Aspirin use and endometrial cancer risk and survival

Abstract

The role of acetylsalicylic acid (aspirin) as a chemo-preventive and adjuvant therapeutic agent for cancers is generating attention. Mounting evidence indicates that aspirin reduces the incidence and mortality of certain obesity-related cancers, particularly colorectal cancer. In endometrial cancer, previous studies examining the effect of aspirin remain inconsistent as to the reduction in the risk of endometrial cancer. While some evidence indicates protective effects in obese women, other studies have showed a potential deleterious effect of these medications on endometrial cancer outcomes. However, exposure measurement across studies has been inconsistent in recording dose, duration, and frequency of use; thus making comparisons difficult. In this article, we review the evidence for the association between endometrial cancer and obesity, the pharmacological differences between regular- and low-dose aspirin, as well as the potential anti-tumor mechanism of aspirin, supporting a possible therapeutic effect on endometrial cancer. A proposed mechanism behind decreased cancer mortality in endometrial cancer may be a result of inhibition of metastasis via platelet inactivation and possible prostaglandin E₂ suppression by aspirin. Additionally, aspirin use in particular may have a secondary benefit for obesity-related comorbidities including cardiovascular disease in women with endometrial cancer. Although aspirin-related bleeding needs to be considered as a possible adverse effect, the benefits of aspirin therapy may exceed the potential risk in women with endometrial cancer. The current evidence reviewed herein has resulted in conflicting findings regarding the potential effect on endometrial cancer outcomes, thus indicating that future studies in this area are needed to resolve the effects of aspirin on endometrial cancer survival, particularly to identify specific populations that might benefit from aspirin use.

Keywords: Aspirin; Endometrial cancer; Review; Risk; Survival.

Fig. 1.

Impact of obesity in endometrial cancer progression. Excess estrogen from peripheral conversion of androgens to estrogen, mainly androstenedione in adipose tissue, causes continued stimulation of the endometrium to develop endometrial cancer. Adipose tissue also secretes a variety of both anti- and pro-inflammatory cytokines classified as adipokines (TNF-α, IL-6, and leptin), which cause a state of chronic systemic inflammation. Chronic inflammation promotes cellular proliferation, mainly by releasing pro-inflammatory cytokines, enhancing insulin resistance, suppressing the immune system, and generating reactive oxygen species for DNA damage. Abbreviations: TNF-α, tumor necrosis factor alpha; IL-6, Interleukin-6; and ROS, reactive oxygen species.

Fig. 2.

Aspirin: mechanism of action against cyclooxygenase pathway. Aspirin exerts its anti-inflammatory effects mainly by inhibiting COX, a key enzyme responsible for PG biosynthesis from AA. Two major isoforms of COX, COX-1 and COX-2, catalyze the conversion of AA to prostanoids which are metabolized by tissue-specific synthases to different prostanoids. COX-1 is constitutively expressed in most tissues and is highly expressed in platelets, where it is involved with platelet activation via the generation of TXA₂, and gastric epithelial cells where it protects gastric mucosa via the generation of PGE₂. COX-2 is expressed in several tissues and is induced in response to pro-inflammatory cytokines, which can lead to PGE₂ production. Aspirin irreversibly inactivates both COX-1 and COX-2 and has several different pharmacological effects ranging from anti-platelet action at low doses to anti-inflammatory action at high doses is dependent on drug availability in the target tissue and recovery of COX activity through de novo enzyme synthesis. Abbreviations: AA, arachidonic acid; PG, prostaglandin; COX, cyclooxygenase; TXA₂, thromboxane A₂; and GI, gastrointestinal.

Fig. 3.

Low-dose aspirin: decrease in plasma concentration after the first pass through the liver. Aspirin concentration is significantly different between pre-systemic circulation and systemic circulation. Low-dose aspirin (green circle) is absorbed in the upper intestine and circulated to the liver via portal vein. Low-dose aspirin concentration decreases after it is metabolized in the liver and further is diluted in the systemic circulation. The low-dose aspirin plasma concentration in the portal vein is sufficient for the inactivation of the platelet COX-1. Low-dose aspirin concentration is represented by the width of the green bar.

Fig. 4.

PGE₂ promotes cancer progression. PGE₂ is a known factor for enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion, induction of the transition from EMT, regulation of stem cell homeostasis, and suppression of immune response. PGE₂ also stimulates aromatase expression and thereby regulates estrogen production. Abbreviations: PG, prostaglandin; and EMT, epithelial-mesenchymal transition.

Fig. 5.

Aspirin and the PI3K/AKT/mTOR pathway in endometrial cancer. The activation of RTK induced by adipokines leads to activation of the PI3K/AKT/mTOR pathway in endometrial cancer. The direct association between ER and RTK also stimulates the PI3K/AKT/mTOR pathway. The PIK3CA mutations activate the kinase activity of PI3K, which is antagonized by PTEN through its phosphatase function. Up-regulation of PI3K enhances COX-2 activity and PGE₂ synthesis in the setting of obesity. Thus, suppression of PGE₂ production as would theoretically be achieved with use of aspirin, could be a promising strategy for the treatment of endometrial cancer. Dashed lines represent the suggested pathways in endometrial cancer. Abbreviations: RTK, receptor tyrosine kinase; PG, prostaglandin; COX, cyclooxygenase; PI3K, phosphatidylinositol 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; mTOR, mammalian target of rapamycin; TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; ER, estrogen receptor; and PTEN, phosphatase and tensin homolog.

Fig. 6.

Low-dose aspirin: proposed anti-tumor mechanisms in endometrial cancer. Activated platelets are integral to the process of metastasis. Low-dose aspirin treatment inhibits activation of platelet, leading to suppression of tumor-promoting mechanisms. Increase in PGE₂ is strongly associated with several pathways which contribute to endometrial cancer progression. Low-dose aspirin treatment may suppress endometrial cancer progression by inhibition of activated platelet. Abbreviations: PG, prostaglandin; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; and MMR, mismatch repair.