An aspirin a day keeps cancer at bay

Abstract

It has long been hypothesised that aspirin prevents cancer deaths by preventing metastasis. A recent study demonstrates this to be mediated through inhibition of Thromboxane A₂ (TXA2) leading to reversal of suppression of T cell immunity. I appraise the context and future research implications of these findings.

Aspirin prevents cancer development and metastasis

The benefit of aspirin in reducing cancer-risk started becoming apparent in the 1980s [1, 2] and by the middle of the second decade of the 21st century a very large body of evidence [3–5] had accumulated indicating that aspirin reduces incidence of and deaths due to certain cancers, particularly colorectal cancer. It was also apparent from synthesis of this evidence [3, 5] that the magnitude of aspirin’s effect in preventing deaths due to such cancers is greater than its effect in preventing development of these cancers (Tables 1 and 3 in Cuzick et al. [3]). It was therefore hypothesised [3, 5] that aspirin prevents cancer metastasis, very likely through its anti-platelet action but the exact mechanism of action remained unclear. A recent comprehensive animal model study by Yang and colleagues [6] has now shed light on the possible mechanism. It suggests that platelet-derived Thromboxane A₂ (TXA2) activates the ARHGEF1 pathway that then suppresses T cell immunity directed against metastasis. Aspirin abrogates TXA2 signal and prevents suppression of T cell immunity, thus leading to fewer metastases. Although the authors investigated breast cancer mouse models for some aspects and also investigated development of liver metastases where the effects were much weaker, the vast majority of work focussed on lung metastases using a melanoma cell line. Current evidence suggests that aspirin’s effects are cancer-specific [1, 2] and robust evidence to suggest its effect in melanoma is lacking. Therefore, it is possible that these effects may not be observed for other cancer types or for other metastatic sites, possibly due to varying role of T cell immunity. However, this study provides the most plausible explanation yet of the effects of low-dose aspirin observed in a large body of evidence.

We have previously reviewed possible mechanisms of aspirin’s anticancer action [2]. Since then, a mechanism for prevention of colorectal cancer through modification of gut microbiome, particularly potentially carcinogenic Fusobacterium nucleatum has been suggested [7]. However, the clinical aspirin dose required for activation of majority of these mechanisms (Fig. 1) is uncertain and therefore which of these mechanisms play a role in humans using low-dose (75-100 mg/d) or standard-dose (300-325 mg/d) aspirin is unclear. Majority of the beneficial effects of aspirin on cancer, including reduction in cancer deaths, have been observed at low-dose; at this dose, anti-platelet activity through inhibition of cyclooxygenase-1 (COX-1) remains the main plausible mechanism. Yang and colleagues [6] demonstrate that such COX-1 inhibition leading to inhibition of TXA2 can prevent development of metastasis. The study provides the Jigsaw puzzle piece that fits and therefore pursuing these results in clinical and translational studies should become a high research priority.

Fig. 1. Aspirin - mechanisms of action.

COX-1 cyclooxygenase-1, COX-2 cyclooxygenase-2, TXA₂ thromboxane A₂, PGE₂ prostaglandin E₂, CRC colorectal cancer, GI gastrointestinal.

Future research directions

Mechanistic studies in humans

Yang and colleagues’ study [6] was based on animal models and seeking evidence corroborating its findings in human would be a necessary next step. There are several recently completed or ongoing trials (Table 4 of Thorat M.A. 2018 [2]) of aspirin in primary prevention and adjuvant therapy settings. Translational studies using materials from these trials would prove to be valuable. Yang and colleagues [6] suggest that the ARHGEF1 pathway activation leads to suppression of T cell mediated immune response through an increased proportion of exhausted T cells. Studies evaluating T cell subtypes and the proportion of exhausted T cells among tumour infiltrating lymphocytes (TILs) in new primary tumours (primary prevention trials) and recurrences (adjuvant trials) in aspirin-treated individuals as compared with those receiving placebo need to be undertaken.

Biomarkers

The anti-metastatic activity of aspirin was dependent on TXA2-receptor (TXA2-R) expression by cells of the haematopoietic lineage [6]. TXA2-R may therefore be a biomarker predictive of aspirin benefit in adjuvant setting. Recent data from the ADD-Aspirin trial [8] indicate that the levels of urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, were persistently elevated in cancer patients and aspirin (100 mg/d and 300 mg/d equally) lowered these by 77–82%. The follow-up of recently completed trials like ASCOLT [9] and ABC trials is too short [10] for aspirin’s benefit to emerge and long-term follow-up of all aspirin trials with evaluation of such biomarkers should be a research priority.

New clinical trials

As aspirin appears to reverse suppression of T cell mediated adaptive immunity, it may have additive or even synergistic effects with cancer immunotherapy. If a clinically meaningful effect exists, it may be possible to further improve outcomes in patients on immunotherapy or reduce the dose of immunotherapeutic agents. Clinical trials in cancer patients on immunotherapy for advanced disease to investigate whether aspirin improves objective response rates merit strong consideration.

High level of TILs is an indicator poor prognosis in certain cancer subtypes like hormone receptor positive breast cancer. Cancers like high-grade serous ovarian carcinoma are associated with high expression of programmed cell death 1 (PD-1) receptor in TILs. These tumours likely represent ineffective immune response due to a high proportion of exhausted T cells. It would be worth investigating if aspirin improves pathological complete response in such tumours treated with neoadjuvant chemotherapy.

Lastly, the evidence suggests that aspirin prevents development of specific cancers. However, if aspirin did not prevent development of a certain cancer type but prevented it from metastasising, the overall effect of reduction in deaths due to that cancer type would be small making the detection of such signal in observational studies difficult. Therefore, current evidence does not rule out the possibility that aspirin prevents development of metastases in many other cancers. Current trials of aspirin in adjuvant setting are investigating its benefits in specific cancers, generally late stage II or stage III cancers. As compared with stage I cancers, clinically undetectable metastases may be more established in these later stages and re-activated T cell immunity may not be able to successfully eradicate these. Therefore, the merits of tumour-agnostic adjuvant trial of low-dose aspirin stratified by stage at presentation and U-TXM levels are at least worth debating.

Research focussed on clinical role of aspirin in cancer and the role of platelets in carcinogenesis as well as in cancer progression needs further reinvigoration.

Author contributions

MAT wrote the main manuscript text, and prepared figure. All authors reviewed the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Competing interests

MAT serves on the executive board of the International Cancer Prevention Society (formerly ISCaP) which received an educational grant from Bayer for a conference in 2014. MAT is a member of data monitoring committees of aspirin trials: Add-Aspirin, CaPP3, and COLO-PREVENT. MAT is a Subject Editor of BJC Reports, and he has recused himself from all decisions about this paper.