In the largest-ever study of advanced thyroid cancer genetics, researchers have identified key potential drivers of advanced differentiated and anaplastic thyroid cancers, with the findings suggesting important roles of strategies such as immunotherapy and the oral tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai) in the clinical management of patients with aggressive forms of the cancers.
“As a clinician, I learned from this study that every patient with advanced thyroid cancer that we consider for systemic therapy should be genotyped — knowledge of genetic background may affect how we treat that patient,” first author Nikita Pozdeyev, MD, PhD, of the University of Colorado Cancer Center, in Aurora, explained in a press release.
“There are many drugs targeting many genetic changes that are approved for other cancers, which we would not usually think to use in thyroid cancer. Some of the findings in this paper will potentially change that,” he added.
In general, “genetic alterations associated with anaplastic transformation are of prognostic significance,” he added. “Patients with tumors harboring these mutations deserve more thorough evaluation and aggressive treatment.”
The results were published online in Clinical Cancer Research.
Samples From Around US Gave Sufficient Analytical Power
Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, with an estimated 60,000 new cases per year in the United States. Most patients with DTC are cured by surgery with or without radioactive iodine, so analysis of early stage thyroid cancers is most often not necessary, but there is significant morbidity and mortality associated with distant metastatic disease and anaplastic transformation.
Anaplastic thyroid cancer (ATC) is an uncommon but aggressive form of thyroid cancer associated with very poor outcomes.
At present, systemic therapies for advanced DTC and ATC are given regardless of the tumor’s genetic landscape, in part because of insufficient knowledge of genetic events underlying thyroid cancer progression or anaplastic transformation.
So Pozdeyev and colleagues set out to define the genetic landscape of these advanced cancers and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.
They analyzed tumor samples submitted by oncologists from around the United States and were able to examine large numbers of these cancers. The team genetically profiled 583 advanced DTC samples and 196 ATC samples, a large number for a cancer which is quite rare.
This gave them “sufficient analytical power to use machine learning and statistical analysis to make sense of the data,” Pozdeyev says.
ATC had significantly more genetic alterations per tumor than any other thyroid cancer subtype.
Novel Mechanism of Malignant Transformation
Among the key findings were that several subsets of advanced DTC and ATC showed defective DNA mismatch repair mechanisms, setting up conditions for an accumulation of higher numbers of mutations.
That distinction is important in terms of potential treatment, as having a high mutation burden in tumors is a biomarker indicative of patients who would likely benefit from immunotherapy, such as “treatment with immune checkpoint inhibitors,” for example, pembrolizumab and nivolumab, Pozdeyev told Medscape Medical News.
The researchers also showed that one of these mutations, MMR deficiency, could play a key role in thyroid cancer progression.
“MMR deficiency, when caused by loss-of-function mutations in MMR genes, was independent of mutations in BRAF, RAS, and RET oncogenes and may represent a novel mechanism of malignant transformation in thyroid cancer,” the authors report.
ATC Subset Susceptible to Lenvatinib
The analysis, using combined data from the next-generation sequencing assays MSK-IMPACT and FoundationOne, also showed that amplifications of the genes KDR, KIT, and PDGFRA are seen in a subset of anaplastic cancers.
Those genes play key roles in the encoding of receptor tyrosine kinases, which allow for cancer cell growth and proliferation and, importantly, are targeted by the multikinase inhibitor lenvatinib, which is already approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma and refractory DTC that has progressed despite radioactive iodine therapy.
To further evaluate the potential effects of lenvatinib, the researchers conducted in vitro experiments by treating a cohort of thyroid cancer cell lines with the drug.
They found that the subset of ATC cell lines with amplification of the KDR, KIT, and PDGFRA genes was indeed uniquely sensitive to lenvatinib, suggesting the drug may have a role in the treatment of these types of tumor.
Tests Assess Targeted Panels of Cancer Genes in Clinical Setting
Although the MSK-IMPACT and FoundationOne tests do not use whole exome or whole genome data, they have an important advantage of evaluating a targeted panel of cancer-associated genes with high sequencing depth, Pozdeyev said.
“Fewer genes are sequenced (compared with whole exome or genome), but each one is sequenced much more thoroughly,” he explained.
“As a result, low frequency alternate alleles can be detected, which is very important for impure specimens (contaminated by nontumor cells), such as anaplastic thyroid cancers.”
And a key advantage of the MSK-IMPACT and FoundationOne tests is that they are used in the clinical setting, whereas whole exome and whole genome sequencing are currently only research tools.
“Thus, our findings can be directly translated into clinical practice,” Pozdeyev stressed.
“There is an advantage of studying aggressive thyroid cancers. These are the cancers that kill, and knowing the genetic background of the tumor helps with both prognosis and treatment,” he underscored.
The study was supported by a research grant from the American Thyroid Association/Thyroid Cancer Survivors’ Association and a Paul R. Ohara II Seed grant to Pozdeyev. Pozdeyev reported no other relevant financial relationships. Disclosures for the other authors are listed in the article
Clinical Cancer Research. Published online April 2, 2018. Abstract
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