POINT: Liquid Markers for Risk Stratification of Pulmonary Nodules, Ready for Prime Time? Yes!

Indeterminate pulmonary nodules are commonly identified on lung imaging and represent a challenge for physicians, who estimate malignancy risk to decide how best to manage these lesions that could ultimately represent either lung cancers or benign processes.1Ost D.E. Gould M.K. Decision making in patients with pulmonary nodules.Am J Respir Crit Care Med. 2012; 185: 363-372Crossref PubMed Scopus (192) Google Scholar For those nodules at higher malignancy risk, a lung biopsy, surgical resection, or empirical treatment is recommended. For low-risk nodules, serial surveillance with CT imaging is indicated.2Gould M.K. Donington J. Lynch W.R. et al.Evaluation of individuals with pulmonary nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e93S-e120SAbstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar However, even validated malignancy risk estimations are not universally accurate and carry the inherent risks of performing unnecessary invasive procedures for benign nodules or of delayed diagnosis and possible upstaging of lung cancers.3Choi H.K. Ghobrial M. Mazzone P.J. Models to estimate the probability of malignancy in patients with pulmonary nodules.Ann Am Thorac Soc. 2018; 15: 1117-1126Crossref PubMed Scopus (40) Google Scholar In fact, physician assessment of risk has been shown to outperform traditional clinical risk models; however, physicians often ignore guideline-based recommendations for the next diagnostic test in the workup of a pulmonary nodule.4Tanner N.T. Porter A. Gould M.K. Li X.J. Vachani A. Silvestri G.A. Physician assessment of pretest probability of malignancy and adherence with guidelines for pulmonary nodule evaluation.Chest. 2017; 152: 263-270Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The promise of noninvasive biomarkers is their potential to enhance clinical decision-making in these challenging circumstances. To ground any discussion regarding the prime time status of liquid biomarkers for risk stratification of pulmonary nodules, we must first agree on the definition of prime time. We argue that because there is clearly a definitive lack of clinical utility evidence in support of using liquid biomarkers for risk stratification of pulmonary nodules in routine clinical practice, prime time for this pro-con debate should be defined as follows: ready for clinical implementation based on efficacy extrapolated from multiple rigorous clinical validation and registry studies. The official American Thoracic Society5Mazzone P.J. Sears C.R. Arenberg D.A. et al.Evaluating molecular biomarkers for the early detection of lung cancer: When is a biomarker ready for clinical use? An official American Thoracic Society policy statement.Am J Respir Crit Care Med. 2017; 196: e15-e29Crossref PubMed Scopus (88) Google Scholar policy statement on lung cancer biomarkers, published in 2017, directly addressed the challenges of a criterion standard clinical utility study. The authors concluded that "large, well-designed and conducted studies, capable of determining the impact of testing on clinical decisions and outcomes, are required to confirm the clinical utility of a molecular biomarker."5Mazzone P.J. Sears C.R. Arenberg D.A. et al.Evaluating molecular biomarkers for the early detection of lung cancer: When is a biomarker ready for clinical use? An official American Thoracic Society policy statement.Am J Respir Crit Care Med. 2017; 196: e15-e29Crossref PubMed Scopus (88) Google Scholar We argue that although there are currently no published prospective randomized controlled trials assessing the clinical utility of pulmonary nodule biomarkers that fit these criteria, several biomarkers have demonstrated promise through consistent results across multiple clinical validation studies and prospectively collected data from registries, and some are already commercially available. Numerous diagnostic biomarkers have been developed over the past two decades to assist in earlier diagnosis of lung cancer. These measure proteins, microRNA, circulating tumor cells, circulating tumor DNA, and methylated DNA, among others.6Paez R. Kammer M.N. Tanner N.T. et al.Update on biomarkers for the stratification of indeterminate pulmonary nodules.Chest. 2023; 164: 1028-1041Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The focus of this point/counterpoint is on liquid biomarkers, but it warrants mentioning that these concepts also largely pertain to commercially available biomarkers that measure epithelial gene expression profiling. We will focus our discussion predominantly on peripheral blood-based biomarkers, which can be categorized as measuring either tumor-specific antigens or tumor-associated antibodies. These biomarkers have been assessed either alone or in combinatory panels with or without the incorporation of clinical risk factors. Commercially available examples include Nodify XL2 (Biodesix), which incorporates five clinical risk factors (age, smoking status, nodule diameter, nodule border characteristics, and nodule location) and the use of multiple reaction monitoring mass spectroscopy to identify two proteins,7Silvestri G.A. Tanner N.T. Kearney P. et al.Assessment of plasma proteomics biomarker's ability to distinguish benign from malignant lung nodules: results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) trial.Chest. 