An aspirin a day keeps ovarian cancer at bay?

KEYWORDS:

• Aspirin
• ovarian cancer risk

1. Introduction

Ovarian cancer is the eighth most common cancer and eighth most common cause of cancer-related deaths among females, with approximately 300,000 new cases and 185,000 deaths in 2018 worldwide [1]. Ovarian cancer is characterized by poor prognosis, particularly among those diagnosed with distant stages, which accounts for almost 60% of newly diagnosed cases [2,3]. Currently, there is a need for an effective prevention strategy that would lower ovarian cancer incidence and, consequently, reduce the disease-associated mortality.

It has been demonstrated that use of aspirin could reduce risk of certain malignancies including colorectal, esophageal, and gastric [4]. This antineoplastic activity has been linked to its anti-inflammatory mechanism of action. In fact, aspirin inactivates cyclooxygenase (COX) enzymes, with low-dose aspirin inhibiting COX-1 and higher doses targeting COX-2 [5]. Inhibition of COX enzyme leads to the blockage of conversion of COX enzyme’s main substrate, arachidonic acid, into the essential components of the inflammatory response, including prostacyclin and prostaglandin E2 [6].

Because inflammation is speculated to be one of the main mechanisms underlying ovarian cancer development and progression [7], antineoplastic effects of aspirin via inactivation of COX enzymes may also impact ovarian carcinogenesis [8]. Therefore, use of aspirin may be a potentially promising avenue for ovarian cancer risk reduction.

2. Epidemiologic evidence on aspirin use and ovarian cancer risk

Multiple observational studies conducted to examine the chemopreventive properties of aspirin use in relation to ovarian cancer have reported an overall decrease in disease risk of approximately 10–11% [4,9]; a more pronounced reduction was observed for the low-dose (<100 mg) and consistent use of aspirin [4]. The most convincing evidence that supports the notion of the protective role of aspirin in relation to ovarian carcinogenesis is provided by the pooled and meta-analysis studies. In fact, one systematic review and meta-analysis of 21 observational studies demonstrated that aspirin use was inversely associated with ovarian cancer risk, RR = 0.88; 95% CI = 0.79–0.98 [10]. Further, a pooled analysis of 12 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC) and including 7,776 ovarian cancer patients and 11,843 controls indicated that aspirin use was associated with a decrease in ovarian cancer risk, OR = 0.91; 95% CI = 0.84–0.99 [3]. Daily use of aspirin and use of low dose aspirin (<100 mg) was associated with even further decrease of ovarian cancer risk, OR = 0.80; 95% CI = 0.67–0.96 and OR = 0.66; 95% CI = 0.53–0.83, respectively.

When interpreting the results of meta-analyses based on pooling data from case-control studies, it is important to acknowledge potential biases that might affect the results of case-control studies, including recall bias. However, the findings of Trabert et al. [3] were further supported by the results obtained from the prospective studies. In fact, a very large prospective study that combined 205,498 women participating in the Nurses’ Health Study I and II resulted in the inverse association between the low-dose aspirin use and risk of incident epithelial ovarian cancer, HR = 0.77; 95% CI = 0.61–0.96, and no association was observed for a standard-dose (325 mg) takers [11]. Moreover, another pooled study based on the data from 13 prospective cohort studies participating in the Ovarian Cancer Cohort Consortium demonstrated a 10% reduction in ovarian cancer risk associated with daily (≥6 days/wk) use of aspirin, RR = 0.90; 95% CI = 0.82–1.00 [8].

It is noteworthy that, to date, there is a very limited understanding of the effect of aspirin use on specific histological subtypes of ovarian cancer. Because ovarian cancer is a highly heterogeneous disease, the association between aspirin and ovarian cancer may vary based on its histological profile. However, research on this topic is sparse with only few studies addressing the existing gap in knowledge. In the study by Trabert et al. [8], it was demonstrated that frequent aspirin use was associated with a 15% risk reduction for serous ovarian cancer, 95% CI = 0.71–1.00. No association was observed for any other histological subtypes. Similarly, in the study based on the OCAC data, for regular use of aspirin, only association for serous histotype reached statistical significance, OR = 0.89; 95% CI = 0.80–0.99 [3].

3. Public health significance of aspirin intake

Aspirin has multiple advantages compared to other potential interventions that could be introduced on a population scale. First, aspirin is a very well-known drug that has long been recommended to use for either primary or secondary prevention of cardiovascular disease (CVD) [12]. Currently, aspirin is the most widely used medication reported to be utilized for primary prevention of CVD by 20.8% females of 40 and above [13]. Epidemiologic evidence suggests that low-dose aspirin can lower OVCA risk, which is the same dose that is recommended for prevention of CVD [14]. Low cost of aspirin is another major advantage that would allow it to be widely available including to the individuals at the low socioeconomic level.

Another advantage is that aspirin represents a thoroughly studied drug with known major side effects such as gastrointestinal and cerebral bleeding [4]. Knowing potential complications of chemoprevention would help health providers in weighing risks and benefits when making a decision on whether or not to use it for cancer prevention in an individual patient, particularly in the light of the recent changes in recommendations with regards to aspirin use. In fact, American College of Cardiology and the US Preventive Services Task Force no longer recommend frequent use of aspirin for the primary prevention of atherosclerotic CVD among individuals older than 70 years of age due to potential side effects of aspirin use [8,15]. However, even with the change in recommendations, preventive strategies could still be applicable to women aged 55–64, the age group in which ovarian cancer is the most commonly diagnosed [2].

4. Conclusion

Use of aspirin could represent a promising chemopreventive strategy to decrease ovarian cancer incidence, particularly with lack of effective early detection measures. However, despite all the obvious advantages of using aspirin as a chemopreventive agent to reduce risk of ovarian cancer, there is still a need to define the appropriate dose, duration [14], frequency, and timing of intake and to have a clearer understanding of aspirin’s mechanism of action with regards its antineoplastic effect including within various histotypes. The gold standard of epidemiological evidence, randomized clinical trials, usually do not to have sufficient statistical power to examine the association between aspirin use and ovarian cancer risk due to low incidence of this disease [4].

Consequently, more experimental and large epidemiologic studies need to be conducted to be able to address the existing gaps in knowledge before making any definite conclusions about the relationship between aspirin use and ovarian cancer risk and about the possibility to use aspirin for prevention of ovarian cancer. Further, any future public health recommendations should be taking into consideration both benefits and risk associated with use of aspirin.

Declaration of interest

AN Minlikeeva was supported by NIH/NCI 4R25CA113951 and NIH/NCI P50CA159981. KB Moysich was supported by NIH/NCI (2R25CA113951, R01CA095023, R01CA126841, P50CA159981) and the Roswell Park Alliance Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.