In a recently published study, Dr JAMA Network OpenResearchers determined the relationship between serological cholesterol levels, statin use, and breast cancer (BC) mortality.
Study: Statin use, cholesterol levels, and mortality in women with breast cancer. Image credit: artemevdokimov/Shutterstock.com
Breast cancer is the most common cancer in women worldwide, with satisfactory survival rates but poor survival after metastasis. According to research statin use can increase the survival rate of breast cancer patients; However, most tests do not take into account underlying blood cholesterol levels.
The primary cholesterol metabolite, oxysterol 27-hydroxycholesterol, stimulates tumor development and metastasis in BC animal models and has been associated with mortality in women with low estrogen levels.
Cholesterol is a precursor to estrogen production, which increases the risk of breast cancer. Previous studies, however, did not consider changes caused by concurrent cholesterol levels or statin use, resulting in inconsistent study results.
About the study
In the current population-based, retrospective cohort study, researchers investigated the effect of statin use and serum cholesterol levels on breast cancer mortality.
The study included Finnish women with invasive breast cancer most recently diagnosed between 1 January 1995 and 31 December 2013. All participants provided information on hormone receptors and one or more cholesterol measurements.
The Cancer Registry of Finland identified BC cases using International Classification of Diseases, Tenth Revision (ICD-10) codes. Data extraction included patient age, date of diagnosis, tumor volume and histological characteristics, and primary breast cancer treatment.
Prior to breast cancer diagnosis, mammography screening records were retrieved from the Mass Visit Registry. Charlson Comorbidity Index (CCI) values were calculated based on comorbidity data from the Care Register for Health Care database and drug purchase data from the Social Insurance Institution database.
Study exposure was to assess statin use, statin dose, and serological levels of cholesterol, triglyceride (TG), high-density lipoprotein (HDL), and high-density lipoprotein (LDL), before and after breast cancer. Outcome measures were mortality from breast cancer and other causes between the date of breast cancer diagnosis and 31 December 2015.
Cox proportional hazards regression modeling was performed to determine hazard ratios (HRs). The team excluded a slightly lower percentage with higher mortality from breast cancer and other causes, more metastatic disease or unknown tumor size, and curative-intent surgery as initial therapy. Data was analyzed between January and May 2022.
The study included 13,378 BC patients, who had a median age of 62 years, and were followed for a median of five years after their breast cancer diagnosis.
During the follow-up period, 16% died, including 7% from breast cancer. In total, 31% of individuals had elevated total serum cholesterol levels (median above 193 mg/dL) before breast cancer diagnosis, and half of patients had elevated total serum cholesterol after BC.
Among BC patients, 41% used statins. Multivariate analysis showed that statin use before breast cancer diagnosis was associated with higher BC mortality risk compared with non-use (HR, 1.4).
Prediagnostic statin use increased the risk of breast cancer mortality even after adjusting for total serum cholesterol levels (HR, 1.2). Conversely, the cohort found a reduced risk of breast cancer death associated with post-diagnostic statin use (HR, 0.9).
Risk reduction was greater as intensity of statin use increased (ie, for low-density lipoprotein, the hazard ratio decreased from 0.73 to 0.66). This was stronger for individuals whose serum cholesterol levels decreased after statin use (HR, 0.5) but not statistically significant for those whose cholesterol levels did not decrease (HR, 0.7). Among the participants, 980 used statins after a breast cancer diagnosis, and 781 had a reduction in mean serum cholesterol levels.
Breast cancer mortality was reduced in statin users among patients with cancer of the estrogen receptor (ER)-positive type (HR, 0.8) and among those with localized tumors (HR, 0.6).
Among patients with metastatic tumors, statin use was associated with increased mortality compared with nonuse (HR, 1.4). However, all-cause mortality was lower in statin users than in nonusers for serological cholesterol levels (HR, 0.8).
Cholesterol-lowering may be beneficial since dietary cholesterol and hypercholesterolemia are associated with breast cancer risk. Cholesterol is needed for cell proliferation, membrane construction and fluidity. Furthermore, cholesterol enhances BC cell proliferation and tumor development through ER activation.
Cholesterol is a precursor to the production of estrogen, a known carcinogen of the mammary gland. Oxysterol derivatives, such as 27-hydroxycholesterol, act as endogenous ER modulators and may promote cancer in women with estrogen deficiency.
Overall, the study results showed that diagnostic statin use was associated with a lower breast cancer mortality than non-use, mediated by serological cholesterol levels, indicating that cholesterol lowering with statins may benefit breast cancer patients.
BC risk was further reduced with more intensive statin use, indicating that statin use may influence BC outcomes through mechanisms other than lowering cholesterol levels.
However, among women with metastatic tumors, the risk was increased for statin users, suggesting that statins may only benefit patients with early-stage breast cancer.
Mika O. Murto, MD et al., (2023) Statin use, cholesterol levels, and mortality in women with breast cancer, JAMA Network Open. doi: 10.1001/jamanetworkopen.2023.43861