroid cancer.
• Sorafenib: It is an oral medication that prevents cancer from spreading by blocking particular proteins. Because Sorafenib enhanced progression-free survival by 41% compared to a placebo, it was approved for use in patients with locally recurrent or metastatic progressive differentiated thyroid carcinoma that no longer responds to RAI treatment.
• Vandetanib: It is a multikinase inhibitor that suppresses RET, a protein that plays a key role in hereditary medullary thyroid cancer.

BRAF:
Genetic mutations that can be targeted occurs in about 40% of papillary thyroid cancer patients. The BRAF gene is an example of an “oncogene,” that sends signals to normal cells that lead them to become malignant. Studies show that Tafinlar alone or combined with Mekinist are well tolerated by patients, resulting in a 50% response rate among the patients with advanced BRAF-mutated papillary thyroid cancer.In patients with BRAF V600E mutations, Selumetinib and the combination of Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) exhibited substantial response rates.

PLX8394 is a ‘next generation’ BRAF inhibitor that prevents BRAF resistance and works against tumors with a wider spectrum of BRAF mutations. According to a preliminary report of 45 patients with refractory BRAF mutant cancers who were treated with PLX8394, 22% of patients with advanced, refractory cancer experienced a partial response to the drug.

RET:
Selpercatinib is an oral precision cancer treatment that targets malignancies with genetic changes in the RET kinase, such as fusions and activating point mutations, which causes excessive RET signaling and uncontrolled cell proliferation. In 10% to 20% of papillary and other thyroid tumors, “RET fusions” have been discovered. The total response rate for previously treated patients is 69%, with 76% of responding patients reporting 6 month or longer responses. The response rate for previously untreated patients is 73%, with 61% of responding patients having 6 month or longer responses. Tyrosine kinase inhibitors like Cabozantinib and Vandetanib can also be used to target RET.

TRK (tropomyosin receptor kinase):
TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) gets abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). TRK signaling becomes unregulated as a result of this abnormality, which can lead to cancer. TRK fusions are targeted by larotrectinib, and data from three ongoing clinical trials in patients with TRK fusions show a 76 % confirmed response rate across tumor types.

ALK (anaplastic lymphoma kinase):
The translocation of the ALK gene is responsible for the initiation and progression of cancer.  Crizotinib targets variations in the ALK mutation and have shown to have strong anti-cancer effects in tumors that test positive for ALK rearrangements.

HER2/3:
HER2/3 receptors as well as ALK gene rearrangements can be seen in certain thyroid malignancies. For patients with advanced thyroid cancer with the BRAF V600 mutation, combining the HER2/3 blocker Lapatinib with the BRAF inhibitor Dabrafenib resulted in a 60%, delaying cancer progression by 15 months.

It is clearly evident that the precision oncology therapeutics of thyroid malignancies is now biomarker-driven and can assist clinicians in making better treatment decisions for thyroid cancer patients. More genomic studies are needed to provide insights that are needed to counter the drug resistance and to control the relapse of the disease.