In a recent study published in JAMA Network Open, researchers determined the relationship between serological cholesterol levels, statin usage, and breast cancer (BC) mortality.

Study: Statin Use, Cholesterol Level, and Mortality Among Females With Breast Cancer. Image Credit: artemevdokimov/Shutterstock.com

Background

Breast cancer is the most prevalent cancer in women across the world, with satisfactory survival rates but poor post-metastasis survival. Statin usage may enhance survival rates in breast cancer patients, according to research; however, most trials do not take underlying blood cholesterol levels into account.

The primary cholesterol metabolite, oxysterol 27-hydroxycholesterol, stimulates tumor development and metastasis in BC animal models and has been linked to mortality in females with low estrogen levels.

Cholesterol is also a precursor for estrogen production, which raises the risk of breast cancer. Previous studies, however, did not consider concurrent cholesterol levels or changes caused by statin usage, resulting in inconsistent study outcomes.

About the study

In the present population-based, retrospective cohort study, researchers investigated the impact of statin usage and serum cholesterol levels on breast cancer mortality.

The study included Finnish women with invasive breast cancer that was recently diagnosed between 1 January 1995 and 31 December 2013. All participants provided data on hormone receptors and one or more cholesterol measurements.

BC cases were identified by the Cancer Registry of Finland using the International Classification of Diseases, tenth revision (ICD-10) codes. Data extraction included patient age, diagnosis date, tumor extent and histological features, and primary breast cancer treatment.

Before breast cancer diagnosis, mammography screening records were retrieved from the Mass Inspection Registry. The Charlson Comorbidity Index (CCI) values were calculated based on comorbidity data in the Care Register for Health Care database and drug purchase data from the Social Insurance Institution database.

The study exposure was statin use, statin dosage, and serological levels of cholesterol, triglyceride (TG), high-density lipoprotein (HDL), and high-density lipoprotein (LDL), measured pre- and post-breast cancer diagnosis. The outcome measure was mortality from breast cancer and other causes between the breast cancer diagnosis date and 31 December 2015.

Cox proportional hazards regression modeling was performed to determine the hazard ratios (HRs). The team excluded females who had higher mortality from breast cancer and other reasons, more metastatic disease or unknown extent of the tumor, and a marginally lower percentage with curative-intent surgery as primary therapy. The data were analyzed between January and May 2022.

Results

The study included 13,378 BC patients, among whom the median age was 62 years, and they were followed for a median of five years post-breast cancer diagnosis.

In the follow-up period, 16% of individuals died, of which seven percent died of breast cancer. In total, 31% of individuals had elevated total serum cholesterol levels (median value above 193 mg/dL) before breast cancer diagnosis, and half of the patients had increased total serum cholesterol post-BC diagnosis.

Among BC patients, 41% had used statins. The multivariate analysis showed that statin usage before breast cancer diagnosis was related to an elevated BC mortality risk compared to non-use (HR, 1.4).

Pre-diagnostic statin usage increased breast cancer mortality risk even after adjusting for total serum cholesterol levels (HR, 1.2). Contrastingly, the team observed a reduced breast cancer mortality risk associated with post-diagnostic statin usage (HR, 0.9).

The risk decline was higher by increasing statin use intensity (e.g., for low-density lipoprotein, hazard ratios reduced to 0.66 from 0.73). It was robust for individuals whose serum cholesterol levels were reduced after statin usage  (HR, 0.5) but was not statistically significant in cases where cholesterol levels did not decline (HR, 0.7). Among the participants, 980 used statins after breast cancer diagnosis, and the median serum cholesterol levels were reduced among 781 individuals.

Mortality from breast cancer in statin consumers was reduced among patients with cancers of the estrogen receptor (ER)-positive type (HR, 0.8) and individuals with localized tumors (HR, 0.6).

Among patients with metastatic tumors, statin usage was related to increased mortality compared to non-usage (HR, 1.4). However, the all-cause mortality rates were lower among those who used statins compared to non-users adjusting for serological cholesterol levels (HR, 0.8).

Cholesterol-lowering may be advantageous since dietary cholesterol and hypercholesterolemia are associated with an increased risk of breast cancer. Cell multiplication, membrane construction, and fluidity require cholesterol. Further, cholesterol increases BC cell proliferation and tumor development through ER activation.

Cholesterol is also a precursor to estrogen production, which is a known carcinogen of the mammary gland. Oxysterol derivatives, such as 27-hydroxycholesterol, operate as endogenous ER modulators and can exacerbate cancers among women with estrogen deficiency.

Conclusion

Overall, the study findings showed that post-diagnostic statin usage was related to decreased breast cancer mortality than non-usage, mediated by serological cholesterol levels, indicating that lowering cholesterol with statins could benefit breast cancer patients.

BC risk was further reduced with more intensive statin usage, indicating that statin usage might impact BC outcomes through mechanisms other than reductions in cholesterol levels.

However, among females with metastatic tumors, the risk was increased for statin users, indicating that statins might benefit only patients with early-stage breast cancers.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.