BRAF Mutation Varies in Thyroid Cancer

RAF Mutation Varies in Thyroid Cancer

Published: Aug 26, 2013

By  Nancy Walsh , Staff Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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Action Points

• BRAF mutation was found to be an independent predictor of central lymph node metastases in the overall cohort of patients with papillary thyroid cancer, including those with aggressive or follicular subtypes.
• Note, however, that this relationship lost significance when only classical variant papillary thyroid cancer was included in the analysis.

Whether BRAF mutations can be used to determine the likelihood of lymph node metastases of papillary thyroid cancer remains unclear because of the mutation's strong association with aggressive subtypes of the cancer, researchers reported.

In a multivariate analysis of almost 400 patients with any thyroid cancer subtype who underwent total thyroidectomy and central lymph node dissection, independent associations with lymph node metastases were found for BRAF mutations (OR 2.37, 95% CI 1.41-3.98, P=0.001), tumor size greater than 2 cm (OR 1.62, 95% CI 1.01-2.61, P=0.045), and extra-thyroid extension (OR 2.77, 95% CI 1.58-4.86, P<0 .001="" a="" according="" href="http://www.hopkinsmedicine.org/profiles/results/directory/profile/0007252/martha-zeiger" style="color: #003f85; outline-style: none; text-decoration: none;" target="_blank" to="">Martha A. Zeiger, MD

, of Johns Hopkins School of Medicine, and colleagues.

However, when the analysis was limited to the most common classical variant, papillary thyroid cancer, and the highly aggressive subtypes that are closely associated with BRAFmutations such as the follicular variant were excluded, there was no significant association between the mutation and lymph node metastases (P=0.244), the researchers reported in theJournal of Clinical Endocrinology & Metabolism.

"Regarding [papillary thyroid cancer] as a homogeneous entity could lead to miscalculations and/or misunderstandings of relationships between independent predictors, such as BRAFstatus, and dependent outcomes, including [lymph node metastases]," Zeiger and colleagues wrote.

While papillary thyroid cancer usually carries a good prognosis, patients with lymph node involvement at the time of diagnosis are at increased risk for recurrence.

Whether or not all patients should undergo bilateral prophylactic lymph node dissection following thyroidectomy has been a subject of controversy, with advocates arguing that some studies have found occult nodal metastases in as many as 80% of patients, and opponents suggesting that most occult micrometastases aren't clinically important.

"Because of the controversy surrounding the appropriate surgical management of [papillary thyroid cancer], more accurate risk stratification is needed to guide treatment," the researchers stated.

They noted that "molecular tumor profiling" has become increasingly popular as a diagnostic and prognostic aid, with the BRAF V600E mutation that activates the MAPK pathway being a focus of considerable attention.

This mutation also has been linked with other types of cancer, such as leukemia, melanoma, and lung cancer.

But the evidence for BRAF mutations as being predictive in thyroid cancer has been conflicting, and studies have had limitations such as selection bias.

Therefore, to clarify the prognostic utility of BRAF mutations for lymph node metastases in thyroid cancer, Zeiger and colleagues conducted a retrospective study of all 388 patients who underwent thyroidectomy followed by central lymph node dissection in four tertiary care centers between January 2009 and December 2011.

A total of 315 of the patients had classical variant papillary thyroid cancer, 41 had the follicular variant, 31 had the tall cell variant, and one had a poorly differentiated tumor.

Among the classical variant group, more than three-quarters were women, and mean age was 46. The mean tumor size was 1.89 cm, and 80% had the BRAF V600E mutation.

The multivariate analysis limited to this group found significant positive associations for lymph node metastases with tumor size greater than 2 cm (OR 2.04, 95% CI 1.20-3.48,P=0.009) and extra-thyroid extension (OR 2.20, 95% CI 1.18-4.09, P=0.013), but not with theBRAF mutation.

Age of 45 and older had a significant negative association with lymph node metastases (OR 0.41, 95% CI 0.25-0.67, P<0 .001="" p="">

In the subgroup with the follicular variant subtype, strong independent associations with lymph node metastases were found for the BRAF mutation (OR 9.69, 95% CI 1.05-89.33,P=0.45) and extra-thyroid extension (OR 34.04, 95% CI 1.4-827.51, P=0.030).

In the other subgroup, which included the aggressive forms such as the tall cell variant, 71% of patients with the BRAF mutation had metastases to the lymph nodes, and none of the patients without the mutation had metastatic disease.

