The serum-based VeriStrat® test is associated with proinflammatory reactants and clinical outcome in non-small cell lung cancer patients

Abstract

BackgroundThe VeriStrat test is a serum proteomic signature originally discovered in non-responders to second line gefitinib treatment and subsequently used to predict differential benefit from erlotinib versus chemotherapy in previously treated advanced non-small cell lung cancer (NSCLC). Multiple studies highlight the clinical utility of the VeriStrat test, however, the mechanistic connection between VeriStrat-poor classification and poor prognosis in untreated and previously treated patients is still an active area of research. The aim of this study was to correlate VeriStrat status with other circulating biomarkers in advanced NSCLC patients – each with respect to clinical outcomes.MethodsSerum samples were prospectively collected from 57 patients receiving salvage chemotherapy and 70 non-EGFR mutated patients receiving erlotinib. Patients were classified as either VeriStrat good or poor based on the VeriStrat test. Luminex immunoassays were used to measure circulating levels of 102 distinct biomarkers implicated in tumor aggressiveness and treatment resistance. A Cox PH model was used to evaluate associations between biomarker levels and clinical outcome, whereas the association of VeriStrat classifications with biomarker levels was assessed via the Mann-Whitney Rank Sum test.ResultsVeriStrat was prognostic for outcome within the erlotinib treated patients (HR = 0.29, p < 0.0001) and predictive of differential treatment benefit between erlotinib and chemotherapy ((interaction HR = 0.25; interaction p = 0.0035). A total of 27 biomarkers out of 102 unique analytes were found to be significantly associated with OS (Cox PH p ≤ 0.05), whereas 16 biomarkers were found to be associated with PFS. Thrombospondin-2, C-reactive protein, TNF-receptor I, and placental growth factor were the analytes most highly associated with OS, all with Cox PH p-values ≤0.0001. VeriStrat status was found to be significantly associated with 23 circulating biomarkers (Mann-Whitney Rank Sum p ≤ 0.05), 6 of which had p < 0.001, including C-reactive protein, IL-6, serum amyloid A, CYFRA 21.1, IGF-II, osteopontin, and ferritin.ConclusionsStrong associations were observed between survival and VeriStrat classifications as well as select circulating biomarkers associated with fibrosis, inflammation, and acute phase reactants as part of this study. The associations between these biomarkers and VeriStrat classification might have therapeutic implications for poor prognosis NSCLC patients, particularly with new immunotherapeutic treatment options.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4193-0) contains supplementary material, which is available to authorized users.

Mass Spectrometry-Based Multivariate Proteomic Tests for Prediction of Outcomes on Immune Checkpoint Blockade Therapy: The Modern Analytical Approach

“…Processes with p values for association with test classification <0.05 are identified as significant. The results were consistent with previously published data: Systemic responses of the innate immune system related to acute inflammation, acute phase, and complement activation showed significant associations with the tests studied, with higher levels of these processes in the poor prognosis test classification subgroups [43,51,53]. Components of complement system, acute phase reaction, and acute inflammation are now recognized as a major regulators of cancer development and progression [58][59][60].…”

“…Similar results are also observed for 3-year survival landmark, Table 2. Both tests have been validated in multiple independent cohorts of melanoma patients [43,46,53] treated with ICIs; the BDX008 test has also shown potential utility in NSCLC patients treated with nivolumab [50].…”

“…The VeriStrat test, originally developed for prediction of benefit from EGFR-TKIs in NSCLC, has been validated in numerous independent studies, demonstrating strong predictive [48,53] and prognostic [54][55][56] properties in various settings. For the purpose of this review we summarize the results of the application of the VeriStrat test to samples from advanced NSCLC patients treated with nivolumab in second and higher lines in the Lung cancer validation set [50], and with various immune checkpoint inhibitors in the scope of the INSIGHT registry study (NCT03289780) [49].…”

Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer

“…Gene set enrichment analysis showed correlation between the VeriStrat test and acute phase response, which provides the mechanistic underpinning of the prognostic utility of the test. Taken together, these data indicate that VeriStrat is in fact a multivariate blood test that assesses multiple aspects of the patient's circulating proteome in assigning good and poor labels .…”

The Translational Status of Cancer Liquid Biopsies

“…Another successful example of a commercialized liquid biopsy test is Veristrat (Biodesix). Veristrat classifies NSCLC patients as "Good" or "Poor" based on a multivariate MALDI-TOF proteomics blood test via detection of inflammatory states associated with aggressive lung cancer [314,315]. Veristrat was used for patient stratification in a randomized phase III multi-center clinical trial with the goal of measuring survival and response to EGFR-TK inhibitor (erlotinib) or chemotherapy [316].…”