Aspirin Use and Reduced Risk of Pancreatic Cancer

This article is featured in Highlights of This Issue, p. 1

Pancreatic cancer is among the most fatal of all cancer types. By 2022, in the United States, deaths from pancreatic cancer are expected to exceed all other cancer types except lung (1). Although cigarette smoking and long-term obesity/diabetes mellitus are two avoidable causes of pancreatic cancer, most cases of the disease are apparently not preventable. Some conflicting evidence suggests that aspirin use may lower risk, and in fact, our study in Connecticut found approximately 50% reduced risk with regular use of either low-dose or regular-dose aspirin (2). During 2006 to 2011, we carried out a second population-based case–control study of pancreatic cancer in Shanghai, China, and thus sought to examine whether or not aspirin use was associated with risk in that population.

Our Shanghai study has been described in detail elsewhere (3). In brief, from December 2006 to January 2011, in 37 Shanghai hospitals, we identified 1,241 newly diagnosed patients with pancreatic cancer and recruited 1,092 (88%), of whom 892 were confirmed to be eligible by review of pathology and clinical records. Patients were identified in each hospital by active, real-time surveillance of admissions for workup of possible pancreatic cancer, and were interviewed in-hospital, generally within 1 to 2 days of admission. Over the same years, we attempted to contact 1,529 age and sex frequency-matched potentially eligible control subjects randomly selected from the Shanghai Residents Registry and interviewed 1,067 (70%) at home. At the in-person questionnaire interviews, after receiving signed informed consent, we obtained venipuncture blood samples from 761 cases and 794 controls. Study subjects were questioned about various standard demographic, lifestyle, and medical history factors, as well as specifically asked about all episodes of regular use of aspirin and other NSAIDs. A show-card listing names of medications of current and past availability was used to promote recall of dates, durations, and frequencies of use. Regular use was considered to be use of at least one tablet per week for 3 months or longer. We did not distinguish regular-dose from low-dose aspirin preparations in recording subject responses. For laboratory analyses, we used commercial ELISA Kits to determine plasma seropositivity for CagA-positive Helicobacter pylori (H. pylori) strain (Ravo Diagnostika p120, Alere GmbH; ref. 4). ABO blood group was determined by custom TaqMan genotyping (Applied Biosystems, Inc.) of two functional SNPs, rs8176719 and rs8176746 (3). The study was approved by the human subjects review boards of the Shanghai Cancer Institute (Shanghai, China) and Yale University (New Haven, CT).

We used unconditional logistic regression methods to estimate ORs and their 95% confidence intervals (CI). All analyses were adjusted for the continuous terms age at interview, education category, age 21 body mass index (BMI), years of cigarette smoking and number of cigarettes smoked per day, and indicator terms for sex, H. pylori CagA seropositivity, ABO blood group A versus non-A, and history of diabetes mellitus more than 3 years in the past. All P values are two-sided. For the calculation of trends in published ORs over calendar time, we used meta-regression of the log ORs (5, 6). We generally followed the MOOSE guidelines (7) in searching the PubMed, Ovid, and EMBASE databases for articles and abstracts on aspirin and cancer in any language published or in-press from the database start through July 25, 2016, as well as in reviewing the reference lists of the obtained articles for additional papers. We did not weight individual studies for quality. We evaluated the adequacy of the time–trend models by calculating, using the method-of-moments variance estimator, the adjusted R², the proportion of between-study variance explained by the linear covariate (8).

Various demographic and risk factor characteristics of the cases and controls are presented in Table 1. The subjects were well matched on age at interview and sex. Cases on average had slightly but significantly higher age 21 BMI than controls, were more likely to carry blood group A and less likely to be H. pylori CagA seropositive, and smoked more cigarettes per day. Cases had a higher frequency of past diagnosis of diabetes mellitus, especially within 3 years before interview, during which time such diagnoses are considered more likely than not to arise from the developing pancreatic cancers.

Results for aspirin use among study subjects are given in Table 2. All but six of the 230 ever-users used aspirin at least daily. Ever-regular use was associated with approximately 50% reduced risk of pancreatic cancer (P = 10^−4.2). A trend in decreasing risk with duration of use was evident (P = 0.0034). More than half of all use started within 4 years of interview. Compared with continuing use, quitting use of aspirin within the recent 2 years was associated with more than doubled risk of pancreatic cancer, comparable with the risk of never having used it. Magnitudes of associations among case subjects limited to local, regional, or distant tumor stages at diagnosis were similar (Table 3). Ever regular use of aspirin was associated with lower risk in women (OR = 0.42; 95% CI, 0.26–0.67) than in men (OR = 0.64; 95% CI, 0.44–0.94); both associations were significant, but not significantly different from each other (P = 0.16). Analyses of all interviewed subjects, not just those who provided blood samples, yielded similar results (data not shown). Regular non-aspirin NSAID use was reported by only 12 subjects and was not analyzed.

The pattern of risk associations in Chinese subjects in Shanghai as seen here is remarkably similar to that in our Connecticut study (2). Both studies demonstrated about 50% reduced risk with ever use of aspirin, as well as some evidence of trends of decreasing risk with increasing durations of use. Typical durations of use were shorter in Shanghai than Connecticut; nevertheless, the relative reductions in risk were comparable. Both studies also showed that people who quit using aspirin in the recent 2 years had about 2- to 3-fold higher risks compared with individuals continuing on the medication and that never-users had about double the risk of current users. These observations suggest that aspirin use may be associated with decreased risk of pancreatic cancer, as well as that individuals with developing pancreatic cancer may become increasingly less tolerant of aspirin and thus more likely to terminate use a little before diagnosis. In spite of this possible dual relationship, long-term aspirin use or use of 5 to 10 years or more in the past has been associated with reduced risk (2). Because most observed associations with reduced risk have been for use within a decade of diagnosis, aspirin use may be inferred to slow tumor development rather than prevent initial tumor occurrence (9).

