Risk assessment for indeterminate pulmonary nodules using a novel, plasma-protein based biomarker assay

Abstract

Background: The increase in lung cancer screening is intensifying the need for a noninvasive test to characterize the many indeterminate pulmonary nodules (IPN) discovered. Correctly identifying non-cancerous nodules is needed to reduce overdiagnosis and overtreatment. Alternatively, early identification of malignant nodules may represent a potentially curable form of lung cancer. Objective: To develop and validate a plasma-based multiplexed protein assay for classifying IPN by discriminating between those with a lung cancer diagnosis established pathologically and those found to be clinically and radiographically stable for at least one year. Methods: Using a novel technology, we developed assays for plasma proteins associated with lung cancer into a panel for characterizing the risk that an IPN found on chest imaging is malignant. The assay panel was evaluated with a cohort of 277 samples, all from current smokers with an IPN 4–30 mm. Subjects were divided into training and test sets to identify a Support Vector Machine (SVM) model for risk classification containing those proteins and clinical factors that added discriminatory information to the Veteran’s Affairs (VA) Clinical Factors Model. The algorithm was then evaluated in an independent validation cohort. Results: Among the 97 validation study subjects, 68 were grouped as having intermediate risk by the VA model of which the SVM model correctly identified 44 (65%) of these intermediate-risk samples as low (n=16) or high risk (n=28). The SVM model negative predictive value (NPV) was 94% and its sensitivity was 94%. Conclusion: The performance of the novel plasma protein biomarker assay supports its use as a noninvasive risk assessment aid for characterizing IPN. The high NPV of the SVM model suggests its application as a rule-out test to increase the confidence of providers to avoid aggressive interventions for their patients for whom the VA model result is an inconclusive, intermediate risk.

Analytical validation of a novel multi-analyte plasma test for lung nodule characterization

“…Biomarker candidates for which sensitive and specific assays could be developed to measure subtle changes in circulating levels associated with the presence of lung cancer where advanced through the assay development and characterization process. We evaluated the customized assays in early discovery work to measure the biomarker levels in a cohort of subjects from an observational study of PET-CT imaging for lung cancer [ 15 ]. Those studies identified that the plasma levels of EGFR, ProSB, and TIMP1 in current smokers were the most informative in assessing the likelihood of malignancy in subjects with an indeterminate lung nodule.…”

“…The SVM model output is a score from 0 to 100% that indicates the probability of malignancy for the nodule. A cutoff value of 50% was identified from earlier training and validation studies as the optimal separation between nodules at lower risk from those at higher risk of being malignant [ 15 ].…”

Overcoming the pitfalls of current lung cancer risk assessment: Improved lung nodule characterization by a novel plasma protein biomarker test

“…The biomarker algorithmbased test correctly identified 44 (65%) of these intermediate-risk samples as lower risk (n = 16) or higher risk (n = 28). The test showed a sensitivity of 94% and a negative predictive value (NPV) of 94% [8] in the intended use population having a cancer prevalence rate of 25% [10]. Almost all subjects (98%) had early stage disease as defined by lung cancer Stage I or II [8].…”

“…A recent publication highlights the clinical validation and performance of a novel, multiplexed, plasma protein signature as a risk assessment tool [8]. The authors established the assay's ability to aid in correctly identifying the risk of malignancy for a pulmonary nodule that falls into the inconclusive intermediate risk for lung cancer as calculated by the VA Clinical Factors Model [9].…”

“…The assay was evaluated with a set of 277 samples, all from current smokers with an indeterminate pulmonary nodule 4-30 mm in diameter from which an algorithm was defined for risk classification. The assay and algorithm were then evaluated in an independent validation cohort of 97 subjects [8].…”