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Medullary thyroid cancer is a rare cancer diagnosed in about 1,200 patients annually in the U.S. Because it¡¯s often a silent disease, many patients are diagnosed at an advanced stage.

Recently, there has been tremendous progress made in treating this disease with targeted therapy. We recently spoke with , to learn more. She shared some challenges in treating this disease and advances that have been made just this year, including findings from a clinical trial she presented at the (Abstract 1913O).

What causes medullary thyroid cancer?

Roughly 25% of patients have an inherited mutation in the RET gene, leading to a hereditary syndrome called Multiple Endocrine Neoplasia type 2A (MEN2A) or MEN2B. These are a constellation of other endocrine tumors, including medullary thyroid cancer and pheochromocytoma, an abnormal tumor of the adrenal glands.

With MEN2A, patients have parathyroid enlargement with unregulated parathyroid hormone secretion, causing high calcium and kidney stones and fractures. Patients with MEN2B don't have the parathyroid issue, but they can have these very striking mucosal neuromas or ganglioneuromas in their lips, tongue or other mucosal surfaces.

We don¡¯t really know how the remaining 75% of patients develop it. There is no known risk factor for medullary thyroid cancer, but we do know certain mutations can lead to the cancer developing. In 40% to 50% of patients with non-hereditary medullary thyroid cancer, it will be caused by an acquired RET mutation in the cells that become cancerous. Another 13% to 15% of patients will have an acquired RAS gene mutation, and in the remainder of patients, we have not identified any mutations.

What are common medullary thyroid cancer symptoms?

In many patients, medullary thyroid cancer can be silent for years before it comes to anyone¡¯s attention in a physical exam or with diagnostic imaging studies performed for other reasons.

If there are any symptoms, a patient might experience diarrhea and/or flushing caused by cancer cells producing proteins that stimulate intestinal activity or lead to dilation of the blood vessels.?

What is standard therapy for medullary thyroid cancer?

The standard of care is surgery ¨C a total thyroidectomy with removal of the lymph nodes in the region. If the disease has already spread to the lymph nodes, it¡¯s unlikely that a patient will be cured by surgery alone, but surgery is important because we don¡¯t want to risk the disease spreading near the airway or esophagus.

For most patients with medullary thyroid cancer, we follow them over time after surgery by monitoring tumor markers, specifically calcitonin and carcinoembryonic antigen (CEA). If those markers rise, we may perform additional imaging to see if the disease is progressing. If the disease is slow-growing, we don¡¯t offer additional therapy because we don¡¯t have any treatments that can cure patients.

How have targeted therapies improved treatment options for medullary thyroid cancer?

In the early 2000s, we started participating in clinical trials with drugs called tyrosine kinase inhibitors, which block proteins important for the cancer cells to grow and survive. A lot of them were targeting a protein called VEGFR, which is important in angiogenesis, or the formation of new blood vessels. Medullary thyroid cancer relies on that process.

Two of these inhibitors gained approval for medullary thyroid cancer ¨C vandetanib in 2011 and cabozantinib in 2012. This was the result of lots of hard work that we and other cancer centers participated in clinical studies. Although these drugs are not curative, they do result in responses in a significant portion of our patients. But there are a number of side effects associated with these medicines, including diarrhea, high blood pressure, skin peeling, mouth sores, weight loss and wound healing problems, amongst others. Experienced physicians can manage these, but most patients do experience some side effects.

How are new RET inhibitors changing the way we treat medullary thyroid cancer?

It has been exciting to be part of the development of a new generation of targeted therapies?that specifically block mutant RET, which is implicated in many medullary thyroid cancers. In collaboration with , and ??we have enrolled many patients on clinical trials for the RET inhibitors, pralsetinib and selpercatinib. MD Anderson does see a large number of patients with medullary thyroid cancers, and we were major contributors to these clinical studies.

The RET inhibitor selpercatinib was approved by the Food and Drug Administration in May 2020 for both lung cancers with RET alterations, as well as medullary thyroid cancer with activating RET mutations and other thyroid cancers with RET fusions.?

What is remarkable with these RET inhibitor drugs is that, in addition to the high percentage of responses we see with both drugs, they have a relatively lower side effect profile and are easier for patients to tolerate. I¡¯ve had many patients see their disease symptoms improve in a matter of days, and patients who were previously on vandetanib or cabozantinib comment on how the side effects are much more bearable.

