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Breast cancer (BC) is not a single illness but a collection of diverse subtypes with varying clinical outcomes. It accounts for around 12.5% of all new annual cancer diagnoses1. Currently, the treatment of BC includes surgery that is, breast conservation or mastectomy, radiation, chemotherapy, hormone therapy, targeted therapy medications, immunotherapy, and/or supportive care2. While progress in BC research has led to a dramatic decline in the disease's mortality rate in recent decades, it is still a significant global health dilemma because of its ever-increasing incidence3. With a rising population of BC survivors, the problem of cancer recurrence grows more critical despite the increase in the long-term survival rate of BC survivors brought about by advanced treatments. Each survivor has a 5–41% probability of experiencing a recurrence in their lifetime4. Finding an effective treatment for BC is essential, and Statins seem to be a promising drug. Statin medications have long been considered part of the conventional treatment when dealing with excessive cholesterol or atherosclerotic coronary artery disease5. Statins are competitive HMG-CoA reductase (HMGCR) inhibitors that decrease cholesterol and improve cardiovascular health. These drugs also demonstrate pleiotropic effects independent of their lipid-lowering effects and exhibit anticancer properties for various cancers, including BC6. Due to common risk factors, many women diagnosed with BC also have cardiovascular problems and take medicines to treat them. Furthermore, current BC treatments might negatively affect cardiovascular health, influencing cancer treatment decisions for women with preexisting cardiovascular disease7. Due to the high incidence and apparent two-way connections, questions have been raised about the potential effect of cardiovascular drugs on BC. The statin class of lipid-lowering medications has gained interest from the cancer community in addition to its use in treating cardiovascular disease. Since high cholesterol fuels BC cells, statin's action of lowering cholesterol by inhibiting HMG-CoA reductase helps improve BC outcomes as well. The pleiotropic effects of statins, including their ability to reduce tumor cell health and increase its sensitivity to cytotoxic therapies by inhibiting cell growth, inducing apoptosis, reducing proliferation and invasion, inducing oxidative stress, and rising radiation sensitivity, make them an attractive therapeutic option8. Patients who take statins, particularly lipophilic statins, as neoadjuvant treatments for BC have seen a decrease in both recurrence and mortality, according to studies in the past9–11. A systematic review was conducted to study the link between statins and BC in mouse models to provide a clinically relevant picture of the potential use of statins in the disease. Twenty-six studies published between January 2007 and July 2022 were used, concluding that statins alone and combined with anticancer therapies demonstrate proven antineoplastic effects across the cancer care continuum. The antineoplastic benefit of statins as single agents in mouse model studies helps inform their synergistic use that future clinical trials can test. Parameters such as statin dose, timing, and BC subtype are essential steppingstones in defining how this drug could treat BC12. Statin use has been linked to increased survival rates in several cancer types13,14. In addition, studies have shown conflicting outcomes for patients with molecular subtypes of BC, with some indicating better outcomes for patients with Estrogen Receptor positive (ER+) BC and others showing better results for patients with ER-negative BC15. To reconcile these conflicting findings, researchers in New Zealand performed a cohort analysis of 14 976 BC patients who had used statins following their diagnosis between 2006 and 2016. Their cohort analysis, presently in publication, found that patients with BC taking statins had a 26% lower risk of dying from BC than patients not taking statins. While statins' protective effects were seen across the board, they were most pronounced in ER-positive patients hazard ratio (HR)=0.77, postmenopausal women (HR=0.74), women at an advanced stage of illness (HR=0.65), and prevalent statin users (HR=0.69). Furthermore, the study found a dose-dependent but inconsistent link between statin use and BC death risk. However, no meaningful results were seen in premenopausal women, new users, early-stage illness patients, or outcomes related to recurrence or distant metastases16. A study was conducted to explore how statin use affected individuals with triple-negative BC (TNBC). This study focused on women over 65 with stages I, II, or III BC. They examined the connection between starting statin therapy within 12 months of a BC diagnosis and overall survival (OS) and BC-specific survival (BCSS). The results showed that women with TNBC who started taking statins one year after their BC diagnosis had improved OS and BCSS. These findings suggest that statins could benefit some BC patients and more research is needed to investigate their potential benefits further17. A study also discovered that statins reduce proliferation and trigger apoptosis in TNBC cells and that p53 mutational status can be a prognostic biomarker in TNBC patients. Because Tp53 is mutated in 80–90% of these cases, statins have been demonstrated to degrade mutant p53 protein. The antiproliferative effects of two commonly used statins were studied in a panel of 15 cell lines representing distinct molecular subtypes of BC. Significantly lower IC50 values were discovered in triple-negative (TN) cell lines than in non-TN cell lines, indicating increased sensitivity. Furthermore, cell lines carrying mutant p53 were more susceptible