Adding Protein EpiScores May Better Predict CRC Survival

DNA methylation-derived biomarkers called Protein EpiScores may improve the accuracy of disease-free and overall survival prediction in patients with colorectal cancer (CRC), compared with traditional clinical risk factors alone, suggest results of a prospective study.

Although Protein EpiScores require further validation before they are ready for clinical use, the present data offer insights into the underlying processes shaping CRC outcomes, lead author Alicia R. Richards, PhD, of Moffitt Cancer Center, Tampa, Florida, and colleagues wrote in Clinical Epigenetics.

“The immediate value of our findings is highlighting biological pathways like immune suppression and coagulation as drivers of poor outcomes,” senior author Jacob K. Kresovich, PhD, of Moffitt Cancer Center, told Medscape Medical News.

What Are Protein EpiScores?

Previous studies have evaluated epigenetic clocks, which are derived from DNA methylation profiles, as markers for CRC risk. However, these clocks cannot pinpoint specific biological drivers of cancer progression, the investigators wrote.

Protein EpiScores may fill this gap; they were developed based on previous work suggesting that DNA methylation profiles may improve disease prediction based on circulating proteins (eg, C-reactive protein) and physiologic traits (eg, smoking status) beyond directly measuring those same variables.

“Protein EpiScores may therefore represent a complementary class of biomarker to direct measurements,” the investigators wrote.

Although Protein EpiScores have helped uncover biological processes driving various conditions such as cardiovascular disease and cancer, this is the first study to evaluate them specifically in the context of cancer survival.

How Did This Study Evaluate Protein EpiScores in Patients With CRC?

The present study involved 136 patients with newly diagnosed CRC from the prospective ColoCare Study.

For each patient, the investigators recorded 107 Protein EpiScores from pretreatment whole blood samples. Disease-free and overall survival were monitored over a median follow-up of 7.3 years and as long as 13.8 years. During follow-up, 26% of patients experienced disease recurrence, and 35% died.

With these data, the investigators compared the predictive power of the Protein EpiScores vs traditional clinical risk factors for disease-free and overall survival. “We used the standard factors doctors routinely collect before treatment starts to assess prognosis, including tumor stage, age at cancer diagnosis, sex, body mass index, race, and tumor location,” Kresovich said. “These are well-established predictors readily available from medical records.”

What Were the Key Findings?

Adding specific Protein EpiScores to the standard clinical risk factors significantly improved prognostic accuracy for survival.

After adjusting for confounding variables, the HCII, VEGFA, CCL17, and LGALS3BP Protein EpiScores were each independently associated with worse disease-free survival, with hazard ratios ranging from 1.62 to 1.71. Adding these scores to the clinical model improved the concordance index (C-index) from 0.64 to 0.70.

The LGALS3BP Protein EpiScore was also independently linked to overall survival, with a hazard ratio of 1.80. Adding this score to the model raised the C-index from 0.70 to 0.75.

Finally, the HCII, LGALS3BP, MMP12, and VEGFA Protein EpiScores were tied to both disease-free and overall survival with hazard ratios above 1.50.

Are These Findings Practice-Changing?

“The improvements [in prognostic accuracy] are modest but potentially meaningful and comparable to gains from other established biomarkers,” Kresovich said. “The 6-point improvement for recurrence (C-index 0.64 to 0.70) resulted in 34% of patients being reclassified into more accurate risk categories.”

In theory, this could have a meaningful clinical impact.

“In cancer care, even incremental gains matter if they prevent undertreating high-risk patients or overtreating low-risk ones,” Kresovich said.

Despite this potential, he was clear that more work is needed.

“If our findings are validated in other epidemiologic settings, these Protein EpiScores could eventually complement existing risk tools, but we’re realistically several years from clinical implementation,” Kresovich said. “We see these current findings more as a research tool that requires validation in larger cohorts before clinical use.”

How Might These Findings Shape Future Research?

Although more studies are needed before clinical rollout, the present findings point to key biological pathways, such as those involving immune suppression and coagulation, which may be driving worse outcomes in patients with CRC.

“This information can guide basic scientists and mechanistic studies to identify potential therapeutic targets,” Kresovich said.

Beyond evaluating Protein EpiScores in larger patient populations, future studies may also need to recruit a more diverse patient population, given the present cohort was 93% White.

Although the investigators noted that “the racial homogeneity reduced potential confounding by ancestry,” they also explained that “Protein EpiScores were developed in European populations, and their translation to individuals with different ancestries has not been closely examined.”

The study was supported by the Miles for Moffitt Team Science Mechanism. The investigators reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.