But RET inhibitors still have side effects. The most common ones are high blood pressure and elevated liver enzymes. We also see low white blood cell levels. It¡¯s important to keep track of lab values for these patients and for them to track their symptoms and blood pressure, but they are overall better tolerated than the prior therapies.

Can you tell us about the latest data on the RET inhibitor pralsetinib?

At the 2020 ESMO Virtual Congress, I presented clinical trial data for the RET inhibitor pralsetinib specifically in patients with RET-mutant medullary thyroid cancer. This was recently approved for RET-altered lung cancer and is under new drug evaluation by the FDA for medullary thyroid cancer.

Overall, we saw very nice responses from patients with medullary thyroid cancer. There was a 60% response rate in patients who previously had been treated with vandetanib or cabozantinib. In patients without prior therapies, there was a 74% response rate. We are still evaluating many patients on this clinical trial, but the majority of patients remained on therapy at one year of treatment.

The side effects are also consistent with what I described earlier: it¡¯s well-tolerated overall.

What¡¯s next for medullary thyroid cancer research?

Although these RET inhibitors are promising, they¡¯re not a magic bullet. Some cancers do progress after therapy. There are a new generation of RET inhibitors in early phase clinical development that may be more effective at treating RET-mutant cancers. We may also consider combining a RET inhibitor with other therapies to target the cancer on multiple fronts. Additionally, we are exploring the possibility of combining other therapies for medullary thyroid cancer.

Of course, not every patient has a RET mutation. We see RAS mutations as I mentioned, and we have a major need for therapies that can target mutant RAS.

Immunotherapy has not shown much promise in treating medullary thyroid cancer either, at least not as a single agent. Perhaps by combining immune checkpoint inhibitors with a targeted therapy we could see benefits, but that needs to be investigated. We also need to continue research to understand mechanisms of resistance to understand what causes patients to progress on therapy.

It¡¯s an exciting time to be a physician in the field of medullary thyroid cancer. Over the last 15 years, we have had an explosion of clinical trials for this very rare cancer. I am very lucky to be a clinician in this environment working to improve care for our patients.

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Cancer research is advancing rapidly, and patients are benefitting from new therapies faster than ever. One example is a type of targeted therapy known as a RET inhibitor.

¡°A few years ago, we were starting to test these drugs, and now they¡¯re giving patients more time,¡± says Under Subbiah¡¯s direction, the Phase I/II ARROW and the Phase I/II LIBRETTO-001 clinical trials opened at MD Anderson in 2017 to investigate the RET inhibitors pralsetinib and selpercatinib for the first time in patients. The clinical trials¡¯ results led to accelerated approval by the Food and Drug Administration (FDA) only three years later.

Pralsetinib and selpercatinib are approved to treat patients with RET fusion-positive non-small cell lung cancer, RET fusion-positive papillary thyroid cancer and RET mutation-positive medullary thyroid cancer. Selpercatinib has since been approved to treat any cancer driven by a RET fusion.

RET mutations are different from RET fusions

The RET gene is vital in tissue development. As with any gene, when there are irregular changes, cells can develop into several health conditions, including cancer. These genetic abnormalities can fall into two categories: RET mutations and RET fusions.

When an abnormality occurs within the RET gene, it¡¯s known as a RET mutation. It can cause an overactive protein called an enzyme that triggers the cell to grow uncontrollably. Some people are born with a RET mutation, and it¡¯s been linked to a hereditary syndrome called multiple endocrine neoplasia type 2. The syndrome can lead to the formation of both cancerous and benign tumors that typically involve the body's hormone-producing glands. Examples include neuroendocrine tumors and pheochromocytoma, which is a tumor of the adrenal gland.

RET fusions, also known as RET gene rearrangements, differ from RET mutations in that the gene isn¡¯t changed. Instead, the gene¡¯s DNA fuses with a different gene, which activates an enzyme that sends a continuous signal to the cell, telling it to grow. This abnormal growth of the cells can develop into a tumor.

Pralsetinib and selpercatinib work to treat RET-altered cancers by targeting the enzyme that causes the cancer cells to grow.

Subbiah notes that RET mutations and RET fusions aren¡¯t the same things. ¡°This distinction can mean the world when knowing which RET inhibitor is available to you,¡± he says.

Pralsetinib and selpercatinib are approved to treat RET mutation-positive medullary thyroid cancer as well as RET fusion-positive non-small lung cancer and thyroid cancers. However, the FDA has approved selpercatinib to treat any cancer driven by a RET fusion. ¡°No matter where a tumor is located in the body, if it¡¯s driven by a rearrangement of the RET gene, selpercatinib can be used,¡± Subbiah says.