In examining the literature to calculate meta-analysis, we found 18 other studies that have investigated aspirin use and risk of pancreatic cancer (Supplementary Table S1; plotted in Fig. 1; refs. 2, 10–26). The summary association (OR = 0.83; 95% CI, 0.78–0.89) was not substantially different for the five studies having data for males (OR = 0.78; 95% CI, 0.67–0.90; refs. 2, 17, 18, 23, and the current study) or the eight with data for females (OR = 0.84; 95% CI, 0.73–0.97; refs, 2, 10, 17, 18, 20, 23, 25, and the current study). Among all of the published studies, six have shown significantly reduced risk with use (2, 10–14). Of the 12 others (15–26), many of those that began accruing patients in the 1990s or later (and thus that were conducted after the general population introduction of aspirin for cardioprophylaxis) show nonsignificant reduced risk with use. In Fig. 1, a trend in the OR for ever-regular use of aspirin is evident according to increasingly more recent midpoint of when the aspirin exposures were ascertained in the study, with decline in OR of 2.3% per year (95% CI, 1.3%–3.3%; P = 10^−5.1; adjusted R² = 91%). For a recent study conducted with midpoint in 2011, the predicted OR = 0.64 (95% CI, 0.57–0.74; P = 10^−10.2). A similar trend in OR is seen for the six studies specifically examining ever-regular use of low-dose aspirin (Fig. 2; refs. 2, 11, 12, 18, 20, 21), with decline in OR of 3.6% per year (95% CI, 1.4%–5.8%; P = 0.0014; adjusted R² = 84%). The predicted OR for a recent study conducted with exposure midpoint in 2011 would be 0.59 (95% CI, 0.45–0.76; P = 10^−4.3). On average, ORs for regular use of aspirin and risk of pancreatic cancer have been declining over the past two decades as the general population use of aspirin has increased. We also examined trends in ORs according to year of study publication, and the results were stronger and more significant, but we felt that mid-year of study accrual better represented the time period of aspirin exposure. Finally, we found similar significant decreasing trends in the ORs over time for both ever use of any aspirin and ever use of low-dose aspirin when analyses were limited to case–control studies and to case–control studies involving aspirin information obtained from clinical records rather than subject interviews (data not shown).

Although our study results and the declining OR trends in the literature provide evidence for a beneficial effect of aspirin use on risk of pancreatic cancer, some limitations of this work should be considered. In our Shanghai study, we ascertained aspirin use by self-report, which could have inherent differences between cases and controls, both in our study and in other similar ones. In case–control studies, given that cases generally tend to overreport past exposures relative to controls (27), such differential reporting would not be likely to explain the reduced risks seen here. Evidence of benefit from cohort (10, 18, 19, 22, 23, 25), randomized trial (12, 20), and case–control (13, 21, 24) studies in which aspirin use information was obtained from clinical databases is weaker but still suggestive, although these studies are mostly older, and the cohort and case–control studies do not reflect more current population frequencies of aspirin use, in which lower ORs are seen. Aspirin is an over-the-counter medication for which use may not be well characterized by standard clinical database information. Analyses of more recent follow-up periods in the cohort studies will be helpful in determining the magnitude of benefit of aspirin use. Finally, various physiologic mechanisms for risk reduction with aspirin use have been suggested, and although a number of these mechanisms are plausible, none has yet been convincingly established. We have discussed these mechanisms at length elsewhere (2).

In conclusion, we observed a significant inverse relationship between aspirin use and risk of pancreatic cancer in a large representative sample of Chinese individuals. The pattern of risk reduction was very similar to that seen in other recent studies in the United States and elsewhere. Although the choice to use aspirin for disease prophylaxis generally depends upon evaluated risks of cardiovascular disease, colorectal cancer, etc., it is likely that such use at least does not increase risk of pancreatic cancer and very probably appreciably lowers it.

No potential conflicts of interest were disclosed.

The authors assume full responsibility for the analyses and the interpretation of the study data. No funders of the study had any involvement in the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication.

Conception and design: H.A. Risch, W. Zhang, M.S. Kidd, H. Yu, Y.-T. Gao

Development of methodology: H.A. Risch, H. Yu

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): H.A. Risch, L. Lu, J. Wang, W. Zhang, H. Yu, Y.-T. Gao

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): H.A. Risch, M.S. Kidd

Writing, review, and/or revision of the manuscript: H.A. Risch, L. Lu, S.A. Streicher, M.S. Kidd, H. Yu, Y.-T. Gao

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): H.A. Risch, W. Zhang, Q. Ni, Y.-T. Gao

Study supervision: H.A. Risch, Y.-T. Gao

The authors thank the staff of the 37 Shanghai hospitals for their support in case reporting and recruitment, the review panel clinicians and pathologists for their thorough case evaluations, and Lu Sun and the other project staff of the case–control study for their invaluable dedication to the study.

This work was supported by grants from the NCI (R01 CA114421, to H.A. Risch, H. Yu, and Y.-T. Gao; F31 CA177153, to S.A. Streicher), by grants from the Science and Technology Commission of Shanghai Municipality (08411954100, to J. Wang, W. Zhang, and Y.-T. Gao), and from the Shanghai Cancer Institute (SB10-06, to J. Wang, W. Zhang, and Y.-T. Gao).

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