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 ( Celebrex ) 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, of the Dana-Farber Cancer Institute, and colleagues dug back into the APC adenoma tissue archives to identify predictors of response to Celecoxib.
To focus their efforts, the researchers 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, researchers hypothesized that the expression of COX-2 and 15-PDGH might relate to the tumor-preventive efficacy of the selective COX-2 inhibitor Celecoxib,
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.
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 less than 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 less than 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 researchers 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 less than 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. ( Xagena )
Source: Gastrointestinal Cancers Symposium, 2017