Genomic Analysis of Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) demonstrates a myriad of genomic alterations, which could represent targets for therapy, according to the results of a study published in Head & Neck.

“Although the genomic landscape of DTCs [differentiated thyroid cancers] such as papillary thyroid cancer (PTC) is well described, the biology and oncogenic drivers of ATC are poorly understood,” wrote authors, led by Saad A. Khan, MD, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas. “Identifying the true prevalence of genetic abnormalities is challenging, as few cancer centers see enough cases to perform a comprehensive analysis on more than a handful of cases.”

In an exclusive interview with Cancer Network, Jennifer M. Perkins, MD, MBA, Associate Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Duke University, Durham, reflected on the disease. “Anaplastic thyroid cancer is such a devastating disease that is almost uniformly fatal that anything we can discover in terms of targeted therapies may be moving towards a clinical implication that could have an impact on this population. It’s also helpful to know how it differs by age of presentation and by the difference in mutations with traditional differentiated thyroid cancer,” she said.

In the current study, researchers performed comprehensive genomic profiling on 90 ATC specimens with identified base substitutions, short insertions and deletions, amplifications, copy number alterations, and genomic rearrangements in as many as 315 cancer-related genes and 28 genes commonly rearranged in cancer.

The median patient age was 65 years (range, 33-86 years, 50 men). Per each case, there was a mean of 4.2 genomic alterations (range, 1-11), including the following: TP53 (66%), BRAF (34%), TERT (32%), CDKN2A (32%), and NRAS (26%). Notably, BRAF V600E and NRAS/HRAS/KRAS alterations were not found in the same patients. When broken down by age, BRAF, CDKN2A, PIK3CA, and JAK2 were more common in those >70 years of age; whereas, myc, PTEN, and NRAS were more frequent in those ≤50 years.

Previous research has demonstrated that akin to DTC, many cases of ATC demonstrate BRAF and RAS abnormalities; however, a pathognomonic ATC genomic marker has yet to be elucidated. The current study centered on 90 ATC patient samples from the FoundationOne platform, which documented genetic abnormalities in 583 DTC cases and 196 ATC cases. Novel aspects of the current study include a focus on patient-age variation, as well as a closer look at mutations of therapeutic importance.

“There may be distinct pathways to the development of ATC in older vs younger patients. ATC in older individuals may represent cancer that arises or transforms from long-standing BRAF-mutated DTC that then dedifferentiated, whereas in younger patients there may have been de novo development of ATC without the concurrent presence of DTC with its high rates of BRAF mutation,” wrote the study authors.

Dr. Perkins pointed to strengths of the study. “I think parsing it out by age in what mutations were most common is helpful. It also raises awareness about getting genomic profiling in patients with these aggressive, unfortunate cancers because now it may impact therapeutic choices. We have a BRAF and MEK inhibitor that are approved so knowing the genetic profile of ATC could change the path of treatment,” she said.

“This study elaborates on potential targeted therapy for patients with ATC. Some of these agents have been in trials while others approved. Some of the genomic profiling findings in this study are not new. Some of the rarer things they found in their cohort are not very prevalent mutations,  so we will have to see how much clinical impact that will have in future studies,” she continued.

Dr. Perkins encouraged other clinicians to consider the findings of this study closely. “It’s really important for people who are not at large academic centers to be evaluating the literature. Because if you are out in the community and don’t have access to clinical trials or genomic profiling for these patients, if possible, the patients should be seen at centers of excellence because there’s potentially more options for care such as targeted therapy and/or clinical trials.”

Looking forward, the current findings need validation of genomic analysis in a higher-powered study using whole genome or exome techniques to add to the targeted panel approach utilized in the current study, according to the authors. Furthermore, future clinical trials could identify patients with genomic alterations with worse prognosis thus resulting in escalated treatments. Conversely, patients with better prognosis could have treatments scaled back.