New NSCLC Treatment Options Needed to Successfully Target Multiple Gene Changes

It may be time to rethink how targeted therapy is initiated and monitored when managing some patients with non-small cell lung cancer (NSCLC). A study recently published in Nature Genetics is suggesting that NSCLC may be driven by multiple genetic changes and blood-based tests may help reveal the changing complex genomic landscape.

The study strongly suggests that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising. It is theorized that drugs targeting an epidermal growth factor receptor (EGFR) mutation may be able to wipe out the cells carrying that mutation alone. However, this approach leaves cells behind and may even enhance cells with other additional mutations.

“We were surprised to find that the majority of NSCLCs harbor multiple genetic alterations that may be driving the progression and resistance of the cancer to targeted therapies. This is in contrast to the prevailing dogma that NSCLCs are 'driven' by only one primary genetic mutation,” said study co-author Collin Blakely, MD, PhD, a medical oncologist and assistant professor of medicine at the University of California, San Francisco.

The single-driver view of lung cancer has been buttressed by influential genomic studies, such as The Cancer Genome Atlas (TCGA), according to the authors. However, these studies have so far focused on genomic alterations in early–stage tumors, which are usually treatable with surgery and chemotherapy, rather than the more deadly advanced-stage tumors that challenge clinical oncologists.

The new study used a cell-free DNA platform to analyze patient blood samples to check for any mutations in 73 genes known to contribute to cancer. Overall, the researchers analyzed liquid biopsy data from 1,122 patients whose tumors contained a mutated EGFR gene and 944 patients whose tumors did not have this mutation.

They found that the 92.9% of tumors from patients with advanced-stage lung cancer harbored multiple changes in cancer-related genes in addition to the EGFR driver mutation. On average, tumors contained 2 to 3 altered genes in addition to EGFR. However, some contained as many as 13.

The researchers were able to identify which mutations cropped up specifically in patients who developed resistance to EGFR-targeted drugs. The findings suggest an urgent need for oncologists to develop new first-line combination therapies capable of targeting multiple genetic pathways in patients’ tumors, rather than waiting for resistance to develop before trying a second drug.

“Lung cancer is not a single-gene disease and new approaches beyond single-agent targeted therapies will be needed to overcome the genetic complexity that exists prior to, and evolves with, treatment,” Dr. Blakely told OncoTherapy Network.