Lung cancer specialists are slowly being faced with the challenge of how to balance the benefits of next-generation tumor tissue testing against those of liquid biopsy in the clinic. During the 2021 International Society of Liquid Biopsy (ISLB) Congress, Natasha Leighl, MD, of Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada, provided attendees with an update on the state of liquid biopsy science and its role in clinical decision making.
“The dream is to get our patients to the right treatment at the right time,” Dr. Leighl said.
There are now multiple cancer types in which oncogenic drivers or next-generation sequencing (NGS) results can drive treatment decisions.
“This is truer in lung cancer than some other cancers, but clearly the field is rapidly changing, and this is becoming more relevant across more tumor types,” Dr. Leighl said.
Perhaps the most important part of molecular testing is that it can affect patient survival. Studies have shown that in patients with advanced lung cancer, those who underwent molecular testing have better outcomes than patients who did not.
“It has become clear that access to targeted therapy is very important,” Dr. Leighl said.
Current Status of Liquid Biopsy
A survey from the IASLC looked at barriers to NGS by region, including responses from about 2,500 respondents from more than 100 countries. The survey showed that cost of NGS was consistently a barrier to its use. Time spent waiting for results, awareness, and access were also barriers.
Additionally, research has shown that up to one-third of patients with advanced lung cancer do not have enough tissue to complete NGS and that one-quarter or more must start treatment without results, Dr. Leighl said.
The IASLC recently released a consensus statement comparing tissue and liquid biopsy in lung cancer. Although tissue biopsy is riskier and more challenging, it yields important incremental information, Dr. Leighl said. Results provide a lung cancer diagnosis, pathologic subtype, and assessment of DNA and non-DNA biomarkers. However, tissue biopsy is not without disadvantages, including limited tissue samples, inability to readily conduct serial testing, and the invasive nature of the process.
In contrast, liquid biopsy is faster and minimally invasive. It can also be repeated over time, providing perhaps a better picture of tumor heterogeneity, Dr. Leighl said.
However, liquid biopsy cannot accommodate PD-L1 testing, and if added to tissue testing, doubles the cost. There is also a significant risk of false negatives.
The current diagnostic algorithms call for a sequential approach, a complementary approach, or a plasma-first approach, Dr. Leighl said. If tissue genotyping is done first, clinicians could get further genotypes using plasma. If time is a concern, a plasma-first approach is an option.
Complementary testing may also yield additional benefits. Dr. Leighl said in a Canadian study researchers were able to identify targetable alterations in 68% of patients with plasma plus tissue compared with 53% with tissue alone.
“The extra proportion of patients that could access targeted therapy led to potentially better outcomes in terms of progression-free survival, but also cost savings because in Canada, immunotherapy appears to cost more than targeted therapy,” Dr. Leighl said.
She noted, though, that some patients in the study found targetable mutations in the tissue alone.
“It is important to remember that if you don’t find something in the plasma you should also look at the tissue,” Dr. Leighl said. “Similarly, if you can’t find abnormalities in the tissue, you should consider plasma testing.”
Liquid Biopsy Paradise
Dr. Leighl said there are many days that lung cancer specialists might feel that use of liquid biopsy is a paradise but admitted that although plasma ctDNA holds promise for treatment monitoring, there is no role yet for use in treatment decision making.
The leading challenge with ctDNA testing is the small volumes of ctDNA circulating in plasma. Compared with more than 10% of DNA in tumor samples that can be assayed, plasma yields less than 0.5% ctDNA. A short half-life means that sensitive assays are required, as is optimal handling of samples to avoid false-negative results.
Looking at concordance, Dr. Leighl said that plasma testing does have lower sensitivity.
In 38 studies of plasma versus tissue NGS in patients with lung cancer, the positive percent agreement between the two methods was not as high as many would have liked, she said. Mutations had the highest positive percent agreement rates, whereas fusions and copy number gain were lower.
Tumor burden and tumor size can both affect plasma ctDNA sensitivity as well, as can the presence of sanctuary sites, such as the presence of brain metastases.
Finally, false positives and clonal hematopoiesis are also issues seen across tumor types.
“As we move toward using ctDNA assays to gauge minimal residual disease and to monitor treatment efficacy, clonal hematopoiesis will become more important,” Dr. Leighl said. “It is important to understand if there is leukocyte variant correction in the assay you are using or whether there is a bioinformatic program that addresses this. You need to be more mindful and request that.”
Currently, it is hard to know what the future will hold for liquid biopsy and ctDNA.
“I think we are going to see liquid biopsy used more and more, not only in the first-line setting but in subsequent treatment selection as well, to help optimize access for patients to the right treatment at the right time,” Dr. Leighl said.
Dr. Leighl reported receiving research funding from Amgen, Array, AstraZeneca, Bayer, BMS, Eli Lilly, EMD, Serono, Guardant Health, Invata, MSD, Novartis, Pfizer, Roche, and Takeda. She has received honoraria from Amgen, Boehringer Ingelheim, BMS, CADTH, EMD, Serono, GlaxoSmithKline, MSD, Novartis, Puma Biotechnology, Sanofi Genzyme, and Takeda. She has received travel support from AstraZeneca, Roche, and Teva-Oncotest.