IntroductionBreast cancer is the most frequent malignancy among women and is a major global burden on the healthcare system1. Approximately 2.3 million new cases and 685,000 deaths due to breast cancer were reported in women in 20202. Hereditary factors play a significant role in the development of breast cancer among women. Some of these genetic predispositions pose a significant lifetime risk of breast cancer3. Among these mutations, BRCA1 and BRCA2 are the most well-known and can lead to breast cancer4,5. The lifetime risk of breast cancer among women who carry the BRCA1 mutation is 45–85%, and the BRCA2 mutation is 40–70%, depending on various environmental as well as genetic factors6,7. The increasing incidence of these genetic mutations (especially BRCA mutations) in the general population, which occurs in 2.5 out of 1000 individuals, emphasizes the need for emergent cancer prevention strategies8. Among these preventive strategies, chemoprevention is an effective method that involves the use of medications for risk reduction in women carrying BRCA mutations9,10. Various chemoprevention therapies are used to reduce breast cancer risk, including aromatase inhibitors (anastrozole and exemestane) and selective estrogen receptor modulators (SERMs) (tamoxifen and raloxifene)11,12. In this study, our key emphasis was on SERMs as a chemopreventive strategy for breast cancer risk reduction.Two major SERMs, tamoxifen and raloxifene, have long been examined for their role in breast cancer prevention. Both drugs play a pathogenic role by blocking the proliferative effects of estrogen in breast tissue, thus reducing the probability of pathogenesis in hormone receptor-positive breast cancers11,13,14. Among the general population at high risk of breast cancer, tamoxifen has been reported as an effective chemopreventive agent in clinical trials, such as the NSABP P-1 study15,16. Raloxifene is another SERM agent that reduces breast cancer risk; however, it is the least used medication owing to its development for the prevention and treatment of osteoporosis17,18,19.The use of chemopreventive agents poses a significant challenge for BRCA mutation carriers. In breast cancer prevention, adherence to chemopreventive strategies may be disturbed due to the adverse effects of aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), which lead to high risks of osteoporosis and thromboembolism among patients. Since BRCA-carrier women who are BRCA carriers are at a higher risk of developing breast cancer than the general population. Therefore, SERMs agents such as tamoxifen and raloxifene are effective because of their preventive outcomes. Few previous cohorts and randomized controlled trials (RCTs) have reported the effectiveness of these SERMs among BRCA1 and BRCA2 mutation carrier populations for risk reduction of breast cancer20,21,22. Tamoxifen and Raloxifene inhibit the formation of tumors stimulated by estrogen by blocking estrogen receptors in the breast tissue. In comparison to tamoxifen, raloxifene decreased the risk of advanced breast cancer by 44–49% in the MORE and STAR trials. It also has fewer adverse effects such as a lower risk of endometrial cancer23,24. However, there is a lack of comprehensive analysis on the effectiveness of tamoxifen or raloxifene in reducing breast cancer risk among women who are BRCA1 and BRCA2 mutation carriers. Therefore, this meta-analysis aimed to evaluate the efficacy of tamoxifen and raloxifene as chemopreventive agents for breast cancer risk reduction among BRCA1 and BRCA2 mutation carriers, focusing on both their potential benefits and associated risks. This study aimed to provide a thorough summary of the role of these drugs in the treatment of women with a high genetic risk of breast cancer by analyzing data from studies published between 2000 and 2024.MethodsStudy designThe “Reporting Items for Systematic Review and Meta-Analysis (PRISMA)” guidelines25 were followed for conducting a recent systematic review and meta-analysis to fulfill research aims of evaluating the risk-benefits of tamoxifen or raloxifene as chemoprevention for risk reduction of breast cancer in women who carry BRCA1 or BRCA2 mutations26. Our study is a meta-analysis of previously published case-control and observational studies; therefore, there is no need for an additional ethical review.Search strategyA comprehensive literature search was conducted using various electronic databases, including PubMed, Cochrane Library, and MEDLINE, to extract and identify related studies published between 2000 and 2024. The relevant research articles were extracted by using MeSH keywords such as (“risk-benefits” OR “risk prevention” OR “risk reduction” OR “risk assessment”) AND (“Breast neoplasm” OR “Breast cancer” OR “chemoprevention”) AND (“Genetic Predisposition” OR “BRCA1 Gene” OR “BRCA2 Gene”) AND (Tamoxifen OR Raloxifene). Previous meta-analyses and reviews were manually searched to extract and identify additional studies from reference lists.Eligibility criteriaThe eligibility criteria assisted in the selection and screening of research articles after searching electronic databases. Only studies that met the following inclusion criteria were included: 1). Studies have investigated women carrying BRCA1 and BRCA2, 2). Studies have analyzed the female population receiving chemoprevention with tamoxifen or raloxifene 3). Studies involving the incidence of breast cancer and the associated hazard ratio (HR) or relative risk (RR) among tamoxifen or raloxifene users and non-users 4). Case control and observational cohort studies 5). Studies published in English and in full text are available.However, these studies were excluded 1). The study population consisted of women who were ER-positive or carried risk genes for other cancer types, 2). Studies involving other drugs for the chemoprevention of breast cancer, rather than tamoxifen or raloxifene 3). Studies have discussed other outcomes such as the incidence of prophylactic bilateral mastectomy 4). Studies based on systematic reviews, meta-analyses, comprehensive reviews, narrative reviews, or editorials were excluded. 5). Studies published in languages other than English, and non-full-text papers were excluded.Data extractionTwo independent reviewers extracted the data using a prespecified table. Data related to demographic information such as authors, year of study, country, study population, sample size, study design, and study follow-up were extracted (Table 1). Information related to primary outcomes, such as the incidence of breast cancer, hazard ratio of breast cancer, and incidence of breast cancer among BRCA1 and BRCA2 carrier women, is shown in Table 2. Discrepancies were resolved by consulting with a third reviewer. The extracted data included the following.Quality assessmentThe Newcastle-Ottawa Scale (NOS) was used to assess the quality of the case-control and cohort studies27. A score of > 7 for included studies was considered low-risk, a score of 5–7 for included studies indicated moderate-risk, and a score of