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Genomic Profiling of Gastric Cancer Identifies Drug-Targetable Mutations
The majority of gastric cancers harbor genomic alterations (GAs) associated with potential benefit from targeted therapies, according to a new study published in The Oncologist on April 16, 2015.
These findings suggest a role for genotype-directed management of locally advanced and metastatic gastric cancer.
To date, the ERBB2 amplification is the only GA in advanced gastric cancer associated with a survival benefit in response to targeted therapy. However, because most patients with gastric cancer do not harbor this rare alteration, most cannot benefit from targeted therapy under current practice guidelines.
To identify additional opportunities for targeted therapy, a team of researchers led by Siraj M. Ali, MD, PhD, at Foundation Medicine, Inc., in Cambridge, MA, conducted comprehensive genomic profiling of patients with locally advanced or metastatic gastric cancer. The goal was to identify clinically relevant GAs, defined as alterations that are currently targetable with therapies approved in gastric cancer or other tumor types, or with therapies currently under development and administered in clinical trials.
“Our study demonstrates the potential utility of comprehensive genomic profiling to match patients to targeted therapies of specific potential benefit in clinical trials,” Dr. Ali said. “This is encouraging in a disease that continues to have a poor prognosis with modern chemotherapy.”
The research team performed comprehensive genomic profiling on 116 gastric cancer specimens harvested from patients with primarily (90.0%) locally advanced or metastatic disease. Thus, the tumor samples were characteristic of gastric carcinomas seen in clinical practice, where the majority of patients present with advanced disease.
The genomic profiling assay detected 501 alterations in 116 samples. Of these, 201 alterations (41%) were clinically relevant, yielding 1.8 drug-targetable GAs per case. In total, 78% of all gastric cancer samples harbored at least 1 clinically relevant GA associated with approved or investigational targeted therapies.
The most common clinically relevant GAs were KRAS (16%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.6%), and PIK3CA (8.6%). Other common alterations that are currently not associated with approved or investigational targeted therapies included TP53 (50%), ARIDIA (24%), and CDHI (15%).
Many current and emerging targeted therapies used in other tumor types are directed to known alterations in receptor tyrosine kinase (RTK) signaling pathways. In the current series, 1 in 5 gastric cancer cases (20.6%) harbored alterations in RTKs such as ERBB2, FGFR2, and MET.
According to the study authors, comprehensive genomic profiling may be used as a tool for identifying appropriate therapy. One patient with MET-amplified gastric cancer was treated with crizotinib, an inhibitor of c-MET and ALK RTKs currently approved for the treatment of non-small cell lung cancer. Following crizotinib initiation, the patient had regression of a liver metastasis and disease control for 5 months.
“The high frequency of clinically relevant GAs in a population reflective of routine clinical practice highlights potential therapeutic avenues in a disease with historically low responses to current therapies and overall poor survival,” said Samuel Klempner, MD, a member of the research team. “The patient response to MET inhibition encapsulates the genotype-directed approach and underscores the need for molecularly directed clinical trials to confirm observations such as seen in our study.”
In addition to driving increased clinical trial participation, identifying clinically relevant GAs in patients with gastric cancer may shape future drug development and research on biomarkers of resistance and therapeutic response.