Statins and BCG response: Is there more to the story?

Identifying reliable predictive biomarkers for Bacillus Calmette–Guérin (BCG) response in the treatment of non-muscle invasive bladder cancer (NMIBC) is an essential, yet unfulfilled need. ¹ Accurate prediction of which patients will respond favorably to BCG therapy would enable personalized treatment strategies and avoid ineffective treatment in nonresponders. In view of this pivotal problem, Krishnan et al. explore “HMG Co-reductase Expression and Response to Intravesical BCG in Patients with High-Grade Non-Muscle Invasive Urinary Bladder Cancer Receiving Statins.”

Statins, a widely prescribed class of cholesterol-lowering drugs, work by competitive inhibition of HMG Co-A Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway for cholesterol synthesis. Statins antitumor and immunomodulatory effects are well-documented in murine models. However, the overall clinical effect of statins in bladder cancer appears to be neutral, as reported in a recent meta-analysis by Symvoulidis et al. ²

Nonetheless, the impact of statins immunomodulatory effects on BCG therapy has been a subject of debate spanning decades. Statins have been implicated in the attenuation of the Th1 immune response, whereas the Th1 immune response is essential to BCG's antitumor effect. ³ Despite this, multiple retrospective reports failed to demonstrate a negative impact of concurrent statin use on BCG efficacy.^4,5 Moreover, a multicenter retrospective analysis of over 1500 patients by Ferro et al. suggested an associated lower risk of recurrence with statin use for high-risk NMIBC treated with BCG ⁶ ; these findings could theoretically be related to statins pleotropic or cholesterol-lowering effects.

Herein, the authors approach this topic with an innovative perspective by investigating if there exist subsets of patients taking statins who will or will not respond to BCG. They evaluate HMGCR expression in BCG responders and nonresponders among NMIBC patients on statins. In this proof-of-principle study, BCG nonresponders displayed slightly higher levels of HMGCR expression. This interesting finding is hypothesis generating as the study is limited by the low sample size and heterogeneity in statin dose.

The differential expression of HMGCR between BGC responders and nonresponders has potential as a biomarker but also simultaneously raises several questions: Can HMGCR expression predict BCG response in patients taking statins? Could HMGCR expression be a prognostic marker of overall outcome, regardless of BCG treatment? Or, as mentioned by the authors, is the elevated expression of HMGCR in nonresponders a compensatory mechanism to counter statin–induced inhibition indicating statin resistance? These questions remain unanswered, and the authors are to be commended for stimulating these avenues of further research by their report.