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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Association between NSAIDs use and breast cancer risk: a systematic review and meta-analysis

YS Zhao, S Zhu, XW Li, F Wang, FL Hu, DD Li, WC Zhang, and X Li.

Review published: 2009.

Link to full article: [Journal publisher]

CRD summary

This review concluded that the incidence of breast cancer in women was slightly reduced by the use of non-steroidal anti-inflammatory drugs. Given substantial flaws in the methodology and analysis, and the presence of publication bias, this conclusion should be treated with extreme caution.

Authors' objectives

To establish whether an association exists between the use of non-steroidal anti-inflammatory drugs and breast cancer.


PubMed (1957 to 2008, including MEDLINE 1966 to 2008), Springer (1950 to 2008), LWW database (Lippincott Williams & Wilkins Total Access Collection) (search dates not presented) and HighWire Press (search dates not presented) were searched. Search terms were reported. Reference lists of retrieved publications were searched for additional studies. Only studies published in English were considered.

Study selection

Cohort or case control (nested) studies that investigated the association between any non-steroidal anti-inflammatory drug (NSAID) use and women with breast cancer (first diagnosed as in situ or invasive) were eligible for inclusion. Reasons for the exclusion of specific studies were: randomised double-blind placebo control in Women's Health Studies; benign disease; survival analyses for post-menopausal women; or recurrence analyses.

The review outcomes were cases of breast cancer, duration frequency and definition of NSAID exposure.

Included studies evaluated the use of aspirin and ibuprofen; most were conducted in the USA.

The authors did not state how many reviewers performed the selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Numbers of cases in exposure and non-exposure groups were extracted; risk ratios (RR), odds ratios (OR) and 95% confidence intervals (CI) were calculated. Study details, frequency of exposure and definition of exposure were also extracted.

Two reviewers independently extracted the data.

Methods of synthesis

Pooled risk ratios and 95% confidence intervals were calculated using a fixed-effect model (Mantel-Haenszel) for homogenous data. Random-effects model (DerSimonian and Laird) was used to combine heterogeneous results. Pooled odds ratios were used for case-control studies and risk ratios for cohort studies. Heterogeneity was assessed using I2 statistics; I2 less than 50% was considered acceptable heterogeneity.

Subgroup analyses were conducted to investigate the impact of study type, duration of exposure to NSAID and how frequently NSAIDs were taken. Publication bias was investigated with funnel plots, rank correlation (Begg and Mazumdar) and linear regression (Egger). In the presence of publication bias, a trim and fill method was used to adjust pooled risk ratios and 95% confidence intervals.

Results of the review

Twenty-six studies were included in the review (n=528,705 women); 16 case control studies (seven hospital-based and nine population-based) and ten cohort studies.

Overall the number of cases of breast cancer were unaffected by exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (RR 0.94, 95% CI 0.88 to 1.00). Heterogeneity was high (I2=92%), so subgroup analyses were carried out.

Study and NSAID type: Individual analysis of case control and cohort studies indicated no significant reduction in risk. Both ibuprofen (RR 0.81, 95% CI 0.67 to 0.97; seven studies, n=unknown) and aspirin (RR 0.91, 95% CI 0.85 to 0.98; 20 studies, n=unknown) were found to significantly reduce the risk of breast cancer.

Duration and frequency of NSAID use: Statistically significant reduction in the risk of breast cancer was found if NSAIDs were taken daily (RR 0.88, 95% CI 0.79 to 0.99; seven studies, n=unknown) or more than four time per week (RR 0.84, 95% CI 0.74 to 0.94; nine studies, n=unknown). Less than daily use or less than four times a week use had no significant effects on risk. No significant risk was observed for exposure durations of greater than five years or less than five years.

Heterogeneity was high for all studies (I2>74%). Publication bias was found for the overall effect of any NSAID on breast cancer risk (p<0.01) and the adjusted results gave a risk ratio of 1.01 (95% CI 0.96 to 1.07), indicating that there was no association.

Authors' conclusions

The use of non-steroidal anti-inflammatory drugs was associated with a small but significant decrease in the development of breast cancer in women. The associations were more obvious with aspirin and ibuprofen use.

CRD commentary

This review addressed a clear research question supported by clear inclusion criteria. The search strategy appeared to include relevant sources. There were no attempts to identify unpublished data or to avoid language bias. Therefore, relevant studies may have been missed and publication bias could not be ruled out. The use of independent reviewers was not used at each stage of the review process to minimise errors and bias.

There were no attempts to assess study quality. There were no details of how breast cancer was diagnosed or measured as an outcome. Given the very high levels of heterogeneity between studies, the method of synthesis may not have been appropriate. Pooling case control and cohort studies is not a recommended analysis method for risk. It was not clear which studies were ibuprofen alone and which were aspirin plus ibuprofen, which made it difficult to judge the significance of the subgroup analysis. In the subgroup analysis, it was not clear whether the results had been pooled and which exposure levels were compared.

This review contained many methodological flaws and publication bias was found to negate the authors primary conclusion. The authors' conclusions should be treated with extreme caution.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that more research is required to clarify the optimal dose, frequency and duration of NSAID use. Further research is required to understand the role of hormone receptor status and race in the association of breast cancer and NSAIDs.


Not stated.

Bibliographic details

Zhao YS, Zhu S, Li XW, Wang F, Hu FL, Li DD, Zhang WC, Li X. Association between NSAIDs use and breast cancer risk: a systematic review and meta-analysis. Breast Cancer Research and Treatment 2009; 117(1): 141-150. [PubMed: 18979210]

Indexing Status

Subject indexing assigned by NLM


Anti-Inflammatory Agents, Non-Steroidal /therapeutic use; Aspirin /therapeutic use; Breast Neoplasms /prevention & control; Female; Humans; Ibuprofen /therapeutic use; Risk Factors



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18979210