Aspirin as a weapon against colorectal carcinomas.

A cheap, trusted medication can do more than just relieve pain: aspirin can reduce the risk of recurrence of a genetically determined colorectal carcinoma.

Aspirin lowers the risk of colorectal adenomas and carcinomas in people with a genetic predisposition to these tumours. Observational studies also suggest that patients who use aspirin after their diagnosis remain disease-free for longer, especially in tumours with a PIK3CA mutation. The Karolinska Institute in Stockholm investigated whether this effect can also be observed in a randomized study.

The antitumour effect of aspirin is believed to stem from inhibition of cyclo-oxygenase-2 (COX-2), an enzyme that is overexpressed in many colorectal tumours. COX-2 increases the production of prostaglandin E₂ (PGE₂), which activates the PI3K–AKT–mTOR signalling pathway and thereby stimulates cell and tumour growth. By inhibiting COX-2, aspirin disrupts an important mechanism through which cancer cells promote their growth.

In 33 hospitals in Sweden, Norway, Denmark, and Finland, patients aged 18–80 with radically resected colon carcinoma (stage II or III) or rectal carcinoma (stage I–III) were screened. Of the nearly 3,000 patients, 37% had a genetic alteration in the PI3K signalling pathway. Half of these patients received 160 mg of aspirin daily for three years, while the other half received a placebo. A distinction was made between patients with PIK3CA hotspot mutations in exon 9 or 20 and patients with other relevant mutations in PIK3CA, PIK3R1, or PTEN.

After three years, the difference between the two groups was substantial. In patients with a PIK3CA hotspot mutation, recurrence occurred in 7.7% of aspirin users compared with 14.1% of placebo users (hazard ratio (HR): 0.49; 95% CI: 0.24–0.98; p = 0.04). For other mutations in the PI3K signalling pathway, the figures were similar: 7.7% versus 16.8% (HR: 0.42; 95% CI: 0.21–0.83).

Disease-free survival was also better in the aspirin group: for PIK3CA hotspot mutations 88.5% versus 81.4% (HR: 0.61; 95% CI: 0.34–1.08), and for other mutations in the PI3K pathway 89.1% versus 78.7% (HR: 0.51; 95% CI: 0.29–0.88).

Aspirin was generally well tolerated. Severe adverse events—such as postoperative complications, deep-vein thrombosis, embolisms, and infections—were slightly more common in aspirin users (16.8%) than in placebo users (11.6%).

In this randomized study, aspirin as adjuvant therapy halved the risk of recurrence of colorectal carcinoma in patients with a PIK3CA hotspot mutation. The benefit appeared similar in other genetic abnormalities in the PI3K signalling pathway. According to the researchers, a simple, low-cost treatment with aspirin in patients with genetically determined colorectal carcinoma may make the difference between disease recurrence and lasting remission.