Precision Cancer Medicine Treatment of Thyroid Cancers

Precision cancer medicines and targeted immunotherapy are increasingly used or the treatment of thyroid cancer.

by Dr. C.H. Weaver M.D. updated 8/2019

Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy that attacks a specific mutation or other cancer-related change in the DNA programming of the cancer cells can be developed or selected for treatment.

Immuno-oncology

Precision immunotherapy treatment of cancer has also progressed considerably over the past few decades and has now become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. Doctors have been trying for years to find ways to harness an individual’s immune system to fight cancer.

The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.

Recent promising clinical results have generated an explosion of interest—and research funding— in the field of immuno-oncology. Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream.

Genetic Mutations

Not all thyroid cancer cells are alike. They may differ from one another based on what genes have mutations that are responsible for the growth of the cancer. Testing is performed to identify genetic mutations or the proteins they produce that drive the growth of the cancer. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.

Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Individuals with thyroid cancer should discuss the role of genomic-biomarker testing with their physician. Genomic markers can be tested for in the biopsy sample or in the blood using a "liquid biopsy." (1-10)

Mutations in Thyroid Cancer that can be Targeted with Precision Cancer Medicines

Multi-kinase Inhibitors

The MAPK/ERK pathway is a chain of proteins in a cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell.

The pathway includes many proteins, including MAPK (mitogen activated protein kinases) which are responsible for communicating the signals. Abnormal activation of different tyrosine kinase receptors in this pathway can ultimately leads to cell proliferation, differentiation, survival and cancer. (1,2)

When one of the proteins in the pathway is mutated, it can become stuck in the "on" or "off" position, which is a necessary step in the development of many cancers. Drugs that reverse the "on" or "off" switch are used as cancer treatments and when they act at more than one location in the process they are call “Multi-kinase Inhibitor” drugs The FDA has approved four different drugs targeting the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. (3,4)

Sutent, Nexavar, and Lenvima have been compared to placebo treatment in radioactive iodine-refractory locally advanced or metastatic thyroid cancer and shown to delay cancer progression. Lenvima significantly prolonged survival without cancer progression by 15 months in one trial.

  • Lenvima (lenvatinib): As an oral anti-angiogenic therapy that targets new blood vessel growth, Lenvima can “starve” cancer of the nutrients it needs to grow. Overall 65% of refractory thyroid cancer patients experienced a partial or complete disappearance of their cancer following treatment with Lenvima. They survived on average 18.3 months without cancer progression compared to 3.6 months for individuals not treated with Lenvima in a comparative trial. (5)
  • Cometriq (cabozantinib) Although medullary thyroid cancers only account for approximately 2-3% of all thyroid cancers they tend to have a somewhat worse prognosis than more common types of thyroid cancer. Cometriq is a tyrosine kinase inhibitor that targets specific biological pathways that contribute to the growth of several types of cancer, including the receptor tyrosine kinase RET as well as MET and VEGFR2. The drug is approved for the treatment of metastatic medullary thyroid cancer. (9)
  • Nexavar (sorafenib): Nexavar is an oral medicine that works by inhibiting certain proteins that contribute to cancer growth. It has been approved for use in patients with locally recurrent or metastatic, progressive differentiated thyroid cancer that no longer responds to RAI treatment because Nexavar increased progression-free survival by 41 percent compared to treatment with a placebo. (7)
  • Sutent (sunitinib): Sutent is approved for the treatment of several cancers. It works by inhibiting multiple proteins in cancer cells to limit cancer cell growth and division and is active in the treatment of thyroid cancer. (8)
  • Caprelsa (vandetanib) Caprelsa is a multikinase inhibitor with several mechanisms of action. Among other things, it inhibits a protein known as RET that plays an important role in hereditary medullary thyroid cancer. (17)

Researchers continue to identify cancer driving genetic mutations responsible for thyroid cancer on an ongoing basis. The following mutations are known to exist in thyroid cancer and precision cancer medicines are either available for use or being developed in clinical trials. Patients should discuss the role of genomic-biomarker testing for the management of their cancer with their treating oncologist.

