Volker Liebenberg

M.D.

Elypta AB

Chief Medical Officer

PLCO (Learn more about this study)

2023-0081

Jan 16, 2024

Cancer risk assessment by GAGome - a noninvasive biomarker for risk-stratified multi-cancer early detection

Early detection of cancer can reduce cancer mortality and liquid biopsy tests hold promise for further improvement enabling multi-cancer early detection (MCED). In line with NCI Division of Cancer Prevention vision, Elypta’s research focuses on MCED biomarkers based on cancer metabolism.
This project proposal emerged from the discovery, that glycosaminoglycan profiles (GAGomes) non-invasively detect multiple types of cancer at an early stage showing exceptional performance in a blinded Dutch population study (Bratulic et al. (2022), https://doi.org/10.1073/pnas.2115328119). With this project, Elypta aims to assess the performance of a novel metabolic cancer biomarker test in a US population to predict the risk of developing cancer and explore benefits of combining GAGome testing with risk models (e.g., PLCOm2012) and MD Anderson Cancer Center's emerging risk biomarkers (Fahrmann et at. (2022), https://doi.org/10.1200/JCO.21.01460) and (Irajizad et al. (2023) https://ascopubs.org/doi/10.1200/JCO.22.02424).
Elypta aims to conduct a MCED biomarker study by determining 1) how well GAGome testing distinguishes between asymptomatic individuals who later developed cancer from those who did not; and 2) how early, before clinical diagnosis, GAGomes can detect cancer. The study is designed as a retrospective population-based nested case-control study to evaluate the performance of the MCED test in lung cancer first and consider including additional cancer types later. Elypta envisions a MCED test, that predicts the risk of developing any-type cancer non-invasively to stratify for further interventions which have shown to shift the stage at cancer diagnosis and improve survival.
The biomarker technology is based on research that demonstrated the cancer-specific reprogramming of glycosaminoglycan (GAG) metabolism. GAGs are long unbranched polysaccharides which are biologically important for tumor growth and invasion, which is thought to be largely regulated thanks to their complex structural profile – or GAGome. Elypta developed mass spectrometry kits to measure the GAGome (Tamburro et al. (2021), http://dx.doi.org/10.1016/j.jchromb.2021.122761). In Bratulic et al. (2022), the test was able to detect any cancer with AUC = 0.83–0.93 and up to 62% sensitivity for stage I cancer at 95% specificity, and also predicted the putative cancer location with 89% accuracy. These findings were validated in a screening-like Dutch population study predicting the diagnosis of any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I) and 99% specificity combining plasma and urine measurements. Overall, GAGomes appeared to be powerful MCED metabolic biomarkers additive to alternative biomarkers (e.g., methylated cell-free DNA), potentially doubling the number of stage I cancers detection.
The value of PLCO samples in the here proposed project is the rapid assessment of the new biomarker in a US population together with data from established risk models and emerging biomarkers (e.g. 4MP, Ostrin et al. (2021), https://doi.org/10.1016/j.jtho.2020.09.024) to further improve and implement cancer risk prediction.

The proposed project has the following specific aims:
• Specific aim #1: Validate the clinical performance (sensitivity, specificity, proportion of subjects diagnosed within 5 years) of a plasma GAGome IVD-grade (i.e., pre-specified and analytically validated) test for the prediction of the 5-year risk of developing lung cancer across subjects in the PLCO study population representative of a cancer screening population.
• Specific aim #2: Analysis of the GAGome performance relationship to the PLCO’s lung cancer risk model (PLCOm2012) and comparison with emerging risk biomarkers (e.g. 4MP) based on available data (see support letter from MD Anderson Cancer Center).
• Specific aim #3: Compute patient survival by test result in the target population.

To achieve the above aims, for this project we request access to data (cancer diagnosis, cancer risk factors and biomarker data, if available, e.g. 4MP) from at least 47,636 PLCO trial participants eligible for the GAGome-based cancer risk test with the aim to analyse specimens from >5778 study participants. 5315 subjects that did not develop cancer in 5 years (nested controls) and 463 cases that developed lung cancer within 5 years of specimen collection (nested cases). A full GAGome analysis requires 150 uL of plasma per analysis.