NEW YORK – Researchers have discovered that TERT promoter mutations, a biomarker previously implicated in a number of cancer types, may help identify high-risk patients with oral cavity cancers and serve as a target for precision oncology drugs.
In a study published last week in JCO Precision Oncology, the researchers from Memorial Sloan Kettering Cancer Center sought to determine why oral cavity squamous cell carcinomas demonstrated unique clinical behavior compared to other head and neck cancers.
Oral cavity cancer, which includes tumors in the tongue, retromolar trigone, floor of mouth, and buccal mucosa, typically has resistance to definitive chemoradiotherapy and propensity for locoregional recurrence compared to other head and neck cancers, said lead author Yao Yu, a radiation oncologist at MSK.
"We tested the most common oncogenes to establish a more comprehensive mutational profile," Yu continued. "There have been other efforts to comprehensively sequence these tumors in the past, but they've mostly been with exome sequencing, which usually does not include TERT promoters. This study is novel because it integrates what we already know about the mutational landscape, in terms of coding mutations, and it adds in this non-coding TERT promoter mutation which appears to be an important event in oncogenesis."
The researchers used the MSK-IMPACT next-generation sequencing panel to sequence tumor samples from 125 patients with newly diagnosed or recurrent oral cavity cancer or other head and neck cancers.
Based on those results, they found that TERT promoter mutations were enriched in oral cavity cancers compared with laryngopharyngeal cancers, which includes larynx, oral pharynx, tonsil, base of tongue, and soft palate tumors. About 81 percent of oral cavity tumors (60 out of 74 samples) had a TERT promoter mutation versus 7 percent for laryngopharyngeal cancers.
In this study, TERT promoter mutations were classified as functional or wild type. Tumors that harbored C228T, C250T, C228A, and C250A mutations were considered to have functional TERT promoter mutations, and other alterations on the TERT gene were considered passenger mutations and characterized as wild type.
The researchers also analyzed retrospective clinical data from patients in the study. In a multivariate analysis of both the overall study population and the oral cavity cancer cohort, TERT promoter mutations were associated with locoregional failure, or recurrent or persistent disease. In a subset of 22 patients with oral cavity cancer whose tumors were sequenced before recurrence, the researchers found that all eight patients who later experienced locoregional recurrences had TERT promoter mutations. This suggested that TERT promoter mutations may be prognostic to identify patients who have a high risk of recurrence.
The standard treatment for oral cavity cancers is surgery followed by adjuvant chemotherapy with or without radiation, Yu said. Currently, there are not any targeted therapies available for these patients. While it needs further validation, Yu suggested that TERT promoter-targeted drugs could help slow tumor growth in these cancers because it appears to play a role in oncogenesis.
Going forward, Yu and his team will continue exploring the role of TERT promoter mutations in these cancers. He hopes to pinpoint when TERT promoter mutations occur in oncogenesis to better understand the biology of the mutation and explore how the TERT promoter can be targeted for treatment.
"We're moving forward with different strategies to target it," Yu said. "It's been a little bit of a challenging area to target. It's a mutation that's common in a lot of different cancer types, so finding something that could target TERT would make a big impact across cancer types."
TERT promoter mutations have previously been identified in several cancer types, including melanoma and glioblastoma.
While genetic sequencing is not common practice for oral cavity cancers, the discovery of these TERT promoter mutations could make sequencing more useful in this setting, if validated. Yu noted that TERT could have several functions, including diagnosing and differentiating oral cavity cancers from other head and neck cancers, predicting risk of recurrence, and treating patients with targeted therapy.
"Until we find something that can specifically target it, it's hard to argue that everyone should get genetic testing, but certainly I think it deserves validation," Yu said. "We found a pretty strong enrichment [for TERT] among recurrent oral cavity cancers and that suggests that these are the cancers that are acting up and contributing to morbidity and mortality."
The presence of TERT promoter mutations could also help determine whether a patient has an oral cavity tumor versus another head and neck cancer. The treatment strategies are different for oral cavity tumors compared to other head and neck cancers. Yu noted that a tumor originating from the oral cavity typically is treated with surgery, while a tumor from the nearby oropharynx region will likely be treated with chemoradiation. Differentiating the tumor type using TERT could help guide treatment even without a targeted therapy.
While validating TERT for targeted therapy may take longer, Yu suggested that TERT as a biomarker to guide surgery versus chemoradiation treatment decisions could be integrated into the clinic "pretty quickly."
If further study validates that TERT is a targetable biomarker, Yu and his team hope to explore the effects of a drug that targets TERT promoter mutations to treat these patients.
"This is the beginning step," said Nancy Lee, senior author of the study and a radiation oncologist at MSK. "We are moving toward changing, and the field is not moving as fast as we like. Our study is a single-institute small study, so we're going to validate it and then we can go to the other institutions and then see if they see the same things. Potentially, at that time, we may have some targets that will be coming into the market that we can use to target TERT promoter mutation."