Correspondence

BRAF V600E Inhibition in Anaplastic Thyroid Cancer

N Engl J Med 2013; 368:684-685February 14, 2013DOI: 10.1056/NEJMc1215697

Article

To the Editor:

Anaplastic thyroid cancer is a rare, highly virulent malignant condition that is associated with a median survival of only 5 months despite the best multidisciplinary care. BRAF is a serine- or threonine-specific protein kinase in the mitogen-activated protein kinase pathway, which regulates cell division and survival. The activating mutant protein BRAF V600E is detected in cutaneous melanoma, classic hairy-cell leukemia, papillary thyroid cancer, and about one quarter of anaplastic thyroid cancers.1,2 The BRAF inhibitor vemurafenib (PLX4032) improves survival among patients with metastatic melanoma3 and induces a response in patients with hairy-cell leukemia.4 In a mouse model, the BRAF inhibitor PLX4720 suppressed growth of mutated human anaplastic thyroid cancer.5

We describe a dramatic response to vemurafenib in a 51-year-old man with BRAF-mutated anaplastic thyroid cancer. He had a 1-month history of enlarging neck masses, hoarseness, dysphagia, and dyspnea. Thyroid masses and jugulodigastric lymphadenopathy were detected on physical examination, and unilateral vocal-cord paralysis and diffuse supraglottic edema were detected by means of direct laryngoscopy. On day 1, hypermetabolic thyroid masses; neck, mediastinal, and pulmonary hilar lymphadenopathy; and lung and bone lesions were detected by means of ¹⁸F-fluorodeoxyglucose–positron-emission tomography (¹⁸F-FDG–PET) and computed tomography (CT). Thyroidectomy and tracheostomy were performed on day 2; anaplastic thyroid cancer associated with papillary cancer was diagnosed.

Figure 1Chest Imaging of the Patient.

On days 4 and 10, low, radiosensitizing paclitaxel (at a dose of 45 mg per square meter of body-surface area) and carboplatin (at an area under the curve of 2) were administered. However, the patient had progressive dyspnea, and 60 to 100% inspired oxygen was administered through the tracheostomy to maintain pulse-oximetry readings of 92 to 94%, so he was moved to an intensive care unit. CT showed worsening pulmonary infiltrates and nodules. Vemurafenib at a dose of 960 mg orally twice daily was started empirically on day 10 with the patient's consent. His condition improved rapidly, radiation therapy to the neck and upper mediastinum was started on day 14, and he was discharged from the hospital on day 16 while receiving vemurafenib. Results of tumor analysis by means of real-time polymerase-chain-reaction assay later showed the BRAF T1799A (V600E) mutation. ¹⁸F-FDG–PET and CT of the chest on day 38 showed nearly complete clearing of metastatic disease (Figure 1).

This case suggests the benefit of BRAF inhibition in anaplastic thyroid cancer with activating BRAF mutations. Observations in more patients will be required to determine the frequency and durability of responses, mechanisms of potential resistance, and side effects. Meanwhile, we suggest that malignant tissue in patients with anaplastic thyroid cancer be tested for V600E and that vemurafenib be considered in confirmed positive cases and as empirical treatment in rapidly progressive cases pending results of mutation analysis.

Michael H. Rosove, M.D.
Parvin F. Peddi, M.D.
John A. Glaspy, M.D.
David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

5 References

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