Prescriptions for Selective Cyclooxygenase-2 Inhibitors, Non-selective Non-steroidal Anti-inflammatory Drugs, and Risk of Breast Cancer in a Population-based Case-control Study

Deirdre P Cronin-Fenton; Lars Pedersen; Timothy L Lash; Søren Friis; John A Baron; Henrik T Sørensen

Disclosures

Breast Cancer Res 

In This Article

Abstract and Introduction

Abstract

Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting.
Methods We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.
Results Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90–1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.
Conclusions Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are inversely associated with the risk of colorectal and other gastrointestinal cancers (for example, stomach and oesophageal cancer).[1–5] The protective effect of NSAIDs against these cancers has prompted studies on breast cancer prevention by NSAIDs.

Research on human cell lines and animal models indicates a role for cyclooxygenase-2 (Cox-2) in breast carcinogenesis,[6] which suggests that selective Cox-2 (sCox-2) inhibitors and NSAIDs may prevent the growth of mammary tumours.[7–14] Some NSAIDs are more potent against Cox-1 (for example, aspirin), others have greater affinity for Cox-2 (sCox-2 inhibitors), while others are relatively non-selective (for example, naproxen).[15] Cox-1 is ubiquitously and constitutively expressed, while Cox-2 is induced in response to stimuli such as cytokines[16] and is overexpressed in approximately 40% of human breast tumours.[17,18] NSAIDs may exert a protective effect against breast cancer by inhibiting Cox-2 and, in turn, reducing the level of prostaglandins, oestrogens and/or prolactin.[5,15,19–24]

Results from epidemiological studies of breast cancer, however, are conflicting.[25,26] To date, five meta-analyses have indicated chemopreventive effects of aspirin or NSAIDs against breast cancer.[1,27–30] Some cohort and case-control studies have reported no reduced risk of breast cancer either from use of non-aspirin NSAIDs (NA-NSAIDs)[31–38] or aspirin.[7,26,31,35–45] Others have suggested a reduced risk associated with NA-NSAIDs[8,46–53] and aspirin,[8,32,46–52,54–59] albeit less marked than that observed for colorectal cancer (approximately 30% versus approximately 50% reduction).[58,60,61] The conflicting evidence may be attributable to a combination of factors including poor precision and chance variation,[39,43,47,48,58] low response rates with possible selection bias,[7,51] short follow-up time following prescription,[36,47,59] limited exposure data,[27,57] or failure to distinguish between different NSAIDs subclasses.[33,34,36,37,53] Only two, case-control, studies have investigated the association of newer sCox-2 inhibitors and breast cancer occurrence; both found decreased breast cancer risks,[47,59] but only one study adjusted for previous use of NSAIDs in the analyses.

To answer some of the research gaps in the epidemiological literature, we conducted a large population-based case-control study nested within a source population with prospectively collected prescription data to examine the association between use of sCox-2 inhibitors, aspirin, or non-selective NA-NSAIDs and the risk of breast cancer occurrence.

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