Promise for the Future of Metastatic Thyroid Cancer

Larisa Greenberg, MD

In thyroid cancer, multiple targeted therapies have improved outcomes for patients. The advancements include progress for patients with metastatic disease, but questions about when to initiate treatment and how to mitigate toxicities from tyrosine kinase inhibitors remain.

According to Larisa Greenberg, MD, the future looks promising for thyroid cancer treatment, despite the unanswered questions. Ongoing clinical trials are investigating the role of immunotherapy, novel targets for thyroid cancer, and optimal treatment initiation.

“I think they further development in molecular biology for their advances in the development of targeted therapy and immunotherapy. We’ll not only meet checkpoint inhibitors or anti-CTLA4 antibodies, but other modes of immunotherapies. Hopefully vaccines may bring better treatment options and potentially some patients could be cured from metastatic disease,” said Greenberg, a medical oncologist at Allegheny Clinic Medical Oncology of Allegheny Health Network.

In an interview with Targeted Oncology™, Greenberg, discussed the current state of thyroid cancer, challenges, and where the field is headed in the near future.

TARGETED ONCOLOGY: Can you discuss the current state of thyroid cancer? What biomarkers are important in this space?

Greenberg: Thyroid cancer is not just 1 disease; it consists of different subtypes. The most frequent subtype of thyroid cancer is differentiated thyroid cancer, and that approximately constitutes 85% of all thyroid cancer. The next common is medullary thyroid cancer, which accounts for about 10%. The next and the most aggressive is anaplastic thyroid cancer. It is very rare, with only 1% of patients, but very devastating. The survival of thyroid cancer at 20 years depends again on the set on aggressiveness of the disease, etc. For example, for patients who have differentiated thyroid cancer, their 10-year survival is 45% and for patients with medullary thyroid cancer, the 10-year survival is about 10%. Anaplastic thyroid cancer is only 6 months, unfortunately.

To our knowledge, the molecular pathogenesis of thyroid cancer is evolving, and the molecular profiling of the tumor cancer now constitutes an important part of the treatment for different subtypes of thyroid cancer. A key question is, how do we treat thyroid cancer in general? In the earliest stage of thyroid cancer, surgery is usually the mainstay of treatment. In some cases, the surgery has to be followed by radioactive iodine treatment. Then, a lot of patients have localized thyroid cancer and are cured by some developed metastatic disease. When it happens, some of these patients may become iodine insensitive or iodine resistant. Radioactive iodine treatment for differentiated thyroid cancer may not be the case and then we have to look into other treatment options. That’s where the molecular profiling of the tissue the biopsy tissue or surgical sample becomes paramount.

By performing molecular profiling, we are able to find a molecular abnormality that is expressed on a thyroid cancer cell and potentially use it for treatment as targeted therapy. The different molecular abnormalities that can be found in differentiated thyroid cancer patients and other types of thyroid cancer are NTRK fusion, RET mutations, BRAF mutations, etc.

What have been some recent advances in the treatment landscape?

In the last 5 to 10 years, we made incredible progress in treatment of metastatic thyroid cancer. The first thing that happens when we have a patient who has metastatic disease is we have to evaluate the performance status of the patient or comorbidities. We also must look at the rate of growth and size of metastatic lesions. If a patient is asymptomatic, the size of the lesions or metastatic lesions is less than 2%, and the rate of advancing of metastatic disease is less than 20%. Over a period of years, we would tend to observe these patients and not to start them on any specific treatment. However, if patient is symptomatic and the rate of the progression of the metastatic disease is more than 20% over a period of year, then we have to think about different treatment options. Many of these patients become radioactive iodine resistant. Therefore, the radioactive iodine treatment is not feasible to employ for the treatment. The other treatment options will be based on molecular profiling of the tumor.

The way we look at the patients with metastatic thyroid cancer is they could have the targetable abnormalities, or they may. If they don't have any targetable abnormalities, we have medications that were approved in the last 10 years. Some of them are within the last 5 years and can be used in initial treatment of these patients. This is usually from tyrosine kinase inhibitors, and the ones who do not target any specific area are the multikinase inhibitors.

What research is ongoing that might improve thyroid cancer treatment soon?

There are ongoing clinical trials looking at different treatment options. One of them for example is investigating the role of immunotherapy in treatment of patients with metastatic thyroid cancer. As of today, we don't have significant data indicated that immunotherapy is 1 of the good treatment choices. However, the trials are ongoing. Specifically, trials are looking at PD-L1 and anti-CTLA4 inhibitors. Another clinical trial is looking at combination of targeted therapy, specifically Lenvatinib [Lenvima] in combination with CTLA1 inhibitors.

The other interesting concept in research that is ongoing in patients who have become radioiodine resistant, is trying to convert those patients from resistant disease to being able to be responsive to iodine treatment. For this matter, there are clinical trials using targeted therapy. I think it's a very interesting concept and quite fascinating.

Then, there are clinical trials that are looking at combination of targeted therapy, specifically BRAF and MEK medications in combination with immunotherapy in patients who express BRAF mutation. The other interesting concept that is ongoing is how I feel the patients who are treated with BRAF inhibitors they eventually become refractory to the drugs and how to fight this. In clinical trials, there is research on PI3K inhibitors, HER 2/3 inhibitors, JAK/STAT pathway activation, and other strategies.

What are the key challenges that oncologists are facing right now, when treating patients with thyroid cancer?

There are always challenges in treating anybody who has metastatic disease. I think, 1 is how to correctly select the patient who should initiate systemic treatment. The patients with metastatic disease may have quite prolonged nature and may be asymptomatic for a long period of time, and never become ill enough that the physician would consider initiation of treatment. Because if or when we start, the treatment is ongoing, we cannot stop the treatment, at least now. I think the careful selection of the patients sometimes become a challenge, especially if you have a patient who has very small amount of disease, but rapidly progressive disease.

The other challenge is the management of tyrosine kinase inhibitor class of drugs and some of the side effects. They can be quite significant, quite severe. It requires very careful monitoring of the patients and self-reporting of the side effects from the patient to the physician.

How do you envision thyroid cancer care evolving over the next 5-10 years?

I think they're further development in molecular biology for their advances in the development of targeted therapy and immunotherapy. We’ll not only meet checkpoint inhibitors or anti-CTLA4 antibodies, but other modes of immunotherapies. Hopefully vaccines or deals may bring better treatment options and potentially maybe some patients could be cured from metastatic disease.