Identifying Novel Biomarkers Ready for Evaluation in Low-Prevalence Populations for the Early Detection of Upper Gastrointestinal Cancers: A Systematic Review

Natalia Calanzani, Paige E. Druce, Claudia Snudden, Kristi M. Milley, Rachel Boscott, Dawnya Behiyat, Smiji Saji, Javiera Martinez-Gutierrez, Jasmeen Oberoi, Garth Funston, Mike Messenger, Jon Emery, Fiona M. Walter

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Detecting upper gastrointestinal (GI) cancers in primary care is challenging, as cancer symptoms are common, often non-specific, and most patients presenting with these symptoms will not have cancer. Substantial investment has been made to develop biomarkers for cancer detection, but few have reached routine clinical practice. We aimed to identify novel biomarkers for upper GI cancers which have been sufficiently validated to be ready for evaluation in low-prevalence populations.

We systematically searched MEDLINE, Embase, Emcare, and Web of Science for studies published in English from January 2000 to October 2019 (PROSPERO registration CRD42020165005). Reference lists of included studies were assessed. Studies had to report on second measures of diagnostic performance (beyond discovery phase) for biomarkers (single or in panels) used to detect pancreatic, oesophageal, gastric, and biliary tract cancers. We included all designs and excluded studies with less than 50 cases/controls. Data were extracted on types of biomarkers, populations and outcomes. Heterogeneity prevented pooling of outcomes.

We identified 149 eligible studies, involving 22,264 cancer cases and 49,474 controls. A total of 431 biomarkers were identified (183 microRNAs and other RNAs, 79 autoantibodies and other immunological markers, 119 other proteins, 36 metabolic markers, 6 circulating tumour DNA and 8 other). Over half (n = 231) were reported in pancreatic cancer studies. Only 35 biomarkers had been investigated in at least two studies, with reported outcomes for that individual marker for the same tumour type. Apolipoproteins (apoAII-AT and apoAII-ATQ), and pepsinogens (PGI and PGII) were the most promising biomarkers for pancreatic and gastric cancer, respectively.

Most novel biomarkers for the early detection of upper GI cancers are still at an early stage of matureness. Further evidence is needed on biomarker performance in low-prevalence populations, in addition to implementation and health economic studies, before extensive adoption into clinical practice can be recommended.
Original languageEnglish
Pages (from-to)793-834
Number of pages37
JournalAdvances in Therapy
Early online date11 Dec 2020
Publication statusPublished - Feb 2021

Bibliographical note

This study and the journal’s rapid service fee were supported by the CanTest Collaborative (funded by Cancer Research UK C8640/A23385) of which Fiona M. Walter is Director, Jon Emery is an Associate Director, Mike Messenger is co-investigator, and Natalia Calanzani and Garth Funston are researchers. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Paige Druce, Kristi Milley and Jon Emery are supported by the Cancer Australia Primary Care Collaborative Cancer Clinical Trials Group (PC4). Mike Messenger is funded by the NIHR Leeds In Vitro Diagnostic Co-operative (UK). No Open Access Fee was received by the journal for the publication of this article.

Data Availability Statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.


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