Genomic Tests Identify Aggressive Prostate Cancer Missed by Biopsy

Genomic testing can identify biologically aggressive prostate cancer tumors that standard biopsies fail to detect, according to recent research evaluating the Cell Cycle Progression (CCP) score. About 7% of patients had Grade Group 5 disease, the most aggressive form of prostate cancer, despite biopsy showing lower-grade cancer.

The CCP genomic score independently predicted hidden aggressive disease. Combining CCP with CAPRA clinical risk significantly improved predictive accuracy. Patients with both high CCP and high CAPRA scores had a dramatically higher probability of Grade Group 5 at final pathology.

Biopsy undergrading remains one of the biggest challenges in prostate cancer. Some patients classified as low or intermediate risk may actually harbor Grade Group 5 disease. Genomic profiling is helping move closer to true precision medicine in prostate cancer. By integrating molecular biology with clinical risk models, clinicians can better identify patients who need treatment intensification and reduce the risk of undertreating aggressive disease.

In separate research, a genome-scale CRISPR-based screen revealed PTGES3 as an unexpected vulnerability in advanced prostate cancer. Researchers performed the screen by systematically turning down thousands of genes one at a time, asking which genes are required for prostate cancer cells to maintain androgen receptor (AR) protein levels.

PTGES3 had not been well studied in prostate cancer. It has been linked to inflammation and steroid receptor chaperoning, but its role in AR-driven disease was unclear. When the team suppressed PTGES3, AR protein levels dropped sharply. Prostate cancer cells stopped dividing, entered cell-cycle arrest and ultimately died.

This effect was observed not only in standard AR-driven prostate cancer models, but also in aggressive and drug-resistant settings, including cancers resistant to enzalutamide, a drug used to treat certain types of prostate cancer. Clinical tumor data further showed that PTGES3 expression is associated with resistance to AR-directed therapies, suggesting it may play a role in the most difficult-to-treat forms of prostate cancer.

PTGES3 was previously thought to act mainly outside the nucleus, helping stabilize steroid receptors in the cytoplasm. But the researchers discovered that PTGES3 also appears inside the nucleus, where AR binds DNA and activates gene programs that drive tumor growth. Rather than acting only as a supporting chaperone outside the nucleus, PTGES3 plays a direct role in AR's function at its target genes.

Using a combination of biochemical experiments and structural modeling, the team showed that PTGES3 binds directly to AR and helps AR engage chromatin, an essential step in activating AR-regulated genes. In other words, PTGES3 is not only helping maintain AR stability, it is also supporting AR's function inside the nucleus.

The discovery of PTGES3's essential role highlights a potential vulnerability in advanced prostate cancer. Many therapy-resistant tumors escape treatment by restoring AR signaling through amplification, mutation, splice variants, or other mechanisms. Because these resistance pathways ultimately converge on maintaining AR activity, targeting a key AR-support factor like PTGES3 could represent a new therapeutic strategy.

By identifying PTGES3 as an essential AR partner, the study points to a new way to attack prostate cancers that have become resistant to current AR-targeted therapies. The findings may also have broader implications beyond prostate cancer. Other hormone-driven cancers, including breast cancer, rely on related nuclear receptor pathways.

The study was supported by the Prostate Cancer Foundation, the Pacific Northwest Prostate Cancer SPORE, the Institute for Prostate Cancer Research, the Mike Slive Foundation for Prostate Cancer Research, grants from the National Institutes of Health, and multiple collaborative research programs focused on improving outcomes for patients with advanced, drug-resistant prostate cancer.