Biomarkers in the Evaluation of Pulmonary Nodules
Lung cancer mortality in the United States has decreased by 29% since 1991. Screening with LDCT and identification of the cancers among the indeterminate pulmonary nodules (IPNs) offers the best chance for improving lung cancer mortality even further.
Low dose CT (LDCT) screening for high risk individuals has been available since 2013 but the adoption rate has been low. Less than one in 20 eligible adults received LDCT screening in the USA and the screening was not aligned with the lung cancer burden, which was higher in the Southern states (1).
It has been estimated that 1.57 million IPNs are identified yearly in the USA on non-screening CT scans. The National Lung Cancer Screening Trial (NLST) also reported a positive screening rate of 24% of which approximately 95% were due to IPNs (2).There are multiple guidelines published for management of IPNs. In general, they recommend assessing the risk of malignancy based on clinical estimate or a risk calculator. Based on this estimate, each patient is placed into a low, intermediate, or high risk probability of cancer (pCA). For the ACCP these are <5%, 5-65%, >65%; for the BTS they are <10%, 10-70%, >70%. A PET scan is recommended for the intermediate risk groups (3,4). In a clinical practice review study in the US, PET scans were performed on only 37% of IPNs of 8-20 mm. Surgical resection of IPNs was similar at 17-21% in all three risk categories. Surgery for benign disease was performed in 35% (27 of 77) of individuals and there was a large percentage of biopsies for benign disease (5). This underscored the need for additional tools to assist physicians in the evaluation of IPNs.
A IPN biomarker should improve the accuracy of the pCA to guide early evaluation or observation and improve clinical outcomes. There have been recent extensive reviews of biomarkers (6,7). My comments will be limited to three biomarkers that, in my estimation, are available and should be considered for clinical use at this time. While biomarkers could be from blood, urine, sputum, or breath, the most extensive evaluations have been performed on blood, specifically proteins, microRNA and autoantibodies.
The three biomarkers are for risk assessment of IPNs (8-30 mm) are from CLIA approved laboratories in the US. First is the integrated classifier XL2 which is a proteomic analysis of 2 proteins, LG3BP and C163A, combined with 5 clinical factors. It is used to identify “likely benign” nodules. In the prospective PANOPTIC study, the analysis was performed on 178 patients with a pCA of 50% or less (16% had lung cancer) (8). The XL2 test classified 66 participants as “likely benign” and only one of these were subsequently proven to be lung cancer. The sensitivity of the test was 97% and the NPV was 98% and outperformed clinical risk stratification models and PET. If the test had been used to make clinical decisions, it would have resulted in 40% fewer biopsies of benign IPNs.
The second test, CDT is a panel of 7 autoantibodies against tumor associated antigens (p53, CAGE, GBU 4-5, MAGE A4, NY-ESO-1, HuD and SOX-2). In clinical validation studies of all histological types and stages of lung cancer the panel performance was 40% sensitivity with a specificity of 93%. A real world clinical study 296 IPN patients had a 25% prevalence of lung cancer. A positive blood test represented a greater than two fold increased relative risk of lung cancer as compared to a negative test. When a “both positive rule” of combining calculated risk pCA (Mayo/Swensen nodule calculator) with a positive CDT it resulted in a specificity of >92% and a PPV of >70% (9). The CDT test has a high specificity and PPV and is best used to identify “likely malignant” IPNs. A positive CDT will frequently move the calculated pCA into the high risk category (>65%) where diagnostic evaluation should not be delayed. The majority of these high risk nodules will prove to be lung cancer.
The third biomarker is the bronchial genomic classifier (10). The test is performed on a epithelial cells by brushing a main bronchus. It has been shown to improve the diagnostic performance of bronchoscopy in suspected lung cancer patients. In 101 individuals with an intermediate risk of cancer the bronchoscopy was negative in 83% (41% were subsequently proven to have lung cancer). With a negative bronchoscopy and adding a negative genomic classifier provided an NPV of 91% and a PPV of 40%. Given the high NPV, the investigators opined that the test can be used in those with an intermediate risk of cancer to limit further invasive testing.
It should be noted that there are some especially promising biomarker blood tests in development and yet to be tested specifically in an IPN population. Cancer personalized profiling by deep sequencing (CAPP-Seq) analyzes ctDNA to facilitate screening but levels are very low in early stage lung cancer (Chabon et al Nature 2020). The Cancer-SEEK test combines circulation proteins with ctDNA and tests for 8 common cancer types including lung cancer. The sensitivity for Stage I lung cancer is about 40% in one small study (Cohen JD et al Science 2018). A targeted methylation analysis of ctDNA was tested against 12 cancer types including lung cancer (Liu MC et al Ann Oncol 2020). The sensitivity in Stage I lung cancer was <25%.
In summary, biomarker research has progressed so that blood biomarkers are available for clinical use.
Fedewa SA et al JNCI published online November 12, 2020
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