RET fusions can occur in a wide range of tumors

RET fusions are found in 2% of non-small cell lung cancers and 20% of thyroid cancers. Unlike RET mutations, they¡¯re also found in other types of cancer.

While enrolling patients in the clinical trials, Subbiah and his team found RET fusions in patients with pancreatic cancer, colorectal cancer, sarcomas and many other cancers.

Although RET fusions are found in less than 1% of all tumor types, they can be found in difficult-to-treat tumor types. ¡°It¡¯s like picking a needle out of a haystack, but we¡¯ve shown the benefit has been dramatic for these patients,¡± Subbiah says.

Next-generation sequencing and liquid biopsies detect RET alterations

RET mutations and RET fusions are detected with next-generation sequencing. The test is performed on a sample of tumor tissue that is removed by an interventional radiologist or by a surgeon.

However, Subbiah says that RET fusions can also be found using a newer approach known as liquid biopsy. ¡°It¡¯s an amazing technology that can detect an altered RET gene by the DNA shed into the bloodstream,¡± Subbiah says.

Although the liquid biopsy is specific, it¡¯s not sensitive, Subbiah says. If a RET mutation or RET fusion is detected with a liquid biopsy, the results are reliable. But if it¡¯s not detected, comprehensive molecular testing on tumor tissue is still necessary to rule out the genetic abnormality.

RET inhibitors are convenient and effective

When compared with other cancer therapies such as chemotherapy, immunotherapy and multikinase inhibitors, RET inhibitors are precise, safe and convenient. Pralsetinib and selpercatinib are taken as a pill once or twice a day, depending on which medication is prescribed. Since they are prescribed to patients whose cancers are fueled by RET alterations, patients experience fewer side effects with better results.

¡°These drugs represent a big shift in cancer therapeutics and a big step forward for precision medicine,¡± Subbiah says.

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Have you ever heard that people with thyroid disorders shouldn¡¯t eat certain vegetables? Or that you can treat an underactive thyroid gland with iodine supplements, and other thyroid disorders with hormone supplements??

If so, you¡¯re not alone. The only problem? None of these claims is accurate. So, before you take any action based upon them, we want to set the record straight on these and seven other common thyroid myths you might¡¯ve heard.?

Myth #1: If you¡¯re feeling tired, gaining weight, losing your hair and unable to concentrate, it must be your thyroid.

Fact: These symptoms can be linked to thyroid problems, but they are more often caused by aging, stress, lack of sleep, and poor nutrition. Many people begin experiencing these issues as they get older.??

These symptoms may also be caused by chemotherapy or cancer. In any event, they are not always due to thyroid problems.?

Myth #2: People with thyroid disorders should avoid certain vegetables.

Fact: Patients with certain types of thyroid cancer may be asked to follow a low-iodine diet temporarily while undergoing diagnostic testing or as a part of their treatment. But people with thyroid disorders can and should eat a healthy, well-balanced diet.??

Some people claim that cruciferous vegetables ¡ª including broccoli, cauliflower, Brussels sprouts and kale ¡ª can interfere with thyroid function. However, these vegetables are still part of a heathy, balanced diet, and you can eat them in moderation, even if you have a thyroid disorder.??

Myth #3: You can address thyroid disorders with over-the-counter hormone supplements.

Fact: Many over-the-counter thyroid supplements are not regulated by the Food and Drug Administration (FDA), and there is no oversight on these products, which are made with hormones taken from animals. There is also very little data on their long-term effects. So, we would not recommend them.?

Myth #4: You can fix an underactive thyroid with iodine supplements.

Fact: Diet alone cannot cure thyroid problems. But iodine supplements can negatively affect the thyroid gland if taken without a physician¡¯s supervision.??

Still, it is very rare for people to be iodine-deficient in the United States. Iodine is usually present in the soil where farmers grow their fruits and vegetables. Also, many foods produced here are fortified with iodine, including:?

• dairy products?
• eggs?
• bread?
• salt?
• seafood??

Myth #5: If you have hypothyroidism, you need a thyroid ultrasound.

Fact: Having hypothyroidism does not automatically mean you need a thyroid ultrasound. You only need an ultrasound if you have signs of a thyroid nodule or other concerns that require further evaluation.??

Most people with hypothyroidism do not need routine ultrasounds.