to both statins than cell lines expressing wild-type p53, implying that the mutational status of p53 represents a possible predictive biomarker for statin responsiveness. Apart from inhibiting proliferation, simvastatin was also found to induce apoptosis and promote cell cycle arrest. The study suggested repurposing statins for clinical trials in patients with TNBC. Based on the findings, the authors indicate that these trials investigate statins in combination with either docetaxel or doxorubicin and include p53 mutational status as a potential predictive biomarker18. A systematic review and meta-analysis were conducted to study the relationship between post-diagnostic statin usage and BC patients with different phenotypes. A total of seven studies with 24 541 patients were identified, and overall, post-diagnostic statin use was associated with improved recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). Subgroup analysis showed that the benefits of statin usage varied from hormone receptor phenotype type. Prospective randomized trials with patients of different hormone receptor types should be done to help identify which subtype of BC patients would benefit from post-diagnostic statin usage19. A new cohort study was conducted in South Korea on the relationship between statin use and the incidence and mortality of breast and gynecologic cancer. The study used the National Health Insurance claims database and focused on women aged 45–70 who had taken statins for at least 6 months. These women were compared to statin non-users of the same age from January 2005 to June 2013. The study found that using the drug for at least 6 months was significantly associated with a lower risk of BC incidence and lower mortality of BC. However, further research is needed to understand these associations fully20. A retrospective study was carried out for the first time in an Asian population (Singapore) on the impact of statin use and BC recurrence. A total of 7858 females with BC were studied, of which 1353 were statin users and 6505 were non-statin users. Similar to previous international studies, statin use was associated with reduced BC recurrence. This primarily benefited patients with ER+ and HER2-invasive BC. Statin use was also associated with a reduced risk of BC recurrence in all BC subtypes in the long term (>6 years post-diagnosis)21. While prior research has found a link between statin use and BC survival, the link between statin use and BC recurrence patterns is yet unknown. Between 2005 and 2014, participants in the Malmo Diet and Cancer Study (MDCS) were diagnosed with incident invasive BC. The follow-up period began with the diagnosis of BC and continued until the first invasive BC recurrence occurrence, death, emigration, or the end of the follow-up period (8 June 2020). The final cohort research included 360 eligible patients, and it was concluded that statin use was associated with a lower risk of distant BC recurrence but not with loco-regional BC recurrence22. An observational, real-life cohort study was carried out to study if statins could improve the effectiveness of a class of targeted BC drugs called T-DM1 (trastuzumab emtansine or Kadcyla), which is a microtubule inhibitor and HER2-targeted antibody conjugate. Statins influence HER-2-based therapies via the caveolin-1 (CAV-1) protein in female BC patients treated with T-DM1. The study included 105 patients with HER2-positive metastatic BC treated with T-DM1. The results show that T-DM1 is more effective across a statin-using population than in statin non-users for treating HER2-positive BC since the median OS was significantly higher in the former. The association between statin use and progression-free survival (PFS) did not reach statistical significance. The authors concluded that statins may be used in BC patients receiving T-DM1 until their observation is further tested in larger prospective datasets23. Recent studies have shown that statins positively affect BC outcomes. Statins' potential cardioprotective and risk-reducing effects in BC mortality and recurrence raise intriguing treatment possibilities. Several clinical trials now look at statins' effects on BC survival rates24–26. The scientific community will be able to endorse statins use for BC management once the results of these large population-diversified trials, along with studies on efficacy outcomes related to different BC subtypes, grade and stage of cancer, demographics, dose-related effects, and safety and comparative efficacy outcomes of the various types of statin drugs, are all in. Still, the study's findings on their offer cause for optimism. It is also advocated that a multidisciplinary strategy, like that used in the treatment of BC, be used to monitor and manage survivors' cardiac and general health. Ethical approval This type of article doesn't need any ethical approval. Consent No patients were included. Source of funding The authors have not received any funds. Author contribution A.A. and T.H.: protocol development, data collection, data analysis, and manuscript writing; R.H.: data collection, data analysis, and manuscript writing; H.H.S.: data collection and manuscript writing; U.H.: manuscript writing; M.A.H.: protocol development, data analysis, and manuscript writing. Conflicts of interest disclosure The authors declare that there are no conflicts of interest. Research registration unique identifying number (UIN) Name of the registry: not applicable. Unique identifying number or registration ID: not applicable. Hyperlink to your specific registration (must be publicly accessible and will be checked): not applicable. Guarantor Aleena Aftab. Provenance and peer review Not commissioned, externally peer-reviewed. Data availability statement Not applicable.
Aftab et al. (Mon,) studied this question.