Statin use, HMGCR expression, and breast cancer survival – The Malmö Diet and Cancer Study

Abstract

Statins, commonly used to treat hypercholesterolemia, have also been proposed as anti-cancer agents. The identification of a predictive marker is essential. The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGcR), which is inhibited by statins, might serve as such a marker. thorough antibody validation was performed for four different HMGCR antibodies. Tumor expression of HMGCR (#AMAb90619, CL0260, Atlas Antibodies, Stockholm, Sweden) was evaluated in the Malmö Diet and cancer Study breast cancer cohort. Statin use and cause of death data were retrieved from the Swedish Prescribed Drug Register and Swedish Death Registry, respectively. Breast cancer-specific mortality (BCM) according to statin use and HMGCR expression were analyzed using Cox regression models. Three-hundred-twelve of 910 breast cancer patients were prescribed statins; 74 patients before and 238 after their breast cancer diagnosis. HMGCR expression was assessable for 656 patients; 119 showed negative, 354 weak, and 184 moderate/strong expressions. HMGCR moderate/strong expression was associated with prognostically adverse tumor characteristics as higher histological grade, high Ki67, and eR negativity. HMGcR expression was not associated with BcM. neither was statin use associated with BCM in our study. Among breast cancer patients on statins, no or weak HMGCR expression predicted favorable clinical outcome. these suggested associations need further testing in larger cohorts. Statins are medications most commonly used by patients with cardiovascular diseases and hypercholesterolemia. Cholesterol is produced by the mevalonate pathway, a metabolic pathway that also produces precursors for steroid hormones and isoprenoids 1. Statins exert competitive inhibition of the rate-limiting enzyme of the mevalonate pathway, 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), an enzyme that has been found to be differentially expressed in breast cancer tumors 2. In recent years, attention in cancer research has been drawn to the mevalonate pathway since statins have been found to exert pleiotropic intratumoral effects, suggesting a possible effectiveness in cancer. Examples of these effects are induction of apoptosis and inhibition of proliferation 3 , and immunomodulatory properties, through inhibition of Ras and Rho family GTPases 4-6 , and by decreasing the production of inflammatory cytokines and activating CD8+ T cells 7. In breast cancer, statins have also demonstrated some anti-neoplastic properties in preclinical studies of breast cancer cells 8-11. These findings are supported by epidemiological data showing protective associations between statin use and breast cancer recurrence and thus prognosis 12-14. However, biomarkers for selection of patients that may benefit from statins are needed. Previous studies have explored the correlation between tumor cell expression of HMGCR and breast cancer prognosis, as well as the association with statin treatment. One study found that high levels of HMGCR tumor expression in breast cancer was associated ...

Association Between Statin Use and Prognosis of Breast Cancer: A Meta-Analysis of Cohort Studies

“…For the remaining 36 studies that underwent full text review, 19 were further excluded for the reasons listed in Figure 1 . Finally, 17 cohort studies were included ( 12 – 28 ).…”

“…Overall, this meta-analysis included 17 cohort studies ( 12 – 28 ) with 168,700 women with breast cancer. The characteristics of the included cohorts were shown in Table 1 .…”

“…Although previous studies generally did not show that statin use is related with reduced risk of breast cancer incidence ( 9 – 11 ), some cohort studies showed that compared with the non-users, users of statin with breast cancer may have better clinical outcomes ( 12 – 17 ). However, other cohort studies did not show that statin use in women with breast cancer was associated with improved prognosis ( 18 – 28 ). Although several meta-analyses have been performed to evaluate the association between statin use and prognosis in women with breast cancer ( 29 – 32 ), only studies published before 2017 were included, and the limited number of studies prevented a comprehensive evaluation of the impacts of study characteristics on the outcomes.…”

“…Although several meta-analyses have been performed to evaluate the association between statin use and prognosis in women with breast cancer ( 29 – 32 ), only studies published before 2017 were included, and the limited number of studies prevented a comprehensive evaluation of the impacts of study characteristics on the outcomes. Therefore, we aimed to perform an updated meta-analysis regarding the association between statin use and prognosis in breast cancer, by incorporating of the recently published cohorts that were not included in previous meta-analyses ( 17 , 24 – 28 ). The relative large number of available studies enables us to perform comprehensive analyses regarding the influences of study characteristics on the outcomes.…”

Statins as Anticancer Agents in the Era of Precision Medicine

“…However, studies that evaluated HMGCR expression as a predictive biomarker of statin sensitivity have yielded conflicting results (31,(36)(37)(38)(39). This is likely due, in part, to the lack of specificity of many commercially-available HMGCR antibodies (2,37,40).…”