Bivariate analysis in this subgroup found that the BRAF mutation was the only independent predictor of lymph node metastases (P=0.006).

These findings suggest that "BRAF mutation may be differentially associated with the risk of [lymph node metastases] across [papillary thyroid cancer] subtypes," the researchers stated.

"Further research is warranted before factors such as BRAF mutation are included in treatment algorithms that do not take into account tumor histology," they cautioned.

This additional research should include prospective studies involving multiple centers, they added.

Limitations of the study included small numbers of patients with the aggressive subtypes and its retrospective design.

The study was supported by the Johns Hopkins University School of Medicine.

The authors reported no financial disclosures.

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Bayer's Nexavar gets priority review as thyroid cancer drug - Yahoo! News

FRANKFURT (Reuters) - Bayer's cancer drug Nexavar was given priority review status by U.S. healthcare regulators for the oral drug's use against a difficult-to-treat type of thyroid cancer, the company said on Tuesday.

The U.S. Food and Drug Administration aims to complete the priority review within six months, rather than the standard review of about 10 months, Bayer said.

Bayer and development partner Onyx Pharmaceuticals are seeking a wider use for Nexavar to include treatment of patients with thyroid cancer that returned despite previous surgery and treatment with radioactive iodine, a group with a particularly poor prospect of survival.

Nexavar is already approved to treat liver as well as kidney cancer and it is also being tested on breast cancer patients.

(Reporting by Ludwig Burger)

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Thyroid Cancer - Symptoms, Causes, Treatment, Exams and Tests for Thyroid Cancer

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What is thyroid cancer?

Thyroid cancer is a disease that you get when abnormal cells begin to grow in your thyroid gland . The thyroid gland is shaped like a butterfly and is located in the front of your neck. It makes hormones that regulate the way your body uses energy and that help your body work normally.

Thyroid cancer is an uncommon type of cancer. Most people who have it do very well, because the cancer is usually found early and the treatments work well. After it is treated, thyroid cancer may come back, sometimes many years after treatment.

What causes thyroid cancer?

Experts don't know what causes thyroid cancer. But like other cancers, changes in the DNA of your cells seem to play a role. These DNA changes may include changes that are inherited as well as those that happen as you get older.

People who have been exposed to a lot of radiation have a greater chance of getting thyroid cancer.

A dental X-ray now and then will not increase your chance of getting thyroid cancer. But past radiation treatment of your head, neck, or chest (especially during childhood) can put you at risk of getting thyroid cancer.

What are the symptoms?

Thyroid cancer can cause several symptoms:

• You may get a lump or swelling in your neck. This is the most common symptom.
• You may have pain in your neck and sometimes in your ears.
• You may have trouble swallowing.
• You may have trouble breathing or have constant wheezing.
• Your voice may be hoarse.
• You may have a frequent cough that is not related to a cold.

Some people may not have any symptoms. Their doctors may find a lump or nodulein the neck during a routine physical exam.

How is thyroid cancer diagnosed?

If you have a lump in your neck that could be thyroid cancer, your doctor may do abiopsy of your thyroid gland to check for cancer cells. A biopsy is a simple procedure in which a small piece of the thyroid tissue is removed, usually with a needle, and then checked.

Sometimes the results of a biopsy are not clear. In this case, you may need surgery to remove all or part of your thyroid gland before you find out if you have thyroid cancer.

How is it treated?

Thyroid cancer is treated with surgery and often with radioactive iodine. It rarely needs radiation therapy or chemotherapy. What treatment you need depends on your age, the type of thyroid cancer you have, and the stage of your disease. Stage refers to how severe the disease is and how far, if at all, the cancer has spread.

Your doctor may also remove lymph nodes in your neck to see if cancer has spread beyond the thyroid

Finding out that you have cancer can be overwhelming. It?s common to feel scared, sad, or even angry. Talking to others who have had thyroid cancer may help. Ask your doctor about cancer support groups in your area.

Can thyroid cancer be prevented?

Most thyroid cancer cannot be prevented.

One rare type of thyroid cancer, called medullary thyroid cancer (MTC), runs in families. A genetic test can tell you if you have a greater chance of getting MTC. If this test shows that you have an increased risk, you can have your thyroid gland removed to prevent thyroid cancer later in life.

