Addition of Aspirin to Standard of Care in Oral Cancer

Overview

Despite accumulating evidence of the benefit of aspirin in cancer, its effect on improving cancer survival is still debated since the mechanism by which it impacts cancer survival is not completely understood and the published data are discordant. There have been 4 randomized controlled trials (RCT) showing mixed results from no effect to improved survival. Several retrospective and observational studies have reported a survival advantage of adding aspirin to the treatment for various cancers. A meta-analysis of 118 studies, 63 of them specifically reporting on cancer mortality and the rest on all-cause mortality, found a 21% reduction in cancer deaths and about 20% reduction in all-cause mortality (pooled hazard ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84). However, the evidence is still lacking and there is need to do more RCT

Aspirin (ASA), an NSAID, is a well-known antipyretic and analgesic agent and is used to prevent recurrent transient ischemic attacks or strokes. In addition to its classical anti- inflammatory function, clinical and epidemiological studies indicate that aspirin can be used as a preventive or therapeutic agent in multiple cancers, including oral cancers While the exact mechanism through which NSAIDs contribute to chemo prevention is not completely understood, Aspirin inhibits the enzyme Cox; Cox-1 and Cox-2 are well characterized. Cox converts a arachidonic acid to prostaglandin H2, which in turn produces biologically active prostaglandins that influence path physiological processes in a range of tissues including angiogenesis, apoptosis, cell proliferation and migration, inflammatory response and thrombosis. Inhibition of prostaglandin synthesis is considered the pre dominant mechanism by which NSAIDs act as anti-inflammatory agents, but it is unclear whether the anti-cancer properties of these agents can be solely attributed to Cox inhibition. Recently, Cox-2 over expression has been identified in a number of different malignancies and it has been hypothesized that Cox-2 prostaglandins promote tumor genesis by inhibiting apoptosis, modulating the immune system and regulating tumor associated angiogenesis. A detailed search of literature and bio informatics analysis of the data obtained showed that the effect of Aspirin on survival and prevention of recurrence and secondary cancer could be due to its effect on following 11 genes PTGS2, PIK3CA, PARP1, PARP2, VEGFA, KDR, PTGES2, NFKB1, P53, FLT1, VEGFR. These genes not only interact and control each other but also control cell cycle regulation through other genes as shown below. These could be due to co expression, physical interactions, shared domains or predicted interactions in absence of data. Based on the gene-gene and protein-protein interactions they can be clustered into three with PTGES2, PTGS2 and p53 being in first cluster (figure 2 below), the NGS data obtained from the previous patients also showed the p53 to be the primary driver gene (unpublished data, submitted) in nearly 50% of the subjects. It has also been shown that patients with p53 mutations have poor survival and increased recurrence rates compared to those without p53 mutations. This coupled with literature showing improved survival and low recurrence in patients receiving Aspirin suggest the need for a RCT as this has never been done before.