Discovery and Evaluation of Protein Biomarkers as a Signature of Wellness in Late-Stage Cancer Patients in Early Phase Clinical Trials

Abstract

TARGET (tumour characterisation to guide experimental targeted therapy) is a cancer precision medicine programme focused on molecular characterisation of patients entering early phase clinical trials. Performance status (PS) measures a patient’s ability to perform a variety of activities. However, the quality of present algorithms to assess PS is limited and based on qualitative clinician assessment. Plasma samples from patients enrolled into TARGET were analysed using the mass spectrometry (MS) technique: sequential window acquisition of all theoretical fragment ion spectra (SWATH)-MS. SWATH-MS was used on a discovery cohort of 55 patients to differentiate patients into either a good or poor prognosis by creation of a Wellness Score (WS) that showed stronger prediction of overall survival (p = 0.000551) compared to PS (p = 0.001). WS was then tested against a validation cohort of 77 patients showing significant (p = 0.000451) prediction of overall survival. WS in both sets had receiver operating characteristic curve area under the curve (AUC) values of 0.76 (p = 0.002) and 0.67 (p = 0.011): AUC of PS was 0.70 (p = 0.117) and 0.55 (p = 0.548). These signatures can now be evaluated further in larger patient populations to assess their utility in a clinical setting.

A proteomics study of rheumatoid arthritis patients on etanercept identifies putative biomarkers associated with clinical outcome measures

“…Frozen serum aliquots were transferred to the Stoller Biomarker Discovery Centre (SBDC, Manchester, UK), where protein spectral maps were extracted for each sample using SWATH-MS, using techniques for sample processing and data acquisition as previously described [ 11 , 12 ]. Samples were processed by the SBDC; SWATH-MS acquisition is discussed in more detail in the Supplementary Methods , available at Rheumatology online.…”

Multiomic Approaches for Cancer Biomarker Discovery in Liquid Biopsies: Advances and Challenges

“…Geary et al used a sequential window acquisition of all theoretical fragment ion mass spectra (SWATH-MS) to identify proteomics signatures in late-stage cancer patients and reported a wellness score. 51 SWATH-MS technology has high precision and accuracy that allows for protein quantification without the need for labels and has been used to identify digitized proteomic signatures in other several cancer types including breast, colorectal, endometrial, and lung cancers. [52][53][54][55] Such studies provide insights into the clinical application of these biomarkers in the diagnosis and follow-up of cancers.…”

Self‐Healing Electronics for Prognostic Monitoring of Methylated Circulating Tumor DNAs

“…[12,13] Clinically, some are used to identify cancers primarily originating from different organ systems, such as α-fetoprotein for liver cancer and germ cell tumors, [14] ß-2-microglobulin for chronic lymphocytic leukemia, [15] calcitonin for medullary thyroid cancer, [16] and prostate-specific antigen for prostate cancer. [17] Despite the wide use of these biomarkers for cancer diagnostics, these protein-based tumor markers are typically detectable at the late stages of cancer progression, [18] when the efficacy of many cancer treatments is substantially compromised. Alternatively, methylated circulating DNAs (ctDNAs) Methylated circulating DNAs (ctDNAs) have recently been reported as a promising biomarker for early cancer diagnostics, but limited tools are currently available for continuous and dynamic profiling of ctDNAs and their methylation levels, especially when such assays need to be conducted in point-of-care (POC) scenarios.…”