Frequently Asked Questions

Learning about thyroid cancer:	What is thyroid cancer? What causes thyroid cancer? What are the symptoms of thyroid cancer? What increases my risk for thyroid cancer? Can I prevent thyroid cancer? When do I need to see my doctor?
Being diagnosed:	How will my doctor diagnose thyroid cancer? What is a thyroid scan? What is a thyroid ultrasound? What types of blood tests will I need? Will I need a thyroid biopsy?
Getting treatment:	How is thyroid cancer treated? What type of medicines will I need to take? Will I need surgery? Will I have to have radiation therapy?
Living with thyroid cancer:	How can I cope with the side effects of treatment? What happens if thyroid cancer comes back?

Article: Experts Call for Redefinition of 'Cancer'

Many growths are slow to progress and nonlethal, only leading to unnecessary treatment, panel says

WebMD News from HealthDay

By E.J. Mundell

HealthDay Reporter

TUESDAY, July 30 (HealthDay News) -- A panel of experts commissioned by the U.S. National Cancer Institute says that the word "cancer" may need to be redefined to prevent overdiagnosis and overtreatment of conditions that are often not lethal.

Writing in the July 29 online edition of the Journal of the American Medical Association, the experts say that widespread cancer screening programs turn up too many growths that would not progress to a lethal stage and are considered "indolent."

Most patients do not understand that distinction, however, and "the word 'cancer' often invokes the specter of an inexorably lethal process," wrote Dr. Laura Esserman of the University of California, San Francisco, Dr. Ian Thompson Jr. of the University of Texas Health Science Center at San Antonio, and Dr. Brian Reid of the Fred Hutchinson Cancer Research Institute in Seattle.

Cancer can take "multiple pathways," the three say, "not all of which progress to metastases and death, and include indolent disease that causes no harm during the patient's lifetime."

This re-examination of what constitutes a cancer diagnosis has been spurred by the explosion over the past few decades of sophisticated screening measures such as the mammogram, colonoscopy and the PSA blood test (for prostate cancer). All were heralded as potentially lifesaving, and many predicted that widespread adoption of these tests would catch disease early and cause cancer rates to fall.

But the cancer screening story has turned out differently, the panel noted, because many of the lesions picked up on screening have turned out to be indolent.

"Screening for breast cancer and prostate cancer appears to detect more cancers that are potentially clinically insignificant," the experts said. The same might be said for screens for thyroid cancers and melanomas -- certainly, lives have been saved because tumors were detected and treated, but "the detection of indolent disease" has risen, too, the panelists wrote.

Issues like this have played out in recent years. The United States Preventive Services Task Force, an influential government panel, caused a furor in 2009 when it called for the abandonment of regular mammography screening for women under 50, reasoning that the benefits of screening for younger women were outweighed by the risks. The same panel also rejected the widespread use of the PSA test, noting that it too often picked up slow-growing lesions that might never harm men's health.

According to the experts writing in JAMA, the best-case scenario for cancer screening is when the tumor is slow-growing but also typically progressive. Colon cancer often acts in this way, the team noted, and colonoscopy has become an "effective" screening program.

In the meantime, however, "overdiagnosis" occurs. The experts say a redefinition of cancer may be needed to quell patient fears over indolent lesions and curb overdiagnosis and overtreatment.

"Use of the term 'cancer' should be reserved for describing lesions with a reasonable likelihood of lethal progression if left untreated," they wrote. Other growths would be classified in a lesser category, "indolent lesions of epithelial origin" (IDLE).

A change in mindset may also be needed for patients and health care workers alike. "Physicians, patients and the general public must recognize that overdiagnosis is common and occurs more frequently with cancer screening," the team wrote.

The recommendations are sure to spur debate, but one outside expert said that debate may be what is needed on this issue.

"We're still having trouble convincing people that the things that get found as a consequence of mammography and PSA testing and other screening devices are not always malignancies in the classical sense that will kill you," Dr. Harold Varmus, director of the National Cancer Institute, told The New York Times. "Just as the general public is catching up to this idea, there are scientists who are catching up, too."

But not everyone agrees. Dr. Larry Norton is medical director of the Evelyn H. Lauder Breast Center at Memorial Sloan-Kettering Cancer Center in New York City. He said the problem is that even some relatively indolent breast growths, such as ductal carcinoma in situ (DCIS), can go on to become progressive, lethal cancers.

"Which cases of DCIS will turn into an aggressive cancer and which ones won't?" he told the Times. "I wish we knew that. We don't have very accurate ways of looking at tissue and looking at tumors under the microscope and knowing with great certainty that it is a slow-growing cancer."