"Actionable" oncogenic drivers—genetic mutations that are critical to the development and maintenance of a cancer and that are susceptible to targeted therapy—were identified in 64% of tumor samples from 733 patients with lung adenocarcinoma in a proof-of-concept study aimed at determining the frequency of such mutations that was reported online May 20 in JAMA.
The researchers used multiplexed genetic testing to screen tumor samples for 10 possible oncogenic drivers simultaneously. In some cases, the results allowed clinicians to individually tailor cancer treatment, and patients who received this targeted therapy showed longer survival times than those who received conventional therapy.
Dr. Mark G. Kris
Thus, this study established that it is feasible to incorporate genomic testing into clinical care for treatment stratification, and that multiplex testing is useful for guiding treatment in the majority of patients with lung adenocarcinoma, said Dr. Mark G. Kris of Memorial Sloan Kettering Cancer Center, New York, and his associates.
Since this study wasn’t designed to assess patient survival, further randomized trials are needed to definitively determine whether selecting therapy based on this method of identifying oncogenic drivers improves survival in the real-word setting, they noted.
The study involved patients with stage IV or recurrent lung adenocarcinoma treated at 14 medical centers across the country during a 3-year period. Each site performed multiplex genotyping on tumor samples using one of three available methods, to search for any of 10 oncogenic drivers: mutations in the EGFR gene (which are known to respond to tyrosine kinase inhibitors such as gefitinib and erlotinib), the ALK gene (known to respond to crizotinib), and the KRAS, NRAS, BRAF, ERBB2 (formerly known as HER-2), PIK3CA, MEK1, and AKT1 genes, as well as amplification of the met protooncogene (MET).
These participants’ treating physicians decided whether or not to recommend a targeted therapy to patients found to have tumors harboring one of these oncogenic drivers.
A total of 1,007 patients had at least 1 gene assessed for oncogenic drivers, and 733 patients were fully genotyped. The main reason why full genotyping couldn’t be done in all the study subjects was that insufficient tissue had been obtained in some tumor samples. (When this trial began in 2009, tumor sampling was only done to establish a diagnosis. Since then, genotyping has become an essential step in choosing therapy, so larger tissue samples are now obtained routinely.)
Of the 733 specimens tested for all 10 onocogenic drivers, 466 (64%) were found to harbor them; 442 specimens had 1 oncogenic driver and 24 had 2 of them. KRAS mutations were the most frequent, found in 25% of tumors; sensitizing EGFR mutations were found in 17%, other EGFR mutations in 4%, and ALK rearrangements in 8%. Each of the other mutations were found in less than 1%-3% of tumors, Dr. Kris and his associates said (JAMA 2014 May 20 [doi:10.1001/jama.2014.3741]).
A total of 260 of these patients received targeted therapy directed at the oncogenic driver(s) found in their tumors, and their median survival was 3.5 years. In contrast, 318 patients who were found to have at least one oncogenic driver did not receive targeted therapy, and their median survival was 2.4 years. And the 360 patients with no oncogenic driver identified in their tumors had a median survival of 2.1 years.
This study was supported by the National Cancer Institute. Dr. Kris reported ties to Ariad, AstraZeneca, Bind Biosciences, Boehringer Ingelheim, Chugai, Clovis, Covidien, Daiichi Sankyo, Esanex, Exelixis, Genentech, Pfizer, PUMA, Novartis, Millenium, and Roche, and his associates reported ties to numerous industry sources.