We appreciate the comments by Dr. Lai and colleagues on our article [1]. Despite plausible anti-tumor effects of statins, epidemiological studies suggest that statins may only elicit modest suppressive effect on pancreatic carcinogenesis. As noted by Lai et al., preventive effects of statins on pancreatic carcinogenesis could theoretically be confined to individuals at higher risk of pancreatic cancer, such as those with established risk factors (e.g., diabetes, smoking, adiposity). However, our data did not support effect modifications for the association of statin use with pancreatic cancer risk by those factors. Given anti-inflammatory properties of statins, patients with long-term inflammation in the pancreas may be more likely to benefit from these medications. Unfortunately, we could not assess this possibility, as data on chronic pancreatitis were not available in the cohorts utilized in our analysis.
Molecular pathological epidemiology has emerged as an integrative research field that considers intertumor variations in molecular and pathological signatures, thereby refining effect estimates of exposures for specific tumor subtypes [2]. This analytical framework has been recently applied for epidemiological research on pancreatic cancer incidence. For example, Oyama H, et al. examined distinct carcinoma types arising among patients with intraductal papillary mucinous neoplasm (IPMN) and demonstrated different risk factor profiles between IPMN-derived and non-IPMN-related carcinomas [3]. Statins potentially suppress downstream proteins of the mevalonate pathway including RAS and the Rho protein family. In colorectal cancer, the association of statin use with the incidence might differ by KRAS mutation status [4]. Importantly, KRAS mutation is the most common driver for the initiation of intraepithelial neoplastic changes in the pancreas. Although this mutation occurs in the vast majority of pancreatic ductal adenocarcinomas, tumor characteristics may differ by specific patterns of KRAS mutations [5]. Therefore, considering KRAS mutation status in pancreatic cancer may not only provide population-based evidence on molecular mechanism of tumor-suppressive effects of statins, but also open opportunities for chemoprevention against pancreatic cancer. In summary, despite the null findings in our study, further investigation is warranted considering variations in risk profiles of baseline populations as well as molecular and pathological features of pancreatic carcinomas.
Acknowledgements:
This work was supported in part by a U.S. National Institutes of Health (NIH) grant R35 CA197735 to S.O., and by Hale Center for Pancreatic Cancer Research, NIH/National Cancer Institute (NCI) U01 CA210171, NIH/NCI P50 CA127003, Department of Defense CA130288, Lustgarten Foundation, Pancreatic Cancer Action Network, Stand Up To Cancer, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple to B.M.W.. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in preparation of the manuscript or decision to publish.
Abbreviations:
- IPMN
intraductal papillary mucinous neoplasm
Footnotes
Conflict of interest: B.M.W. declares research funding from Celgene Inc., and consulting for BioLineRx Ltd., G1 Therapeutics Inc., and GRAIL Inc.. This manuscript was not funded by any of those companies. No other conflicts of interest exist. The other authors declare that they have no conflicts of interest.
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