Discussion
obesity, colorectal cancer, early-stage cancer, cancer, malignancy, tumour
OBESITY, COLORECTAL CANCER, RECURRENCE, GASTROINTESTINAL CANCERS, CANCER, INFLAMMATION, DISEASE, TUMOUR
To our knowledge, this is the largest and most detailed study of thromboxane biosynthesis in patients with early-stage cancer. Increased levels of U-TXM excretion were found in all the tumour cohorts compared to previous studies of healthy individuals measured in the same laboratory [Consistent with previous literature, high U-TXM levels at baseline were also associated with known inflammatory stimuli, or markers thereof, including high BMI, a history of smoking, raised total white cells, neutrophils, and higher platelet counts [The biological plausibility of, and supporting evidence, for the role of platelet activation in colorectal cancer has been reviewed previously [Aspirin’s main mechanism of action at low dose (75–100 mg daily) is the acetylation of platelet COX-1 at serine-529 [The present findings in cancer patients are consistent with the saturability of platelet COX-1 inactivation at low aspirin doses with a three-quarter reduction in TXAIncreasing age, cigarette smoking and obesity all lead to chronic, low-grade inflammation, and are independently well-defined aetiological factors associated with malignancy, attributed in part to their effects on platelet activation [The mechanism(s) by which aspirin exerts an anti-cancer effect remains speculative, but our data suggest a plausible link between the known pharmacological effects of aspirin and previous clinical observations by demonstrating persistently enhanced thromboxane ASince this study was embedded within a randomised-controlled trial which incorporates a placebo arm, it provides a robust and valuable dataset for investigating the effects of aspirin on thromboxane biosynthesis. Nevertheless, there are some limitations. U-TXM is one major enzymatic metabolite of TXAOther limitations of this study are in part related to the design of the main trial including the range of aspirin doses that could be evaluated. Additionally, measurement of serum TXBIn summary, this study found that patients who have had a recent diagnosis of cancer and radical therapy showed evidence of persistently increased thromboxane biosynthesis as measured by U-TXM excretion compared to healthy individuals. This was most marked in the colorectal and gastro-oesophageal participants independent of pro-inflammatory baseline characteristics and recent anti-cancer treatment. Our findings show comparable suppression of U-TXM with aspirin 100 and 300 mg daily and are consistent with the saturability of platelet COX-1 inactivation at low doses. Within this cohort of participants adherence with randomly allocated blinded treatment appeared good. These findings may help interpret the clinical results of the Add-Aspirin trial and other aspirin oncology trials subsequently. This is particularly important given the differences we have observed between the tumour types in this study; as with other anti-cancer drugs the effects of aspirin may vary with different cancer types, molecular pathways driving the disease and the specific tumour microenvironment. Further studies are required to assess whether regular monitoring of U-TXM levels might provide an early indicator of tumour development or recurrence and a novel biomarker particularly in gastrointestinal cancers.