We thank Dr Beales for his comments regarding our systematic review.[1, 2] We acknowledge the limitations regarding the functional significance of statin-induced reductions of cyclooxygenase-2 (COX-2) and intracellular adhesion molecule-1 (ICAM-1) expression in two of the laboratory studies we have referenced.[3, 4]
Although it is not yet possible to mechanistically infer the significance of these proteins in the carcinogenesis of oesophageal adenocarcinoma (OAC) per se, these studies are valuable in identifying plausible candidate pathways and still warrant inclusion in our review. Nuclear factor kappa beta (NF-κΒ) regulates ICAM-1 expression, and inhibition of NF-κΒ has been shown to suppress ICAM-1 in other cancer cell lines, with consequent ICAM-1 dependent inhibition of tumour cell invasion and metastases.[5, 6] The study by Sadaria et al. reported that simvastatin significantly attenuated both phosphorylated NF-κΒ and I-CAM 1, in a dose-dependent manner, and noted concomitant reductions in proliferation and cell viability and increased apoptosis. Further work is required to demonstrate ICAM-1 and COX-2-dependent anticancer effects of statins in OAC cell lines.
We thank Dr Beales for drawing to our attention his preliminary laboratory work and case-control study: it is certainly of relevance that statins induced significant pro-apoptotic effects in nonmalignant Barrett's cells with concentrations of Rosuvastatin achievable in vivo; and his case-control study reveals odds ratios of a similar magnitude to those of our meta-analysis. It would be of interest to know whether statins have differential effects on normal oesophageal squamous mucosa and Barrett's epithelia. Three studies were not included in our review because they were published after the predetermined search date of December 2011.[8-10]
Overall, our conclusions remain unchanged: there is emerging experimental and epidemiological evidence to support a protective effect for statins in the development of OAC, and randomised controlled trials are now warranted.