Pasi A. JÃ¤nne, MD, PhD
Plasma-based genetic testing can effectively be used to determine whether a tissue biopsy is necessary for EGFR
mutation analysis in patients with non—small cell lung cancer (NSCLC), according findings from 3 studies presented during the 2016 European Lung Cancer Conference.
The 3 studies looked at the concordance between mutation findings with tissue- and plasma-based testing for sensitizing EGFR
alterations and the T790M acquired resistance mutation. Under the proposed testing paradigm, patients with tumors that tested positive by liquid biopsy could forego further testing while negative findings would call for a confirmatory tissue biopsy and test.
“The data demonstrates that the responses are equivalent, which hopefully will ultimately lead us to a point where we no longer have to do a biopsy in every patient,” said study investigator Pasi A. JÃ¤nne, MD, PhD, professor of medicine at the Dana-Farber Cancer Institute. “I think we will see more and more plasma testing for genetic alterations in lung cancer, where we are trying to treat a genetically defined patient population.”
The largest of the studies,1
which was known as ASSESS, examined 1162 patients from Europe and Japan with locally advanced or metastatic NSCLC, regardless of histology. The primary endpoint of the study was concordance between EGFR mutation statuses by tissue- and plasma-based testing. Additionally, the study sought to uncover clinical characteristics or patient demographics that may influence detection rates from plasma samples.
For plasma testing, a trend toward increased sensitivity was seen in those with a greater number of metastatic sites and higher metastatic grade. Additionally, age correlated with plasma-based testing sensitivity. Gender, ethnicity, smoking status, and PS did not influence the sensitivity of plasma-based mutation detection. Across all groups, the specificity of testing was >95%.
“If plasma testing is more reliable for some patients with certain characteristics, this may have implications in the way that we conduct mutation testing for patients with NSCLC, and ultimately impact upon treatment decisions,” said lead investigator Nicola Normanno, MD, chief of the Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy.
In those aged <65 years, plasma testing showed a sensitivity of 63.5% compared with 37.3% in those â‰¥65 years (P
= .0002). For distant metastases, plasma testing had a sensitivity of 22.8% in the M1a group versus 63.4% in the M1b arm (P
“The link with age is more difficult to understand,” said Normanno. “Evidence suggests that the biological features of certain tumors change with age. However, the specific biological mechanisms underlying the correlation between the success of plasma analysis and age will need to be investigated further.”
The sensitivity of plasma-based testing increased with the number of organs with metastasis (P
= .2114). In those with no organ involvement, the sensitivity was 11.1% versus 69.4% in those with â‰¥3 organs involved. The sensitivity was 35.9% and 60.5% in those with 1 and 2 organs with metastasis.
“Our data suggests that for the majority of patients with metastatic disease a plasma test could be sufficient to determine EGFR mutation status, particularly when a robust and reliable methodology is used,” said Normanno. “Due to the low sensitivity of plasma genotyping, a biopsy will still be recommended in plasma negative cases.”
Liquid-based biopsy appears to have the most utility for detecting acquired mutations, such as T790M. In many cases, the ability to perform a rebiopsy is limited and the quantity of tissue obtained makes traditional testing challenging.
To uncover the agreement between liquid biopsy and traditional tissue-based tests at detecting T790M alterations, findings were assessed from a pooled analysis of two phase II studies.2
Findings from the studies, AURA and AURA2, were instrumental in the FDA approval for osimertinib (Tagrisso) as a treatment for patients with T790M-mutant NSCLC following an EGFR-targeted TKI.
The testing analysis looked at the concordance between tissue testing using the approved companion diagnostic for osimertinib, the cobas EGFR Mutation Test v2, and a cobas plasma-based assay. The specificity of the test was confirmed using next-generation sequencing (NGS) on data from the AURA2 study alone.
In the pooled analysis, the positive agreement between the tissue and plasma test was 61.4% for the detection of EGFR
T790M alterations. The negative agreement between the two tests was 78.6%. The positive agreement between the plasma test and NGS was 91.5%. The response rates to osimertinib were similar in those identified by tumor tissue and plasma.