Certain genetic alterations associated with anaplastic transformation in thyroid cancer made patients sensitive to the multikinase inhibitor lenvatinib.
It may be time to consider genotyping all patients with advanced thyroid cancer before initiating systemic therapy. Researchers from the University of Colorado, Denver, found selected anaplastic thyroid cancers responded to lenvatinib, an agent already used in the treatment of renal cell cancer (RCC). In a study published in Clinical Cancer Research, researchers examined genetic alterations in a large cohort of thyroid cancers and found many novel genetic events previously not seen in thyroid cancer.
Study investigator Nikita Pozdeyev, MD, PhD, from the University of Colorado’s Division of Bioinformatics and Personalized Medicine, said genetic alterations associated with anaplastic transformation are of prognostic significance. “Patients with tumors harboring these mutations deserve more thorough evaluation and aggressive treatment,” Dr. Pozdeyev told Cancer Network. “We found several novel potential pharmacogenetic associations in thyroid cancer, such as KDR/KIT/PDGFRA amplification, that makes thyroid cancer cells sensitive to the multikinase inhibitor lenvatinib.”
The researchers analyzed the genetic profiles of 583 patients with advanced differentiated thyroid cancer and 196 with anaplastic thyroid cancer. The anaplastic thyroid cancers had more genetic alterations per tumor compared with other thyroid cancer types. However, pediatric papillary thyroid cancers had fewer genetic alterations per tumor compared with other thyroid cancer types.
DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated and anaplastic thyroid cancers. In addition, the researchers found there was an association between KDR, KIT, and PDGFRA amplification and the sensitivity of thyroid cancer cells to lenvatinib in vitro.
Lenvatinib is already approved by the FDA for treating kidney cancer. The researchers treated a cohort of thyroid cancer cell lines with lenvatinib and discovered that the cell line with amplification of KDR, KIT, and PDGFRA was especially sensitive to the drug. The team theorizes that treatment with lenvatinib may be a viable strategy against a subset of anaplastic thyroid cancer patients. “Using cluster analysis, we demonstrated genetic heterogeneity of anaplastic thyroid cancer and proposed three major subtypes of ATC,” said Dr. Pozdeyev.
He said these findings point to an updated schematic of genetic evolution from normal follicular cells, to low-risk thyroid cancer, to high-risk thyroid cancer, and ultimately to anaplastic transformation. “Because of the large size of the study, we were able to detect rare novel genetic alterations in thyroid cancer and use statistical analysis and machine learning to identify subtype-specific mutations and copy number changes,” said Dr. Pozdeyev.
According to Dr. Pozdeyev, genetic analysis of early-stage thyroid cancer is often not necessary. He said these tumors can be successfully treated with surgery and radioactive iodine. However, that is not the case with metastatic disease, and genetic information is paramount. Dr. Pozdeyev said there are a variety of agents targeting many genetic mutations approved for other cancers, which may have a role in treating certain thyroid cancers.