Response

We are grateful to Dr. Tuccori and colleagues for their letter. They have rightly identified a risk of immortal time bias in our analysis, which has the potential to lead to an overestimation of the protective effect of regular use of aspirin and ibuprofen against colorectal cancer. The authors suggested the use of a time-dependent approach to address this issue by including aspirin and ibuprofen intake as time-varying covariates in the survival model. We did consider this approach, but we were unable to use it in our analysis because of lack of data on the study participants’ age at first exposure to regular intake of aspirin and ibuprofen. We decided to undertake the analysis despite the risk of immortal time bias for two main reasons: 1) the relationship between regular aspirin intake and a reduced risk of colorectal cancer has been consistently demonstrated by several large randomized controlled trials both in the context of Lynch syndrome (1) and the general population (2) and 2) the analysis of our data using a case-control design provided very similar estimates to those from the weighted cohort approach presented in our paper (3) for both aspirin and ibuprofen (Table 1). Therefore, while we acknowledge the fact that immortal time bias is an important potential limitation in our analytical approach, we believe that its impact on our findings is likely to be minimal.

Table 1.

Multivariable logistic regression analysis of association between aspirin and ibuprofen use and the risk of colorectal cancer for Lynch syndrome

Aspirin or ibuprofen use	Case Subjects No.	Control Subjects No.	OR* (95% CI)	P
Never user†	765	807	1 (Ref)
Aspirin-only user	63	54	0.52 (0.35 to 0.79)	.002
Ibuprofen-only user	86	40	0.46 (0.29 to 0.72)	.001
Aspirin and/or ibuprofen user	177	109	0.47 (0.35 to 0.64)	<.001

* Adjusted for year of birth (1914–1943, 1944–1954, 1955–1965, 1966–1990) and average lifetime alcohol intake (0, 1, ≥2 drinks per day) and stratified by sex, country (United States, Australia/ New Zealand, Canada), cigarette smoking status (never, former, current), regular physical activity (at least 30 minutes per week for at least three months), and multivitamin intake (<1 month, ≥1 month). All statistical tests were two-sided. Case subjects are defined as participants diagnosed with colorectal cancer prior to the baseline interview. Control subjects are defined as participants with no previous colorectal cancer diagnosis at the baseline interview. CI = confidence interval; NSAID = nonsteroidal anti-inflammatory drugs; OR = odds ratio.

† Never users defined as carriers who reported not having taken either aspirin or ibuprofen or both for at least one month.

Funding

This work was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the Colon Cancer Family Registry centers. AKW is an Australian National Health and Medical Research Council Early Career Fellow. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the CCFR. Authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.

The authors declare no conflict of interest.