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Comprehensive profiling identifies clinically relevant genomic alterations in most gastric cancers
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Comprehensive genomic profiling of advanced gastric carcinoma is feasible and leads to the detection of clinically relevant alterations known to benefit from targeted therapies, according to study results.
Although the addition of HER-2 targeted therapy to chemotherapy improves survival for patients with advanced gastric cancer who harbor ERBB2 alterations, that alteration is rare and, thus, most patients with gastric cancer are not eligible to receive targeted therapies, according to study background.
“Our study demonstrates the potential utility of comprehensive genomic profiling to match patients to targeted therapies of specific potential benefit in clinical trials,” Siraj M. Ali, MD, PhD, associate director of Foundation Medicine, said in a press release. “This is encouraging in a disease that continues to have a poor prognosis with modern chemotherapy.”
Ali and colleagues conducted prospective comprehensive genomic profiling of 116 gastric cancer samples — 90% of which were from locally advanced or metastatic disease — received from academic and community oncologists. The goal was to identify genomic alterations associated with potential response to FDA-approved targeted therapies.
The researchers identified 501 gene alteration in the samples. Forty-one percent of the alterations were considered clinically relevant, which equated to an average of 1.8 drug-targetable genetic alterations per specimen.
Overall, 78% of all the specimens harbored at least one clinically relevant gene alteration that could be associated with a targeted therapy.
The most common clinically relevant alterations identified included KRAS (16%), CDKN2A (14%) CCND1 (9.5%), ERBB2 (8.5%) and PIK3CA (8.6%). Other common alterations identified for which there are no approved targeted therapies available included TP53 (50%), ARID1A (24%) and CDH1 (15%).
Further, 20.6% of the specimens had receptor tyrosine kinase signaling pathway alterations — primarily ERBB2, FGFR2 and MET amplification — that are associated with current or developing targeted therapies in other tumor types.
The researchers said one patient with MET-amplified gastric cancer was treated with crizotinib (Xalkori, Pfizer), a multi-targeted ALK/ROS1/MET inhibitor approved for the treatment of non–small cell lung cancer. That patient experienced a response for 5 months.
“The high frequency of clinically relevant gene alterations 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,” Samuel Klempner, MD, study researcher and assistant clinical professor in the division of hematology/oncology in the department of medicine at the University of California Irvine School of Medicine, said in a press release. “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 [those] seen in our study.” – by Anthony SanFilippo
Disclosure: The researchers report employment with or stock ownership in Foundation Medicine Inc. They also report honoraria and research funding from and consultant/advisory roles with Amgen, Bayer, Bristol-Myers Squibb, Caris Life Sciences, Celgene, Genomic Health, Incyte, Insys and Pfizer.
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