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Manna, E.D.F. Chemoprevention for Breast Cancer. Encyclopedia. Available online: (accessed on 23 April 2024).
Manna EDF. Chemoprevention for Breast Cancer. Encyclopedia. Available at: Accessed April 23, 2024.
Manna, Eliza Del Fiol. "Chemoprevention for Breast Cancer" Encyclopedia, (accessed April 23, 2024).
Manna, E.D.F. (2023, September 07). Chemoprevention for Breast Cancer. In Encyclopedia.
Manna, Eliza Del Fiol. "Chemoprevention for Breast Cancer." Encyclopedia. Web. 07 September, 2023.
Chemoprevention for Breast Cancer

Female breast cancer is the most commonly diagnosed malignancy worldwide. Risk assessment helps to identify women at increased risk of breast cancer, allowing the adoption of a comprehensive approach to reducing breast cancer incidence through personalized interventions, including lifestyle modification, chemoprevention, intensified surveillance with breast imaging, genetic testing, counseling, and prophylactic surgeries. Primary prevention acts on modifiable risk factors to reduce breast cancer occurrence. Chemoprevention with tamoxifen, raloxifene, anastrozole, and exemestane has already shown benefits in decreasing breast cancer incidence in women at an increased risk for breast cancer.

chemoprevention sporadic breast cancer hereditary breast cancer

1. Introduction

Female breast cancer is the most commonly diagnosed malignancy worldwide [1].GLOBOCAN 2020 estimated 2.3 million new cases and 684,996 deaths from breast cancer and showed that female breast cancer surpassed lung cancer as the most commonly diagnosed cancer [1]. One in eight women (12.9%) will develop breast cancer in their lifetime [2][3]. In addition, the burden of breast cancer is rising worldwide in premenopausal and postmenopausal women [1][4].
Familial breast cancer accounts for 15% to 20% of all breast cancer cases, and about 5% to 10% of breast cancers are due to genetic predisposition [5][6][7]. Hormonal and reproductive factors, mammographic breast density, and proliferative breast disease explain approximately half of breast cancer cases [8].
In 2010, the fraction of breast cancer attributable to lifestyle and environmental factors in the United Kingdom was around 27%, of which 18.5% was related to alcohol, diet, overweight, and obesity [9]. Primary prevention may represent an opportunity to act on modifiable factors and intervene before breast cancer develops. Therefore, preventive strategies focused on decreasing excess body weight, alcohol consumption, and increasing physical activity may impact the burden of breast cancer worldwide [1].
Individualized breast cancer risk assessment helps to identify women at increased risk of breast cancer, allowing them to benefit from personalized risk management strategies [10]. A comprehensive approach to reducing breast cancer incidence encompasses adopting personalized risk-reduction interventions, including lifestyle modification, chemoprevention, intensified surveillance with breast imaging, genetic counseling, and testing [11]. Women with an inherited P/LP germline variant, which confers a high risk for breast cancer, may benefit from risk reduction surgery, like bilateral salpingo-oophorectomy and risk-reducing mastectomy [12][13]
Evidence-based risk reduction strategies according to different risk categories should be implemented to decrease breast cancer burden.

2. Chemoprevention

2.1. Chemoprevention for Sporadic Breast Cancer

Chemoprevention with tamoxifen or raloxifene (selective estrogen receptor modulators, SERMs) and anastrozole or exemestane (aromatase inhibitors, AIs) has shown to reduce breast cancer occurrence in women at increased risk of developing breast cancer [14][15][16][17][18]. The choice of the ideal agent should consider patient-specific risk factors (age, baseline comorbidities) and the adverse events of the different agents [3]. The ASCO clinical practice guidelines recommend the use of endocrine therapy with anastrozole (1 mg/d), exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day) for postmenopausal women with an increased risk of developing breast cancer [19]. Risk reduction agents are recommended only for individuals ