Nearly all advanced esophageal cancers harbor genetic mutations that can be targeted with emerging drug therapies, according to a new study published in The Oncologist. These findings suggest a potential role for the use of targeted therapy in addition or as an alternative to conventional treatment in patients with esophageal cancer.
Two main subtypes of esophageal cancer account for more than 95% of all patient cases: esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs). The ESCC subtype is the dominant form in most countries outside of the US, while the EAC subtype is diagnosed more frequently in the US.
Despite the different risk factors and natural histories of ESCC and EAC, both subtypes are aggressive malignancies with a tendency to remain undiagnosed until an advanced stage. Current treatment options are limited for most patients, and outcomes are poor. Each year, esophageal cancer leads to more than 400,000 deaths worldwide.
To identify new opportunities for targeted therapy, a team of researchers led by Jeffrey Ross, MD, Medical Director of Foundation Medicine, Inc., performed comprehensive genetic profiling of esophageal tumor samples. The goal was to detect clinically relevant genomic alterations (GAs), defined as alterations linked to approved therapies or to therapies currently under evaluation and administered in clinical trials.
"Comprehensive genomic profiling shows significant promise in identifying clinically relevant genomic alterations in both ESCC and EAC," Dr. Ross said. "Genetic testing also informs the potential use of targeted therapies in both major types of esophageal cancer."
Dr. Ross and colleagues performed comprehensive genomic profiling on 302 esophageal tumor specimens harvested from patients with advanced ESCC (n = 71) or advanced EAC (n = 231). The genetic tests focused on mutations or other abnormalities that could be targeted with current or emerging drug therapies.
Genetic testing revealed 1,825 total genetic alterations, with 100% of tumors testing positive for at least 1 mutation. Of these, the frequency of clinically relevant GAs was high in both groups. In total, 94% of all ESCC tumors harbored at least 1 clinically relevant GA, with an average of 2.6 drug-targetable alterations per tumor. In addition, 93% of all EAC tumors tested positive for clinically relevant GAs, with an average of 2.7 drug-targetable alterations per tumor.
The mutation profiles varied substantially between the cancer subtypes, suggesting important differences in their underlying pathology and in the potential role of targeted therapies. The most common clinically relevant GAs in patients with ESCC were PIK3CA (24%), NOTCH1 (17%), and PTEN (11%). By comparison, EAC tumors were more likely to test positive for mutations in KRAS (23%), ERBB2 (23%), and EGFR (15%).
In the clinical setting, comprehensive genomic profiling may be used as a tool for identifying appropriate therapy, according to the study authors. "The high frequency of clinically relevant alterations - 94% in ESCC and 93% in EAC samples - underscores the need for clinical trials that incorporate molecular testing to direct the selection of targeted therapies in patients with esophageal cancer," Dr. Ross said.
Richard M. Goldberg, MD, of the Ohio State University Comprehensive Cancer Center and a Senior Editor of The Oncologist, commented, "This study provides preliminary and compelling evidence that genotyping of the tumors of patients with esophageal cancer may prove to be a useful tool for clinical trial selection in patients with this disease, particularly after progression on first-line therapy."