ELCC: NSCLC mutation testing highlights ctDNA’s limitations

Mitchel L. Zoler/Frontline Medical News Dr. Egbert F. Smit

The ASSESS study is the largest evaluation of using ctDNA to test the status of a lung tumor for the presence of a mutation in the gene for the epidermal growth factor receptor. It also gives us insight into the feasibility and effectiveness of using this approach in routine practice, outside of a rigorously designed trial. The result was that mutation testing using plasma specimens to obtain circulating tumor DNA was generally doable but resulted in low sensitivity and a low positive predictive value.

The low sensitivity seen overall in ASSESS likely resulted from the multiple testing reagents, commercially available testing kits, and in-house techniques used by individual laboratories in this international study done in diverse settings. Some of the tests for epidermal growth factor receptor (EGFR) mutations are quite sensitive, and others less so. The specific testing method used matters quite a lot. The heterogeneity of methods used in ASSESS reflects the diversity of what usually happens in real-world practice.

Based on the sensitivity limitations, I currently see using ctDNA to test for EGFR mutations only when this is the only option for mutation assessment because a conventional biopsy of the primary tumor failed to provide enough DNA for EGFR mutation testing. Although it is hard to find specific numbers on how often this situation arises in current practice, it seems to happen roughly 10%-30% of the time. So, for about one-fifth of patients with newly diagnosed or recurrent stage III or IV lung cancer EGFR mutation assessment using ctDNA will be necessary.

The data from ASSESS and other studies show that when ctDNA testing identifies an EGFR mutation you can rely on its accuracy. The problem is when ctDNA testing fails to identify an EGFR mutation. In those situations you need to be cautious as you can’t rely on a negative result as being a true negative. I would also be cautious about using ctDNA testing to follow lung cancer patients, as the clinical importance of finding new EGFR alleles appearing in the patient’s blood over time is not yet clear. We need more studies that follow these patients and changes in their EGFR ctDNA over time to determine the clinical relevance of these changes.

The results from ASSESS add to the existing body of evidence that ctDNA testing to find EGFR mutations is feasible in a real-world setting.

Dr. Egbert F. Smit is a professor of pulmonary medicine at the VU University Medical Center in Amsterdam.He had no relevant disclosures. He made these comments in an interview and as the designated discussant for the ASSESS study at the meeting.