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Oncology Advances Spring 2015

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Dana-Farber/Brigham and Women's Cancer Center | 7 Nearly all patients with anaplastic thyroid cancer will die from uncontrolled disease in the neck, often within a few months of diagnosis. Median overall survival is approximately five months. A team of surgeons, medical oncologists, cancer researchers and geneticists at Dana-Farber/Brigham and Women's Cancer Center is working to change those odds and improve outcomes for patients with this rare malignancy. The ultimate goal, said surgeon Matthew A. Nehs, MD, of the Division of Endocrine Surgery at Brigham and Women's Hospital (BWH), is to provide every patient who has been diagnosed with anaplastic thyroid cancer with therapy tai- lored to his or her specific tumor. Using a combination of pathology, histology, and molecular and genetic profiling, the team is working to identify the characteristics that make a specific tumor sensitive to a specific surgical approach, therapeutic radiation, chemotherapy, targeted therapy or combination. Clinical Approach "The strategy of the interdisciplinary team is first to identify who has a mass suspicious for an anaplastic or other aggres- sive form of thyroid cancer. Second, we biopsy the tumor to identify how aggressive it is and then do genetic testing to look at the DNA sequences to find where they have gone awry," Dr. Nehs said. Most patients will then go on to surgery followed by sys- temic chemotherapy or targeted therapy, and depending on the tumor location and extent, may also receive external beam radiation. Radioactive iodine ablation, a mainstay of therapy for stage III papillary and follicular thyroid cancers, is not an option in anaplastic cancers, because the tumors generally have an undifferentiated histology and are no longer able to take up radioactive iodine, Dr. Nehs said. "The lack of truly effective therapeutic options makes it im- perative to find new methods for treating this cancer. We are using the tremendous knowledge that has emerged over the last decade about DNA technology and molecular therapies and are applying it in a rational way to provide new therapies for this otherwise incurable disease," said Dr. Nehs. Resistance Profiling The potential benefits of this approach are illustrated by the case reported in a recent issue of the New England Journal of Medicine. (N Engl J Med 2014;371:1426-33). The study was led by Dana-Farber/Brigham and Women's Cancer Center physicians Dr. Jochen Lorch and Dr. Nikhil Wagle. The patient was a 57-year-old woman diagnosed with anaplastic thyroid cancer following a total thyroidectomy and central neck dissection in 2010. She had disease progression despite undergoing a course of weekly chemotherapy and Pinpointing Resistance Mutations in Anaplastic Thyroid Cancer concurrent radiation, and subsequently enrolled in a Phase II clinical trial of everolimus, an inhibitor of mTOR (the mam- malian target of rapamycin). She had a sustained response to everolimus 18 months in duration, but at the end of that time was again found to have progressive disease. An enlarged mediastinal lymph node was found to contain metastatic anaplastic thyroid cancer. The investigators used whole exome sequencing to look at the protein-coding ge- netic regions of the original tumor, the post-treatment tumor, and on a sample of the patient's blood. They found that prior to treatment, the tumor had a muta- tion that inactivated a tumor-suppressor gene but also re- sulted in activation of the mTOR pathway, which accounted for the tumor's sensitivity to everolimus. But after 18 months of therapy with the mTOR inhibitor, the tumor developed a somatic mutation in the gene encoding for mTOR that rendered everolimus and other agents in its class ineffective. The mutation was not present in the original tumor, but had arisen as tumor defenses evolved over the course of therapy – demonstrating the value of using tumor biopsies taken before, during, and after therapy to potentially identify novel mechanisms of drug resistance and point the way to alternative therapies. Matthew A. Nehs, MD Division of Endocrine Surgery, Brigham and Women's Hospital CT scan of a patient with anaplastic thyroid cancer whose tumor invades the critical structures of the neck and deviates the airway

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