NEW YORK (GenomeWeb) – Researchers from Foundation Medicine have used the firm's targeted next-generation sequencing assay to profile more than 300 tumor samples from patients with esophageal cancer, identifying genomic alteration patterns that distinguish between two subtypes of the disease.
In addition, the team found potentially druggable mutations in more than 90 percent of the samples.
Reporting their work in The Oncologist this week, the researchers wrote that the study "suggests new avenues for molecularly directed therapies in esophageal cancer."
Esophageal cancers cause more than 400,000 deaths worldwide each year, and two subtypes account for the vast majority of cases: esophageal adenocarcinoma and esophageal squamous cell carcinoma. Both subtypes are typically treated with chemoradiation and/or surgery and "the vast majority of patients with advanced disease die of their illness within the first two years after treatment has been started," the authors wrote.
For esophageal adenocarcinoma, anti-ERBB2 targeted therapy is approved for patients with amplified ERBB2 genes. By contrast, no targeted agents exist for esophageal squamous cell carcinoma, and patients with that subtype are not tested for ERBB2 status.
In the study, researchers evaluated 71 tumor samples from patients with esophageal squamous cell carcinoma and 231 tumor samples from patients with esophageal adenocarcinoma using the FoundationOne assay, which sequences the coding regions of 315 genes and introns from 28 genes frequently rearranged in cancers. All patients had either stage III or IV cancer.
In 61 of the 71 (94 percent) ESCC patients and 215 of the 231 (93 percent) EAC patients, researchers found at least one clinically actionable mutation. Foundation Medicine defines clinically actionable to be a mutation for which there is an approved agent available to target, even if the agent is approved for a different tumor type, as well as any clinical trial based on that alteration. On average, the ESCC tumors harbored 2.6 clinically actionable mutations per sample while the EA tumors had 2.7.
Interestingly, the subtypes had different patterns of mutations. The ESCC tumors were more likely to contain PIK3CA, PTEN, and NOTCH mutations — found in 24 percent, 11 percent, and 17 percent of ESCC tumors, respectively, compared to 10 percent, 4 percent, and 4 percent of EA tumors, respectively.
The EAC tumors were more likely to harbor KRAS and ERBB2 mutations — each found in 23 percent of EAC tumors, compared to 6 percent and 3 percent, respectively, of ESCC tumors. In addition, human papillomavirus-16 and HPV-18 were each detected in 3 percent of ESCC tumors, but not at all in the EAC cases.
The different genomic alteration frequencies "reflected activation of distinct biological pathways between ESCC and EAC," the authors wrote. For the ESCC cohort, PI3K/AKT/MTOR signaling, epigenetic regulation, fibroblast growth signaling, Keap/NRF2, and the Notch signaling pathways were the most relevant. For the EAC cohort, the altered pathways included ERBB, transforming growth factor signaling, and RAS/MEK/MAPK. Cell cycle pathway genes were equally altered in both subtypes.
The researchers also found a number of drug targets in each subtype. For the ESCC cohort, therapy-related targets included PTEN, which was altered in 11 percent of samples; EGFR, which was altered in 8 percent of samples; and FGFR, which was altered in 7 percent of samples. There are approved therapies targeting each of those genes, although the drugs are not approved specifically for esophageal cancer.
EGFR mutations were also found in a significant portion of EAC patients, at 14 percent, suggesting that they may be sensitive to EGFR inhibitors. Targeting ERBB2 is already an established approach for treating EAC patients, and indeed, 23 percent were found to have alterations in that gene. Other targets found in EAC patients included FGFR2 alterations in 5 percent of patients, PIK3CA alterations in 10 percent of patients, and MET alterations in 4 percent of patients. One patient with a MET amplification responded to crizotinib and was stable for two months, suggesting that further investigation is needed on targeted therapy for patients with MET amplifications, the authors wrote.
"The frequent identification of clinically relevant genomic alterations in our series underscores the need for increased molecularly directed clinical trials to confirm the improved patient outcomes observed in our cases," the authors wrote.