BRAF: Genetic mutation occurs in ~ 40% of papillary thyroid cancer patients that can be specifically targeted. The BRAF gene belongs to a class of genes known as “oncogenes,” which send signals to normal cells that cause them to become cancerous. Studies show that Tafinlar alone or combined with Mekinist are well tolerated by patients, resulting in a 50 to 54 percent response rate among the patients advanced BRAF-mutated papillary thyroid cancer. (15)

MEK: The MEK 1–2 inhibitor Selumetinib and the combination of Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) in patients with BRAF V600E mutations have produced high response rates. (13,14)

MET: The MET signaling pathway is abnormal in some patients with Thyroid cancer and stimulates cell growth, invasion, metastasis and promotes resistance to apoptosis. Inhibition of the MET pathway is beneficial in blocking the growth of a number of different cancers. MET inhibitors are a class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase. These inhibitors may have therapeutic application in the treatment of some Thyroid cancers. (11)

RAS Genes: KRAS and NRAS: RAS is estimated to be present in 20% of papillary and 40% of follicular thyroid cancers. (18)

RET: occurs in ~ 15% of papillary and can occur in medullary thyroid cancer. only account for approximately 2-3% of all thyroid cancers they tend to have a somewhat worse prognosis than more common types of thyroid cancer. Some medullary thyroid cancers over express the receptor tyrosine kinase (RET) which can be targeted with precision cancer medicines known as tyrosine kinase inhibitors like Cometriq (cabozantinib), Caprelsa® (vandetanib). (18,19)

PIKC3A: Occurs in 42% of anaplastic and 24% of follicular thyroid cancers.

PTEN Occurs in~ 12% of anaplastic thyroid cancers.

PAX8-PPAR occurs in ~35% of follicular thyroid cancers.

TRK: Rare. TRK (tropomyosin receptor kinase) fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. Vitrakvi (larotrectinib orLOXO-101) targets TRK fusions and clinical data from three ongoing clinical trials in patients whose tumors harbor TRK fusions demonstrate a 76% confirmed response rate across tumor types. (20)

ALK: Rare. The anaplastic lymphoma kinase (ALK) gene translocation is responsible for initiating and driving cancer growth. The ALK mutation was initially identified in lung cancer and is present in some patients with thyroid cancer. Crizotinib and several other precision cancer medicines that target variances in the ALK mutation are available and produce significant anti-cancer responses among cancers that test positive for ALK rearrangements. (11,12)

HER2/3: Some thyroid cancers have HER2/3 receptors as well as ALK gene rearrangements. These mutations tend to serve as escape mechanisms from treatment with Multi-kinase Inhibitor medications through activating MEK. Using the HER2/3 blocker Lapatinib in combination with the BRAF inhibitor Dabrafenib for patients with advanced thyroid cancer and the BRAF V600 mutation yielded a response rate of 60% delaying cancer progression of 15 months (range, 2–34+ months). (16)

All patients should discuss the role of molecular testing in the management of their cancer with their treating oncologist. New precision cancer medicines are increasingly available, and others are undergoing evaluation in clinical trials.

References:

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  1. Cooper DS, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167–1214. doi: 10.1089/thy.2009.0110.
  1. Haugen BR, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133. doi: 10.1089/thy.2015.0020.
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  1. FDA approves Nexavar to treat type of thyroid cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376443.htm
  1. Advanced Thyroid Cancer Responds to Targeted Therapy with Sunitinib [press release]. Endocrine Society website. Available at: https://www.endocrine.org/news-room/current-press-releases/advanced-thyroid-cancer-responds-to-targeted-therapy-with-sunitinib.
  1. Brose MS, Sherman SI, Schöffski P, et al. Correlative analyses of RET and RAS mutations in a phase III study of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Presented at the 83rd Annual Meeting of the American Thyroid Association, October 16- 20, 2013, in San Juan, Puerto Rico. Thyroid. October 2013, 23(S1): A-1-A-114. Abstract 4.
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  1. Godbert Y, et al. Remarkable response to Crizotinib in woman with anaplastic lymphoma kinase–rearranged anaplastic thyroid carcinoma. J Clin Oncol. 2015;33(20):e84–e87. doi: 10.1200/JCO.2013.49.6596.
  1. Hayes DN, et al. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012;18(7):2056–2065. doi: 10.1158/1078-0432.CCR-11-0563.
  1. Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, et al. Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC) J Clin Oncol. 2017;35(15 suppl):6023.
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  1. Wells SA, Robinson BG, Gagel RF et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA). Presented at the 2010 annual meeting of the American Society of Clinical Oncology. Chicago, IL, June 4-8, 2010. Abstract 5503.
  1. Brose MS, Sherman SI, Schöffski P, et al. Correlative analyses of RET and RAS mutations in a phase III study of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Presented at the 83rd Annual Meeting of the American Thyroid Association, October 16- 20, 2013, in San Juan, Puerto Rico. Thyroid. October 2013, 23(S1): A-1-A-114. Abstract 4.
  1. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. The Lancet Oncology. Published early online August 14, 2012. doi:10.1016/S1470-2045(12)70335-2.

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