Researchers have developed a lung “metagene” model that accurately predicts the risk of recurrence for patients diagnosed with early-stage (IA) non-small-cell lung cancer (NSCLC), according to results published in the August 9 New England Journal of Medicine.

Previous studies have shown the benefit of adjuvant chemotherapy after surgery for patients with later stages of NSCLC, but not for stage IA disease. However, about 25 percent of patients in that stage subsequently have a recurrence, suggesting a need to identify a subgroup that might benefit from adjuvant drug treatment, noted the researchers, led by Dr. Anil Potti of the Duke Institute for Genome Sciences & Policy at Duke University.

They combined gene-expression profiles in a cohort of 89 patients with early-stage NSCLC to create a metagene model that predicted the risk for recurrence. “The metagene represents the dominant average expression pattern of the gene cluster across the tumor samples,” they explained. In the initial cohort, the lung metagene model predicted disease recurrence with an overall accuracy of 93 percent.

The investigators then evaluated the metagene model in two independent groups of 25 patients from an American College of Surgeons Oncology Group (ACOSOG) study and 84 patients from a Cancer and Leukemia Group B (CALGB) study. The model had an overall predictive accuracy for recurrence risk of 72 percent for the ACOSOG cohort and 79 percent for the CALGB patients. “The lung metagene model was consistently accurate across all the early stages of NSCLC,” the researchers reported.

“Our study is a critical first step in the use of genomic tools to refine prognosis and improve the selection of NSCLC patients who are appropriate for adjuvant chemotherapy,” noted the investigators.

The metagene model for NSCLC described in the study is similar to a potential genomic strategy for treating early-stage breast cancer, which is being tested in a large clinical study called TAILORx. In that study, a molecular test to analyze the expression patterns of certain genes in a woman’s breast tumor that point to a high risk of recurrent disease are used to assign patients to an appropriate treatment regimen.

The researchers in the NSCLC study noted that the refinement of prognosis with the use of the metagene model “provides the opportunity for a prospective, randomized, phase III clinical trial that would evaluate the benefit of identifying a subgroup of patients with stage IA disease estimated to be at high risk for recurrence.”

In the proposed study, patients initially classified as having clinical stage IA disease would undergo surgery, and the metagene model would then be used to identify patients predicted to be at high risk for recurrence. “Patients at high risk would then be randomly assigned to observation (the current standard of care for stage IA disease) or adjuvant chemotherapy, in order to evaluate the extent to which the use of genomic reclassification improves survival,” the scientists suggested.

Dr. Martin Gutierrez, staff clinician in NCI’s Center for Cancer Research (CCR), agreed on the need and value of testing the NSCLC metagene model in a follow-up clinical study. The use of adjuvant chemotherapy for stage I lung cancers “has been controversial,” he noted. If the metagene model is confirmed by a phase III study, “it might help identify early-stage patients who are at high risk for relapse and decrease the likelihood of exposing low-risk patients unnecessarily to chemotherapy,” Dr. Gutierrez suggested.

By Bill Robinson