Mitchell Machiela

ScD MPH

National Cancer Institute

Senior Investigator

PLCO (Learn more about this study)

PLCO-1998

Nov 24, 2025

Synthetic Clinical Trial based on Polygenic Risk Scores

Polygenic Risk Scores (PRS) are a promising tool for assessing germline susceptibility based on common variants, with potential use in prevention due to its ability to identify high-risk individuals for complex phenotypes such as cancer. For example, women in the top 1% of PRS-based risk for breast cancer have a risk similar to that of a monogenic mutation, for which various risk-reduction strategies can be employed. PRS is a promising approach to implement targeted actions for risk groups. However, there is limited evidence of the clinical utility of PRS—specifically, whether its use in refining screening practices improves cancer detection and thus reduces cancer-related mortality. These studies, which are prospective, costly, and complex, will take years to yield results. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial evaluated screening for prostate, lung, colorectal, and ovarian cancers in over 150,000 individuals. Recently, 117,551 PLCO participants have been genotyped for association studies. Accordingly, PLCO data can be used to investigate the clinical utility of PRS.

Our hypothesis is that screening may reduce the risk of cancer-specific death in patients with higher PRS-based susceptibility for cancer, compared to controls with the same risk. We aim to evaluate whether individuals in the top 10% of PRS show a clinical benefit from screening programs within the PLCO protocol. We will use harmonized genotyping data from PLCO and perform PRS assessment for the four tumor types studied. We will retrospectively compare tumor-specific survival between high germline risk patients (top 10% PRS) who were included in either the screening arm or the control arm. As an indirect comparator, we will perform the same comparison for the remaining patients (bottom 90%), aiming to assess whether the benefit of screening is greater in the high-risk group.

Aim 1: Evaluate whether participants in the top 10% of risk for one of the four tumor types evaluated in the PLCO trial have greater benefit from screening. Our strategy will be to retrospectively compare tumor-specific survival (Kaplan-Meier) between high germline risk patients (top 10% PRS) who were included in either the screening arm or the control arm. As an indirect comparator, we will perform the same comparison for the remaining patients (bottom 90%), aiming to assess whether the screening benefit is exclusive or greater in the high-risk group. We also aim to perform an overall survival analysis for the entire PLCO follow-up.

Aim 2: Investigate if participants in the top 10% of risk for one of the four tumor types have tumors that are detected earlier or are less aggressive. We will compare the clinical characteristics of tumors diagnosed in high germline risk patients (top 10% PRS) who were included in either the screening or control arm. Available staging or specific markers (e.g., Gleason score for prostate cancer) will be evaluated. Additionally, the same bottom 90% comparison strategy will be used for this aim.

Aim 3: Evaluate continuous PRS (threshold-free approach) on screening effectiverness. The PLCO PRS data will be used to estimate potential optimal PRS cutoffs for screening inclusion. We will use a Cox regression with tumor-specific survival and continuous PRS to assess the association between PRS and screening impact.

Aim 4: Evaluate if incorporating an overall survival PRS with tumor-specific PRS helps refine the screening benefit. We will incorporate an overall survival PRS into the risk model of cancer-specific PRS to exclude patients with low probability of more than 5 years of life.