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Study Finds Possible New Gene Target for Lung Cancer

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Key Points

  • In the ECOG 2501 clinical study, one patient with stage IV lung cancer achieved a near-complete response to sorafenib within 2 months of being treated with sorafenib and remained progression-free for 5 years.
  • Whole-genome sequencing revealed high levels of ARAF S214C mutations in the patient’s cancer cells and additional ARAF mutations across 1% of an independent group of lung cancer cases.
  • The findings suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

Researchers have identified a potential new gene mutation that may drive lung cancer development and growth. In a study in the Journal of Clinical Investigation by Imielinski et al, a patient with advanced lung cancer who was found to have the ARAF S214Csomatic gene mutation achieved nearly a complete response within 2 months of being treated with sorafenib (Nexavar) and remained progression-free for 5 years while remaining on the drug.

Study Details

In the ECOG 2501 clinical study of 306 patients with lung cancer, nine patients responded to sorafenib and one patient, a 66-year-old former light smoker (< 5 pack per year smoking history), had the most durable and longest response to the therapy. The patient was diagnosed with stage IV lung adenocarcinoma in 2002 and received multiple failed therapy regimens (gemcitabine and vinorelbine, gefitinib [Iressa], bortezomib [Velcade]) between 2002 and 2005 and a palliative lobectomy in 2006.

She began treatment with oral sorafenib, a broad-spectrum kinase inhibitor with activity against BRAF, RAF1, RET, PDGFRA, and KIT, among other gene mutations, as part of the trial; within 2 months the patient’s CT scans showed a near-complete response. The patient remained progression-free and asymptomatic for 5 years while continuing to take sorafenib. In 2011, the patient relapsed and died.

DNA Sequencing Unearths Possible Target for Sorafenib

The researchers used parallel DNA sequencing of the patient’s tumor and peripheral blood samples before sorafenib treatment to analyze for acquired gene mutations. They also sequenced RNA from the patient’s tumor and normal tissue to determine a possible genetic difference responsible for the sustained response to sorafenib. More than 100 alterations were found in the structure of genes in the patient’s tumor compared to her normal cells and one, ARAF S214C, was a plausible target for sorafenib.

The researchers found additional ARAF mutations across 1% of an independent group of patients with lung cancer. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner, suggesting that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.  

“If recurrent but rare mutations underlie cancer growth and responsiveness, they are not likely to be statistically called out as a potential driver of cancer through a genome scan of several hundred or even thousands of cases because they are so rare,” David Carbone, MD, a senior author of the study and Director of The Ohio State University Comprehensive Cancer Center-James Thoracic Oncology Program, said in a statement. “But for the patients who do have these specific genetic mutations, having this information is critical.”

According to Dr. Carbone, the study suggests that researchers can discover important new gene mutations that drive cancer development and progression by analyzing genes in cancer cells from patients who fare far better or far worse than others in a specific clinical trial.

“Our study suggests that a powerful, alternate approach to driver mutation discovery may be through the analysis of outlier patient responses and the identification of driver mutations through the preponderance of genomic, biochemical, and functional evidence,” wrote the study authors.

Dr. Carbone and Matthew Meyerson, MD, PhD, of Dana-Farber Cancer Institute, are the corresponding authors for the Journal of Clinical Investigation article.

Dr. Meyerson is a founder and equity holder of Foundation Medicine, a for-profit company that provided next-generation sequencing diagnostic services used in this study.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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