Aspirin Linked to Lower CRC Recurrence in Patients With PI3K Mutations

Three years of aspirin use reduced colorectal cancer recurrence by 50% in patients with PIK3CA mutations vs placebo.

Aspirin reduced colorectal cancer recurrence by 50% in patients with PIK3CA mutations after 3 years of use compared with placebo, as demonstrated in 3-year results from the ALASCCA trial (NCT02647099) presented at the 2025 ASCO Gastrointestinal Cancers Symposium.¹

“This is the first trial to show that mutations in this specific signal pathway, also beyond PIK3CA, predict aspirin response, expanding the target population to more than a third of the patients [with non-metastasized colorectal cancer],” Anna Martling, MD, PhD, FACS, FASCRS, Karolinska Institutet, Lund University, Akademiska University Hospital, said during a presentation of the results. “This is also an example of repurposing a safe, inexpensive, and globally available drug and it stresses the importance of genomic testing in colorectal cancer patients.”

The randomized placebo-controlled trial met its primary end point, reducing the risk for disease recurrence by 51% in patients with PIK3CA exons 9/20 (Group A; HR, 0.49; 95% CI, 0.24-0.98; P = .044) and 58% in patients with PIK3R1/PTEN/other PIK3CA alterations (Group B; HR, 0.42; 95% CI, 0.21-0.83; P = .013) with aspirin use for 3 years.

“This [hazard ratio in Group B] considerably expands the chargeable population to almost 40% of the patients,” Martling added.

In Group A, the 3-year recurrence rate was 7.7% (95% CI, 4.2%-12.5%) among those given aspirin, compared with 14.1% (95% CI, 9.2%-20.0%) in the placebo arm; the rates were 7.7% (95% CI, 4.2%-12.6%) vs 16.8% (95% CI, 11.4%-23.1%), respectively, in Group B.

As a secondary end point, there was no statistically significant difference in 3-year disease-free survival (DFS) rates among those who received aspirin vs placebo in Group A (88.5% [95% CI, 82.3%-92.6%] vs 81.4% [95% CI, 74.4%-86.7%], respectively; HR, 0.61; 95% CI, 0.34-1.08; P = .091). However, aspirin use significantly improved DFS rates in Group B (89.1% [95% CI, 83.1%-93.1%] vs 78.7% [95% CI, 71.4%-84.4%], respectively; HR, 0.51; 95% CI 0.29-0.88; P = 0.17).

In addition, Martling noted that, although the trial was not originally powered for subgroup analyses, the advantage of aspirin compared to placebo was observed in all subgroups of patients with colon cancer and rectal cancer; those who received or did not receive neoadjuvant and/or adjuvant treatment; across stage I, II, and III disease; and across females and males.

Severe adverse events occurred in 57 patients who received aspirin, compared with 38 in the placebo arm, with the most common being late post-operative complications (15 vs 8, respectively), deep vein thrombosis (9 vs 7), embolism (6 vs 4), infection (4 vs 4), heart disease (4 vs 3), inflammatory disorder (3 vs 4), and hemorrhage (4 vs 0).

“Aspirin is a well-established and a safe medical medication with well-known side effects,” Martling said. “The incidence of adverse events was as expected.”

She also highlighted the urgent need for improved therapeutic strategies and new biomarkers in colorectal cancer. “In more recent years, aspirin has been shown to reduce the number of colonic polyps in high-risk patients, as well as lower the incidence of colorectal cancer in individuals taking aspirin for cardiovascular reasons,” Martling explained, adding that previous research has also shown that post-diagnosis aspirin may eventually improve DFS. Further, evidence supported that PIK3CA mutations may be a predictor of aspirin’s treatment effect.²

Therefore, Martling et al aimed to examine the effect of aspirin on colorectal cancer recurrence by using alterations in the PIK3CA pathway as a potential predictive genetic biomarker.

“Could a safe and inexpensive and widely available drug be repurposed to prevent recurrence in early-stage colorectal cancer next?” Martling hypothesized.

Across 33 hospitals in Sweden, Denmark, Finland, and Norway, 3,508 patients were screened for an alteration in the PI3K pathway, of which 37% were identified (Group A, n = 515; Group B, n = 588). Of the 626 patients who continued to trial, 157 and 156 patients in Groups A and B, respectively, received 160 mg aspirin daily for 3 years, while 157 and 156 in each respective group received placebo.

Time to colorectal cancer recurrence (TTR) in Group A served as the primary outcome of the study, while secondary outcomes included DFS in Group A, TTR in Group B, DFS in Group B, and safety.

Median age was 66 years (range, 31-80). In total, 52% of patients were female, with 67% having been diagnosed with colon cancer (stage II, 53%), and 33% with rectal cancer (stage II, 40%). Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy.

References

1. Martling A, Lindberg J, Myrberg IH, et al. Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial. J Clin Oncol. 2025;43(4):LBA125.
2. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Eng J Med. 2012;367(17):1596-606. doi:10.1056/NEJMoa1207756.