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    • Some of the identified signals can be attributed to

    2018-11-14

    Some of the identified signals can be attributed to confounding by indication. This is most notable for the observed associations with lung cancers. As an example, drugs used to treat obstructive lung diseases exhibited a strong association with squamous cell carcinoma of the lung (OR, 2.61), which is likely explained by these drugs being used for chronic obstructive pulmonary disease (COPD), which is caused primarily by smoking (Supplementary Results I). Nevertheless, our algorithm succeeded in identifying established or previously reported associations, such as the association between use of female hormone therapy and risk of ductal and lobular adenocarcinomas (International Agency for Research on Cancer, 2007) (OR 1.92 and 2.65, respectively, Supplementary Results V), and the association between the antihypertensive drug hydrochlorothiazide and lip cancer (Friedman et al., 2012) (OR 6.93, Supplementary Results V). Such findings provide assurance that our approach is capable of identifying true associations. Some of the signals we have identified clearly warrant further investigation. For example, the two ep4 pivmecillinam and sulfamethizole displayed odds ratios of about 13 and 6, respectively, for squamous cell carcinoma of the bladder (Supplementary Results V). Both drugs are used specifically to treat urinary tract infections and, as such, this signal might reflect a carcinogenic effect of inflammation due to recurrent infections. However, as both drugs are designed to accumulate in the bladder lumen and because the signal was very strong, this signal should be considered a candidate for future studies. Such studies should be designed specifically for the individual drug–cancer association, by employing focused and comprehensive confounder adjustment and by focusing on etiologically relevant exposure windows for the specific cancer outcomes under study. When deciding whether a given drug–cancer association is worthy of further study, i.e., prioritizing the many signals reported in this study, parameters other than the strength of the association should be considered. Thought should be given to the potential for confounding by indication or contraindication as discussed above, as well as biological plausibility, e.g., by considering the pharmacological mechanism of the drug and/or drawing upon findings in other studies, whether experimental, clinical or observational. In addition, the potential public health impact of a putative association should be considered, as reflected by the number of attributable cases, the aggressiveness of the cancer outcome and the age of those affected. Finally, several drugs evaluated by the International Agency for Research on Cancer (IARC) have been categorized as probably (Group 2A) or possibly (Group 2B) carcinogenic to humans, because epidemiological evidence has not been definitive, or because carcinogenicity has been demonstrated only in experimental animals (International Agency for Research on Cancer, 2012; Friis et al., 2015). Additional studies and continued monitoring of the potential carcinogenicity of these drugs are of paramount importance. Another valuable next step would be a full-scale replication of our study, a common approach in, e.g., genome-wide screening studies (NCI-NHGRI Working Group on Replication in Association Studies et al., 2007). This would require access to data sources comparable to the Danish registries, and should ideally hold data on potential life-style confounders or health-seeking behaviour. The combined results of the index and replication studies would help prioritize the signals that warrant further research. The following are the supplementary data related to this article.
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    Acknowledgements
    Introduction Progress in understanding the biology of advanced prostate cancer prompted development of therapy for castration-resistant disease; however, no parallel advances have brought improvement to prevention or treatment of early prostate cancer. This limitation, reflected in the difficulty in interpreting findings of the Prostate Cancer Prevention Trial (PCPT) (Thompson et al., 2003) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (Andriole et al., 2010), led to denial of approval of 5α-reductase inhibitors as prostate cancer preventatives, despite their striking reduction of low-grade cancers. In both studies, the 5α-reductase inhibitors reduced the frequency of low-grade cancers but not potentially lethal high-grade cancers, pointing to the urgent need to elucidate the biologic significance.