Document text
Principal Investigator: Steven J Skates
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $390,494
Funding agency: National Cancer Institute
Project Summary
This project aims to discover and validate plasma biomarkers for the early detection of ovarian cancer. A
hallmark of cancer is uncontrolled cell division, leading to a doubling time of the tumor. This exponential growth
stands in stark contrast to the stable or slowly changing profile of plasma proteins in almost all other diseases
or in healthy subjects. This project will leverage this unique hallmark to discover and validate plasma protein
biomarkers for the early detection of ovarian cancer. We will discover early detection (ED) plasma protein
biomarkers by identifying the proteins that significantly rise over time in an exponential fashion in a substantial
fraction of cases and yet remain relatively stable over time in most controls. This requires plasma assays over
a large suite of proteins with CVs lower than the protein's biological variation over time which can be as low as
a CV of 10%. Furthermore, a low volume requirement is essential for access to precious biospecimens formed
from long-term large early detection trials. Olink AB has developed proximity extension assays (PEAs) for a
suite of ~1,500 proteins with CVs ranging from 6-12% and with a minimal volume requirement of
3 µL. Applying the Olink proteomic assays to serial pre-diagnostic plasma from subjects in the PLCO who were
diagnosed with ovarian cancer during the study (cases n=50) and to serial plasma samples from a 4:1
matched control (n=200) : case (n=50) cohort will provide longitudinal data on ~1,500 plasma proteins from
cases and controls by which to identify ED candidate biomarkers. Prior to cancer developing in each case, a
biomarker will be stable over time, while after cancer inception the biomarker will rise exponentially reflecting
tumor doubling. This behavior is represented by a change-point model in cases while the same biomarker in
women without ovarian cancer (controls) will have a flat profile. ED biomarkers will be the proteins which have
a change-point in a substantial fraction of cases while remaining stable in most (98%) controls. We will identify
the top 20 ED biomarkers where the criteria for inclusion is a combination of fraction of cases, complementarity
to proteins already selected, and time of rise with earlier risers having priority. After identification of the 20 ED
biomarkers, Olink will develop a custom panel of 20 ED markers with absolute quantification. The custom
panel will assay the same PLCO plasma samples as used in discovery. These data will be analyzed with a
multivariate longitudinal change-point model to form a multiple marker longitudinal algorithm for ED. This
classifier will be locked down. The classifier will be validated by assaying the custom panel of 20 ED
biomarkers on an independent PLCO serial plasma sample set, from cases (n=50) and 10:1 matched controls
(n=500). From these data the classifier will be assessed for two dimensions of sensitivity for early detection: (i)
the number of months prior to detection in PLCO, and (ii) proportion of cases detected, while (iii) maintaining a
high specificity goal of 98% - or a false positive rate of 2%. This low false positive rate requires a large number
of controls (n=500) for its accurate assessment.
Terms: <2-dimensional><Acute-Phase Proteins><Acute-Phase Reactants><Age><Algorithms><Assay><Behavior><Bioassay><Biological><Biological Assay><Biological Markers><Blood Plasma><Blood Proteins><Blood Sample><Blood Serum><Blood specimen><CA-125><CA-125 Antigen><CA125><Cancer Antigen 125><Cancer Cause><Cancer Etiology><Cancers><Carbohydrate Antigen 125><Cell Communication and Signaling><Cell Signaling><Cell division><Consumption><Custom><Data><Detection><Diagnosis><Diagnostic><Disease><Disorder><EP4><Early Diagnosis><Early identification><Epididymal Secretory Protein E4><Generalized Growth><Goals><Growth><HE4><High Risk Woman><Inflammation><Intracellular Communication and Signaling><Investigation><Light><Longitudinal Studies><Major Epididymis-Specific Protein E4><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Measures><Modeling><Ovary Cancer><Pattern><Performance><Persons><Photoradiation><Pilot Projects><Plasma><Plasma Proteins><Plasma Serum><Probabilistic Models><Probability><Probability Models><Process><Proteins><Proteomics><Putative Protease Inhibitor WAP5><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Sampling><Screening for Ovarian Cancer><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Statistical Models><Symptoms><Technology><Test Result><Testing><Time><Tissue Growth><Validation><Variant><Variation><WAP Four-Disulfide Core Domain Protein 2><WAP5><WFDC2><WFDC2 gene><Woman><Women's trial><ages><analyzing longitudinal><arm><at-risk females><at-risk women><bio-markers><biobank><biologic><biologic marker><biological signal transduction><biomarker><biomarker discovery><biomarker identification><biorepository><blood-based biomarker><blood-based marker><cancer biomarkers><cancer diagnosis><cancer markers><candidate biomarker><candidate marker><cohort><customs><dJ461P17.6><detection sensitivity><early biomarkers><early detection><early detection biomarkers><early detection markers><female trial><females at high risk><high risk females><identification of biomarkers><identification of new biomarkers><long-term study><longitudinal analysis><longitudinal outcome studies><longterm study><malignancy><marker identification><mortality><neoplasm/cancer><new technology><novel><novel technologies><ontogeny><ovarian cancer><ovarian cancer detection><ovarian cancer early detection><ovarian cancer early screening><pilot study><programs><protein biomarkers><protein markers><response><screening><screenings><statistical linear mixed models><statistical linear models><trial among women><trial in females><trial in women><tumor><two-dimensional><validations><women at high risk>