The NELSON trial and the US National Lung Cancer Screening Trial (NLST) marked major advances in lung cancer by establishing that low-dose computed tomography (LDCT) screening of high-risk individuals is effective at catching the disease in early stages when curative approaches can be used, in turn reducing mortality by 20% to 40%.1,2 The wealth of circulating biomarkers now under investigation begs the question of whether mortality can be reduced further in high-risk individuals by augmenting or even replacing LDCT screening with biomarker-based screening.
According to Nir Peled, MD, PhD, of the Soroka Cancer Center and Ben-Gurion University in Israel, who addressed this question during the session on “Increasing Roles for Liquid Biopsy: Moving from Research to Clinical Application,” lung biomarkers are emerging to support LDCT programs, but none are yet validated for clinical implementation.
Guidance on lung cancer screening from medical societies, including the National Comprehensive Cancer Center (NCCN), the European Society of Radiology, and the European Respiratory Society, do not currently incorporate biomarkers into the risk-assessment algorithm.3,4 “Basically, smoking and age are the most significant inclusion criteria for screening as a service. Unfortunately, we do not see within those parameters any clue for biomarkers whatsoever,” said Dr. Peled.
However, this does not mean that biomarkers do not have a role to play. “Generally speaking, we wish to reduce invasive investigation and, of course, we would like to reduce the cost, which means we need a biomarker with a very strong negative predictive value,” Dr. Peled explained. “On the other hand, we would also like to improve time to therapy. When we are running a screening trial or service, we would like to have [a biomarker with] a very strong positive predictive value.”
Biomarkers for Screening
Along this line, Dr. Peled feels that a logical place to implement biomarkers into the screening paradigm is after detection of a solid nodule. NCCN guidelines currently base screening follow-up procedures on the size of the suspicious lesion. “Why wouldn’t we use biomarkers to support us with the assessment routine to allow us a faster or slower approach to investigation?”
Dr. Peled asked. Dr. Peled described several potential biomarker candidates that could be used in the screening setting, including protein markers, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), tumor-macrophage fusion cells (TMFs), and microRNA from exosomes. Research performed to date with these types of markers appears promising, yet much work remains to be done, particularly when it comes to the detection of very early-stage disease.
Promising protein biomarkers for lung cancer detection include squamous cell carcinoma antigen, ProGRP, non-specific elastase, CYFRA 21-1, carcinoembryonic antigen, and CA5. These markers tend to demonstrate higher sensitivity in SCLC than NSCLC (Figure). However, even in SCLC, no one protein biomarker is sufficiently sensitive for the detection of disease, indicating that a panel of protein biomarkers is needed to boost sensitivity to sufficient levels to minimize the number of false-negative results.
Even when multiple biomarkers are used in combination, other aspects of disease can limit sensitivity, as has been observed with ctDNA. The CancerSEEK test, which combines assessment of circulating proteins along with mutations in ctDNA, demonstrated about 60% sensitivity for detecting lung cancer when the specificity was set to greater than 99%.5 A key limitation of the platform is reduced sensitivity for stage I cancers versus stage II or III cancers.
This shortcoming is not unique to CancerSEEK. A recent review of four different ctDNA-based screening platforms, one of which was CancerSEEK, showed very low sensitivity across all assays for individuals with stage I NSCLC—a finding attributed to low DNA shedding from the primary lesion.6
“[This] means, again, that circulating free DNA, at this point of time, is not sensitive enough to be an isolated platform for screening for lung cancer,” said Dr. Peled.
A potentially promising area of research presented by Dr. Peled involves detection of circulating TMFs. As he explained, CTCs sometimes fuse with macrophages to escape detection by the immune system, and these TMFs can be detected in the blood by targeting cytokeratins on the surface of CTCs. A prospective trial seeking to identify the prognostic value of TMFs found that circulating TMFs were detectable in more than 75% of patients with NSCLC, but were rare in cancer-free individuals with a long smoking history and were completely absent in healthy controls.7 Again, however, TMFs were more readily detected with advancing disease.
As the data increasingly show, a single biomarker will not be up to the task of screening for lung cancer given limitations in sensitivity. “The main urgent unmet need for this is for a liquid panel, and not a single biomarker, that can serve us for this purpose,” Dr. Peled concluded.
1. van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009;361:2221-2229.
2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lungcancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Lung Cancer Screening, Version 1.2020. Available at nccn.org. Accessed October 3, 2020.
4. Kauczor HU, Baird AM, Blum TG, et al; European Society of Radiology (ESR) and the European Respiratory Society (ERS). ESR/ERS statement paper on lung cancer screening. Eur Respir J. 2020;55(2):1900506.
5. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926-930.
6. Guibert N, Pradines A, Favre G, Mazieres J. Current and future applications of liquid biopsy in nonsmall cell lung cancer from early to advanced stages. Eur Respir Rev. 2020;29(155):190052.
7. Manjunath Y, Mitchem JB, Suvilesh KN, et al. Circulating giant tumor-macrophage fusion cells are independent prognosticators in patients with NSCLC. J Thorac Oncol. 2020;15(9):1460-1471.