2018; 154: 491-500Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar and Nodify CDT (Biodesix), which uses a tumor-associated antibody panel.8Massion P.P. Healey G.F. Peek L.J. et al.Autoantibody signature enhances the positive predictive power of computed tomography and nodule-based risk models for detection of lung cancer.J Thorac Oncol. 2017; 12: 578-584Abstract Full Text Full Text PDF PubMed Google Scholar The Pulmonary Nodule Proteomic Classifier (PANOPTIC) trial was a multicenter prospective observational study that retrospectively evaluated the performance of the Nodify XL2. Among the 178 individuals with pulmonary nodules determined by a pulmonologist or thoracic surgeon to have a probability of cancer ≤ 50% (cancer prevalence of 16%), Nodify XL2 classified 66 (37%) as likely benign, of which 65 were determine to have a benign diagnosis (negative predictive value of 98%).7Silvestri G.A. Tanner N.T. Kearney P. et al.Assessment of plasma proteomics biomarker's ability to distinguish benign from malignant lung nodules: results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) trial.Chest. 2018; 154: 491-500Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar Thus, this test may be useful among individuals with nodules with low-to-intermediate pretest probability of malignancy to assist in excluding malignancy. On the other hand, the Nodify CDT test may be useful in ruling in malignancy among individuals with higher pretest probabilities of malignancy. In a separate study including 296 individuals with a cancer prevalence of 25%, the addition of the Nodify CDT test to the Mayo Clinic clinical risk model increased specificity at increasing malignancy risk thresholds.8Massion P.P. Healey G.F. Peek L.J. et al.Autoantibody signature enhances the positive predictive power of computed tomography and nodule-based risk models for detection of lung cancer.J Thorac Oncol. 2017; 12: 578-584Abstract Full Text Full Text PDF PubMed Google Scholar These published studies on liquid biomarkers represent a key first step to develop and validate promising risk prediction tools, as suggested by the American Thoracic Society policy statement.5Mazzone P.J. Sears C.R. Arenberg D.A. et al.Evaluating molecular biomarkers for the early detection of lung cancer: When is a biomarker ready for clinical use? An official American Thoracic Society policy statement.Am J Respir Crit Care Med. 2017; 196: e15-e29Crossref PubMed Scopus (88) Google Scholar In the meantime, well-designed prospective randomized controlled trials must be undertaken to confirm the clinical utility of liquid biomarkers. Because clinical validation studies are associated with very defined criteria for interpretation and physician utilization, these studies should particularly determine the following: (1) if outcomes support those determined by extrapolation from prior studies and (2) if there is increased benefit or reduction in harm compared with the current standard of care. This is particularly important because biomarker utilization outside of the studied patient populations, and misinterpretation and misuse of biomarker results, may result in reduced accuracy or even harm to patients. There is currently an enrolling clinical trial sponsored by Biodesix9Biodesix. NCT04171492Google Scholar that seeks to randomize individuals to one of the two following pulmonary nodule risk stratification strategies: (1) open-label use of the Nodify XL2 test or (2) usual care blinded to the results of the Nodify XL2 test. Importantly, it will provide a platform by which important elements to ensure accurate use and interpretation (eg, test ordering, clear result sharing, interpretation) can be optimized for best clinical practice. The launching of this and other similar studies represents strong evidence that liquid biomarkers are ready for clinical implementation and moving ever closer to routine clinical use. From a pragmatic standpoint, physician skill and comfort in managing intermediate-risk pulmonary nodules varies,10Tanner N.T. Brasher P.B. Jett J. Silvestri G.A. Effect of a rule-in biomarker test on pulmonary nodule management: a survey of pulmonologists and thoracic surgeons.Clin Lung Cancer. 2020; 21: e89-e98Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar physicians do not always follow guidelines,4Tanner N.T. Porter A. Gould M.K. Li X.J. Vachani A. Silvestri G.A. Physician assessment of pretest probability of malignancy and adherence with guidelines for pulmonary nodule evaluation.Chest. 2017; 152: 263-270Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar and there is not always a standard of care for each situation.2Gould M.K. Donington J. Lynch W.R. et al.Evaluation of individuals with pulmonary nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e93S-e120SAbstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Therefore, there is need for an additional validated datapoint to guide decision-making that liquid biomarkers can fill. Even in patients with significant risk factors for lung cancer as in the US National Lung Screening Trial, there was a nearly 30% false-positive rate with CT screening, frequently due to noncalcified granulomas which also tend to be falsely positive on PET imaging.11Aberle D.R. Adams A.M. et al.National Lung Screening Trial Research TeamReduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (8106) Google Scholar,12Jonas D.E. Reuland D.S. Reddy S.M. et al.Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2021; 325: 971-987Crossref PubMed Scopus (264) Google Scholar Nevertheless, a solitary pulmonary nodule is most commonly considered indeterminate on imaging, unless it demonstrates an overt radiologic feature favoring benignity.13Sim Y.T. Poon F.W. Imaging of solitary pulmonary nodule-a clinical review.Quant Imaging Med Surg. 2013; 3: 316-326PubMed Google Scholar A biomarker provides the additional datapoint to classify a nodule as very low risk for malignancy when other false-positive or nondiagnostic tests may lead physicians down the path of unnecessary invasive procedures or even surgery. The reliability of a negative biopsy for suspected lung cancer (transthoracic or bronchoscopic) has long been called into question, and this conundrum is now heightened with increasing use of novel peripheral bronchoscopy platforms, which have expanded the access to nodules for sampling but may be less reliable as rule out tests.14Nadig T.R. Thomas N. Nietert P.J. et al.Guided bronchoscopy for the evaluation of pulmonary lesions: an updated meta-analysis.Chest. 2023; 163: 1589-1598Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar An emerging use for biomarkers is in the setting of a negative bronchoscopy among patients with an intermediate risk of lung cancer (ie, < 66%). Although not a liquid biomarker, an RNA biomarker from bronchial brushings has demonstrated that the posttest probability of malignancy was decreased to < 10% when bronchoscopic findings and the classifier score were negative.15Silvestri G.A. Vachani A. Whitney D. et al.A bronchial genomic classifier for the diagnostic evaluation of lung cancer.N Engl J Med. 2015; 373: 243-251Crossref PubMed Scopus (203) Google Scholar This classifier may help avoid invasive procedures 50% of the time in nodules with low and intermediate pretest risk of malignancy.16Vachani A. Whitney D.H. Parsons E.C. et al.Clinical utility of a bronchial genomic classifier in patients with suspected lung cancer.Chest. 2016; 150: 210-218Abstract Full Text Full Text PDF PubMed Google Scholar In addition, recommendations for surgical resection were higher with a positive compared with negative biomarker result, indicating that fewer patients requiring surgical referral were inappropriately observed with further surveillance imaging.17Sethi S. Oh S. Chen A. et al.Percepta genomic sequencing classifier and decision-making in patients with high-risk lung nodules: a decision impact study.BMC Pulm Med. 2022; 22: 26Crossref PubMed Scopus (2) Google Scholar This is relevant because it has been shown that physicians may inappropriately observe high-risk nodules when they should refer to surgery instead.4Tanner N.T. Porter A. Gould M.K. Li X.J. Vachani A. Silvestri G.A. Physician assessment of pretest probability of malignancy and adherence with guidelines for pulmonary nodule evaluation.Chest. 2017; 152: 263-270Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar,18Tanner N.T. Aggarwal J. Gould M.K. et al.Management of pulmonary nodules by community pulmonologists: a multicenter observational study.Chest. 2015; 148: 1405-1414Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar In conclusion, we should consider the core tenet of what constitutes the ideal biomarker for pulmonary nodule risk stratification: a tool that influences clinical decision-making to improve patient care by providing a rationale for noninvasive surveillance of benign nodules or for more aggressive surgical referral when necessary.5Mazzone P.J. Sears C.R. Arenberg D.A. et al.Evaluating molecular biomarkers for the early detection of lung cancer: When is a biomarker ready for clinical use? An official American Thoracic Society policy statement.Am J Respir Crit Care Med. 2017; 196: e15-e29Crossref PubMed Scopus (88) Google Scholar We argue that liquid biomarkers have demonstrated efficacy extrapolated from multiple rigorous clinical validation and registry studies and are capable of assisting physicians in classifying nodules as very low or high risk without substantially increasing the number of invasive diagnostic procedures performed for benign nodules or delaying therapeutic procedures for malignant nodules. Thus, they are ready for prime time clinical implementation. R. Y. K. is supported by a National Cancer Institute Career Development Award Grant K08CA279881. C. R. S. receives support from the US Department of Veterans Affairs BLR&D, Merit Review grant Grant I01-BX005353.