Will Large Gene Study Help to Personalize Thyroid Cancer Tx?

The largest study to date on thyroid cancer genetics, published in Clinical Cancer Research, found a subset of thyroid cancers carry a high mutational burden and identified specific genes that may drive certain thyroid cancer subtypes. The  findings suggest distinct new subtypes of anaplastic thyroid cancer (ATC) and possible avenues for treatment. Nikita Pozdeyev, MD, from the University of Colorado Cancer Center, Aurora, and coauthors examined data (genetic profiles generated with targeted next-generation sequencing cancer-associated gene panels) on 583 patient samples of advanced differentiated thyroid cancer (DTC) and 196 samples of ATCs.

In the study, more genetic alterations per tumor were found in anaplastic thyroid cancers. In pediatric papillary thyroid cancer, Pozdeyev and colleagues found fewer genetic alterations per tumor, compared with other thyroid cancer types. In a subset of differentiated thyroid cancers and anaplastic thyroid cancers, high mutational burden was linked to DNA mismatch repair deficit and activity of APOBEC cytidine deaminases.

Anaplastic thyroid cancers also had copy number losses and mutations of CDKN2A and CDKN2B; amplification of CCNE1; amplification of receptor tyrosine kinase genes KDR, KIT, and PDGFRA (which, in vitro, was associated with sensitivity of thyroid cancer cells to lenvatinib); amplification of immune evasion genes CD274, PDCD1LG2, and JAK2; and activating point mutations in small GTPase RAC1.

Based on the data, the authors believe there are three genetically distinct types of anaplastic thyroid cancer.

The investigators wrote that they had uncovered “[m]any novel genetic events previously not seen in thyroid cancer,” as well as genetic alterations that are associated with anaplastic transformation, shedding new light on the genetic evolution of thyroid cancer. The findings are expected to help better tailor targeted therapies.

However, it is too early to know the ultimate impact on patient outcomes, according to Rajeev Sharma, MBBS, MD, from the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York. “I think we are at a crossroads in thyroid cancer therapy,” Dr. Sharma told Cancer Network. “In general, most of the thyroid cancers are well differentiated, with excellent prognosis and overall survival. Identifying the genetic alteration is a leap forward in cancer genomics, especially for subsets of patients with metastatic and anaplastic thyroid cancer. Whether genetic analysis of these cancers will improve overall survival or not, only time will tell. More prospective clinical studies are needed to evaluate this issue in coming years.”

Dr. Sharma said that over the last few years, gene- and molecular-based assays like Thyroseq and Afirma gene expression classifier have prevented unnecessary surgery in a subset of patients with thyroid nodules whose status was indeterminate based on fine-needle aspiration biopsy.

The current study findings also open the possibility of one day being able to better tailor thyroid cancer treatment. “For more advanced metastatic thyroid cancers, a few drugs that target intracellular molecular pathways and [are] indicated for other cancers like liver cancer are approved (lenvatinib, vandetanib, and sorafenib),” Dr. Sharma told Cancer Network. “Hopefully in future, patients with advanced refractory and anaplastic cancer might be well served with targeted gene therapy once we know more about genetic abnormalities in [these] tumor cells.”

Devaprabu Abraham, MD, from the Division of Endocrinology at the University of Utah, Salt Lake City, where he is an adjunct professor of surgery and pathology, agrees with Dr. Sharma. He said it is too soon to say whether identifying new genetic mutations in certain patients will lead directly to improved outcomes.

“Mutation testing is used in the diagnosis and to guide therapy in thyroid cancer patients,” he said. “Will genetic tests improve overall survival, when [thyroid cancer] is already the least lethal epithelial cancer? Impossible to tell without long-term studies. However, in select high-risk patients, it will no doubt help tailor targeted therapies better.”