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

Pulmonologists frequently encounter indeterminate pulmonary nodules. Predicting the risk of developing lung cancer is a difficult task as evidenced by the high rate of overdiagnosis and overtreatment of indolent disease. There is an unmet clinical need for a non-invasive, easy to administer, diagnostic assay to help prevent the potentially serious consequences of overdiagnosis. Here we report on the clinical work-up of a high-risk patient with an indeterminate pulmonary nodule. This case suggests that applying a new blood test in a point of care setting in a community-based practice can accurately characterize scan identified, or incidentally found, lung nodules. The novel assay may potentially minimize aggressive interventions in patients with benign disease. *Correspondence to: Amanda L Fish, MagArray Inc, Milpitas CA, USA, E-mail: Amanda.Fish@magarray.com Received: March 10, 2019; Accepted: March 25, 2019; Published: March 28, 2019 Introduction With cigarette smoking as the acknowledged root cause, lung cancer remains a leading cause of cancer deaths worldwide, with high mortality largely attributed to its diagnosis late in the disease process when cure is not possible [1]. The National Lung Screening Trial (NLST) brought hope that screening high-risk patients with a yearly chest low-dose CT scan could lead to a 20% relative risk reduction in lung cancer deaths [2]. This decrease in mortality was paralleled by an increase in the diagnosis of stage I non-small cell lung cancer, implying that this screening paradigm leads to decreased mortality by shifting the stage at diagnosis to an earlier, curative stage. Coupled with the increase in chest CT scans performed for lung cancer screening, CT imaging is increasingly used for the diagnosis and evaluation of thoracic and extra-thoracic disease, all leading to increased identification of pulmonary nodules [3]. In the National Lung Screening Trial (NLST), 24% of screened patients were found to have a concerning pulmonary nodule with only 4% of those ultimately determined to be malignant, even in this high-risk population [2]. The current paradigm for management of pulmonary nodules > 8 mm diameter is centered on estimates of a pretest probability for malignancy. Those nodules with a high pretest probability (> 65%) are aggressively managed (typically surgical resection), whereas those at low risk (05%) are managed conservatively. Intermediate-risk nodules (5%-65%), which constitute almost one-half of the pulmonary nodules identified by chest CT scan, require further diagnostic evaluation, including other imaging, bronchoscopy, percutaneous biopsy, or surgical biopsy [4]. Even minimally invasive procedures carry significant risks and anxiety to patients, and the cost of diagnostic evaluation increases 28fold when biopsy is performed [5,6]. Patients with intermediate-risk nodules would therefore benefit from additional risk stratification tools to determine those truly in need of more aggressive evaluation, and those for whom a less risky approach is warranted. These desires have led to considerable interest in identifying blood-based biomarkers that can differentiate lung cancer from benign disease nodules [7]. 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]. Among the 97 validation study subjects, 68 were grouped as having intermediate risk by the VA model. 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]. The novel blood test demonstrated efficacy in accurately identifying patients at low risk of lung cancer to rule-out the need for risky aggressive actions. Thus, the plasma protein assay has the potential to aid clinicians to more accurately characterize radiologically-indeterminate pulmonary nodules in current smokers Smester G (2019) Overcoming the pitfalls of current lung cancer risk assessment: Improved lung nodule characterization by a novel plasma protein biomarker test Volume 3: 2-4 Biomed Res Rev, 2019 doi: 10.15761/BRR.1000125 and help provide additional insight to support a more informed clinical decision about performing an invasive evaluation of the patient’s lung nodule [8]. Case report: Peace of mind for patient and provider The REVEAL test aids decision making and reduces the psychologic toll of uncertainty in a patient with indeterminate lung nodules and prevents unnecessary risky interventions. A 73-year-old male from the Dominican Republic presented on August 2, 2018 complaining of a dry cough and shortness of breath on exertion as well as hypertension, back and neck pain and leg cramps. He was diagnosed with COPD/Emphysema in the Dominican Republic 5 years before presenting to the clinic. He brought with him a thoracic CT (performed on 4/17/18) from his country demonstrating combined emphysema and interstitial lung disease (ILD) with reticulonodular densities in the posterior lateral right mid lung, exhibiting ground glass airspace opacities, fibrosis, and bullous disease concentrated primarily in the upper lobes. The patient had a 25-year history of smoking two packs of cigarettes per day, and over 50 years of occupational exposure to wheat flour in a factory. He had a history of gout but denied any active symptoms. The patient reported home oxygen saturations in the 80s and poor compliance with supplemental oxygen and prescribed inhalers including LABA/IC and SABA. He denied chest tightness or wheezing. His surgical history is remarkable for right shoulder rotator cuff repair, a procedure on his right wrist, and hammertoe repair. Previous blood work indicated renal insufficiency and hyponatremia, which the patient confirmed are chronic. He denied any allergies, asbestos exposure, or recreational history with lung irritants. He stated he has five domesticated dogs at his home. The patient is divorced. His social history includes daily alcohol use. He is currently retired. His family history includes a grandfather with diabetes and a brother with hypertension, obstructive sleep apnea, and psoriasis. The patient also reported several relatives with a history of colon cancer which prompts him to undergo a colonoscopy every 2 years. His physical exam was significant for slight prolonged expiration and 1+ pitting edema in both lower extremities. No rhonchus, wheezing or crackles were evident. Spirometry performed exposed small airway disease and restrictive lung disease, but not a pattern of COPD. Pulmonary function tests were ordered which revealed restrictive pattern, small airway disease and decreased DLCO. A review of symptoms was positive for acid reflux treated with Prilosec. No collagen vascular disease was evident except for mild elevation of CRP and ESR. A baseline polysomnograph was positive for severe obstructive sleep apnea syndrome. A thoracic CT was performed on August 3, 2018 per chest ILD protocol and showed bullous disease and ground glass opacification. Additionally, a dominant 7x5 mm, spiculated, LUL nodule was described for the first time. The patient was referred to the Mayo Clinic in Jacksonville, Florida for an open lung biopsy to characterize his lung pathology. However, due to his increased risk of bleeding from pulmonary hypertension, it was deferred. A repeat chest CT at Mayo Clinic in September 2018 was consistent with the findings previously described, including the lung nodule. The patient opted for surveillance of the nodule and medical management with a course of prednisone for the ILD. On October 15, 2018 a novel multiplexed, plasma-protein assay – REVEAL -was ordered to better characterize the patient’s indeterminate lung nodule found on CT. His pre-test probability, calculated by the VA Clinical Factors Model, indicted 53%, placing the patient’s risk of malignancy in the intermediate risk range. A simple, venous blood draw in the office was conducted and the plasma sent to the CLIA certified testing laboratory. The assay result was provided within three days as a score of 34 (Figure 1) indicating a 94% probability the patient’s nodule was lower-risk, benign disease. Based on this new information, the patient agreed with us to proceed with a serial surveillance strategy. Three months later, a follow up thoracic CT was performed indicating resolution of the ILD and reduction of the size of the LUL nodule to 6.2 × 2.8 mm. The prednisone was reduced and CellCept was added. From a pulmonary standpoint, the patient continues to do well. He is scheduled to return to the clinic in four months for a full PFT and a chest CT.