Aspirin is a non-steroidal anti-inflammatory drug with a long history. It is suitable for antipyretic and analgesic use and is widely used in the prevention of cardiovascular thrombosis . Recent studies have found that the long-term regular use of aspirin can significantly reduce the incidence of colorectal cancer, gastric cancer, liver cancer and other malignant tumors and improve the survival of patients with its anticancer effects [46–49]. The mechanism of action of aspirin in terms of signaling pathways is as follows. ① Apoptosis-related signaling pathway: NF-κB dissociates with inhibitor IK-B to enter the nucleus and activates antiapoptotic genes, which inhibits the apoptosis of tumor cells under the stimulation of inflammation and angiopoietin. Aspirin inhibits the activity of IKK by directly acting on it, thus preventing the activation of NF-κB and reducing the level of NF-κB [50–52]. Moreover, two important apoptosis-related genes, bcl-2 and Bax, have opposite antiapoptotic functions. By downregulating the expression of bcl-2 and upregulating the level of Bax, aspirin stimulates the death effect factor to increase caspase-3 activity and thereby promote cancer cell apoptosis [53–55]. ② Cell proliferation-related pathway: The P13K/Akt signaling pathway widely exists in cells and is a signal transduction pathway involved in the regulation of cell growth, proliferation and differentiation. Aspirin can irreversibly inhibit cyclooxygenase, thereby inhibiting the production of thromboxane A2 in platelets and inhibiting the P13K/Akt signaling pathway, thereby blocking or alleviating inflammation [56, 57]. Moreover, aspirin can inhibit the mTOR signaling pathway and transcription factors and activate the apoptosis-related proteins caspase-3 and Bim, thereby inhibiting cell proliferation and inducing cell apoptosis [58, 59]. ③ Autophagy-related pathway: AMPK not only directly inhibits the mTOR signaling pathway but also regulates the activity of ULK1 through phosphorylation, which is related to activating autophagy. Aspirin inhibits the growth and proliferation of cancer cells by targeting the AMPK pathway to affect autophagy [60–62].
A population-based case-control study analyzed data from 376 BCa cases and 463 controls in New Hampshire and found that aspirin significantly reduced the risk of BCa, especially for tumors containing TP53 mutations (Fortuny J) . Similarly, Castelao J et al illustrated that there was a nonsignificant trend towards increased BCa risk in people with a longer duration of painkillers than in people who do not use painkillers, and regarding the effect of the correlation of different types of analgesics and BCa risk on the direction and strength of the obvious difference, aspirin showed weaker role . However, in a cohort study by Genkinger JM et al .In the USA, there was no association between the frequency and dose of aspirin and BCa risk, which was not altered by known risk factors such as age, smoking or total fluid intake. Furthermore, a population-based cohort study using a database from the Hong Kong Hospital authority tracked 612509 subjects for 14 years, and the results showed that the long-term use of low-dose aspirin is associated with a lower risk of various cancers, including esophageal cancer, pancreatic cancer and stomach cancer, except for bladder, kidney and prostate cancer . To compensate for the lack of related research focusing on the population in Northeast China, we performed a retrospective study to explore the association of aspirin intake and risk of BCa and found that the regular use of aspirin was not associated with a reduced risk of BCa. Moreover, subgroup analyses stratified by sex showed that there was no correlation between aspirin intake and the risk of BCa in male patients and female patients. Although the findings suggested possible relationships between aspirin intake and the risk of cancer at the site of the colon, breast, and liver [46, 48, 49], studies of aspirin use and the risk of BCa have yielded mixed results. Several case-control studies have suggested a reduced risk of BCa among aspirin users, while other studies have indicated no association. Therefore, we conducted meta-analyses and found that patients with aspirin intake did not have a significantly lower risk of BCa than those without aspirin intake after combining ten included studies with 10000 patients. Subgroup analysis by research region also suggested that aspirin intake had no significant influence on the prevention of BCa in Asian populations, European populations (OR = 1.115, 95% CI = 0.870–1.431, p = 0.390) and North American populations.
Although the antitumor properties of aspirin have attracted increasing attention from scholars, the results regarding the impact of aspirin use on the prognosis of BCa are inconsistent. In terms of the effects of aspirin on tumor recurrence, a case-control study from Italy and a retrospective study from the USA showed a significant association between aspirin and recurrence in patients with BCa (Pastore A, Gee JR) [40, 45]. In the former (Pastore A) , the results suggest that long-term aspirin use may reduce the risk of tumor recurrence in patients with NMIBC. In a more detailed analysis, fewer patients with aspirin experienced recurrence, and there were fewer lesions with recurrence. For the latter (Gee JR) , the 5-year RFS of aspirin users was 64.3%, which was significantly higher than that of non-aspirin users (26.9%), even after multivariate analysis adjusted for other factors. Considering the effect of aspirin on the survival rate of cancer patients, Lyon TD's study  found that daily aspirin significantly improved survival outcomes after radical resection, including CSS, OS and MFS. It has also been observed that patients receiving low-dose aspirin had significantly better outcomes than patients receiving high-dose aspirin and those without aspirin. In contrast, a cohort study from the United States found no significant association between aspirin use and the overall survival of BCa patients .In addition, a prospective study by Singla N et al . showed that the use of aspirin does not affect the survival of patients with any tumors, including CSS, OS, recurrence-free survival and cystectomy-free survival, regardless of the dose (81 or 325 milligrams a day). In response to these mixed findings, we performed a meta-analysis to investigate the impact of aspirin intake on the prognosis of patients with BCa and found that aspirin had no significant effects on the OS and CSS of BCa patients. In addition, patients with aspirin intake did not have a significantly lower risk of BCa recurrence than those without aspirin intake. Until now, available data have not supported a connection between aspirin exposure and the prognosis of BCa despite few prior studies.
Our limitations are as follows: one limitation is that this case-control study is a single-center study, which may lead to certain bias or heterogeneity. To the greatest extent possible to avoid such shortcomings or loopholes, we performed a meta-analysis to investigate the relationship between aspirin intake and the risk and prognosis of BCa. Some included studies did not provide available values of HR, RR or OR from multivariate analysis, so we performed calculations from the univariate data and compared them through formula calculations. The statistical methods we used cannot replace all the research methods, and the conclusions we obtained without correlation are limited to the scope of our research, which may have some statistical errors [63, 64]. Second, we only focused on researching patients who regularly consumed aspirin. Due to the limited available information from clinical data, stratification analysis according to different doses or durations was not conducted. Moreover, other confounding factors affecting the occurrence or prognosis of BCa, including a history of cigarette smoking, alcohol consumption, etc., were not adjusted in our study.
The above factors may influence the results regarding the connection between the risk of BCa and the use of aspirin , which will be one of the focuses of our future research. Third, both our case-control study and meta-analysis showed no differences between aspirin intake and the risk and prognosis of BCa. However, previous in vitro studies have shown that aspirin may play a role as a chemopreventive agent in the OH-BBN/BDF BCa model , which suggests that there is heterogeneity between human epidemiological experiments and in vitro cell experiments, and the experimental scheme needs to be improved.