Study Identifies Potential Biomarkers That Predict for Celecoxib CRC Chemoprevention

Study Identifies Potential Biomarkers That Predict for Celecoxib CRC Chemoprevention

Dr. Jiping Wang
Ten years ago, the Adenoma Prevention With Celecoxib (APC) trial showed that the selective cyclooxygenase-2 (COX-2) inhibitor reduced the incidence of post-polypectomy adenoma by 38% and advanced adenoma by 63% when used in patients at high risk for the development of colorectal adenomas. Unfortunately, a small but significant attendant increase in the risk of cardiovascular toxicity precluded widespread adoption of celecoxib as a chemopreventive.

In an effort to tip the scales in favor of patients who stand to derive greatest benefit from celecoxib chemoprevention, Jiping Wang, MD, PhD, of the Dana-Farber Cancer Institute, and colleagues dug back into the APC adenoma tissue archives to identify predictors of response to celecoxib (Abstract 524).

To focus their efforts, the investigators relied on biologic markers within the COX metabolic pathway that allude to levels of prostaglandin E2 (PGE2), an inflammatory mediator implicated in cholangiocarcinogenesis. COX-2 promotes PGE2 expression, and 15-prostaglandin dehydrogenase (15-PGDH) acts to degrade PGE2 when present, such that both enzymes together function to maintain PGE2 homeostasis. “Therefore, we hypothesized that the expression of COX-2 and 15-PDGH might relate to the tumor-preventive efficacy of the selective COX-2 inhibitor celecoxib,” Dr. Wang said.

Of the original 1,822 participants with endpoint data in the APC trial, a subset of 1,295 (71%) had biomarker data available that were used for the current analysis.

The findings revealed that neither COX-2 nor 15-PGDH were prognostic for adenoma recurrence based on their pretreatment levels. Both markers did, however, show predictive strength.

Dr. Frank A. Sinicrope
The 8% of individuals with high COX-2 expression at baseline demonstrated a 63% reduction in the risk of adenoma recurrence with celecoxib chemoprevention, as compared with placebo (relative risk [RR] 0.37; p = 0.0001). This risk reduction with celecoxib was still present, but attenuated, in the remaining 92% of individuals with low baseline COX-2 expression (RR 0.64; p < 0.0001).

Likewise, the absence of 15-PGDH at baseline, identified in 89% of patients, which would theoretically lead to an accumulation of PGE2, predicted for a reduced risk of adenoma recurrence with celecoxib versus placebo (RR 0.60; p < 0.0001). In contrast, a significant chemopreventive benefit with celecoxib was not observed in the other 11% of participants with 15-PGDH present at baseline, where PGE2 levels would already be expected to be lower (RR 0.73; p = 0.15).

Synthesizing these two pieces of data, the investigators confirmed that individuals estimated to have high adenoma PGE2 levels at baseline, based on high COX-2 expression and/or absence of 15-PGDH, attained a 41% reduction in adenoma detection with celecoxib treatment as opposed to placebo (RR 0.59; p < 0.0001). As a corollary, celecoxib conferred no benefit in preventing recurrence in individuals estimated to have low adenoma PGE2 levels at baseline (RR 0.95; p = 0.82), based on low COX-2 expression and the presence of 15-PGDH.

“These results suggest that PGE2 is a significant driver of tumorigenesis in the colorectum for many, but not all, [patients with] adenoma,” Dr. Wang said.

“Going forward, we certainly need chemoprevention for our high-risk patients,” discussant Frank A. Sinicrope, MD, FACP, of the Mayo Clinic, said in his critique of these findings. “The future is precision prevention where biomarkers can be used to select patients most likely to benefit. I would congratulate the authors on their study and their attempt to try to make precision prevention a reality.”

Based on the data presented, Dr. Sinicrope believes that the 15-PGHD biomarker represents the best candidate for further analysis. “For patient selection for future trials with enrichment design, the low prevalence of high COX-2 in this study is limiting. Further evaluation of 15-PGHD certainly remains of interest,” he said, given that the absence of 15-PGHD expression clearly predicted benefit from celecoxib.

—Kara Nyberg, PhD