Statins and breast cancer prognosis: evidence and opportunities

Abstract

SUMMARY Much preclinical and epidemiologic evidence supports anticancer effects of HMG-CoA reductase inhibitors (statins). Epidemiologic evidence does not support an association between statin use and reduced breast cancer incidence, but does support a protective effect of statins—particularly simvastatin—on breast cancer prognosis. We argue that the current evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins. We advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well-tolerated, and in expensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several design opportunities—including candidate predictive biomarkers of statin safety and efficacy—and offer solutions to key challenges to enrolment, follow-up, and analysis of such a trial.

The role of statins as therapeutic agents in cancer

“…Furthermore, this benefit was confined to patients who used lipophilic statins and did not extend to users of hydrophilic statins. This strengthens the hypothesis derived from preclinical studies that the anti-cancer effect of statins may be independent of its cholesterol lowering effect and mediated by modulation of cell signaling (Ahern et al 2014;Manthravadi et al 2016). There is also a paucity of data pertaining to the role of statins across a spectrum of breast cancer molecular subtypes.…”

“…Ahern et al (2014) suggested that statins, particularly simvastatin, may reduce the risk of breast cancer recurrence. Murakami et al (2016) demonstrated that lovastatin is a potential chemopreventive agent against breast cancer.…”

“…In this regard, the results from different studies have been inconsistent. While some studies hint at a role of estrogen receptor status as a predictive biomarker for statin efficacy (Botteri et al 2013;Ahern et al 2014), others have found no such association (Desai et al 2015;Manthravadi et al 2016). Gray et al (2016) suggest that statin use appears to be associated with reduced mortality in colorectal cancer.…”

Statin use, Candidate Mevalonate Pathway Biomarkers, and Colon Cancer Survival in a Population-Based Cohort Study

“…It has previously been hypothesised that the potential anti-cancer effect of statins is restricted to lipophilic statins. (Ahern et al, 2014) Also, the serum statin concentrations achieved with cardiovascular protective doses of the medication (e.g. simvastatin 40mg) may not be sufficient to induce the anti-cancer effects observed in preclinical studies.…”

Tumor responsiveness to statins requires overexpression of the ARF6 pathway

“…9 In accordance with this result, a recent report showed that the recurrence rates of breast cancer can be reduced by statins. 10 Other types of cancers, such as lung adenocarcinomas and head and neck squamous cell carcinomas, also overexpress the ARF6-based pathway (see refs. 4, 7).…”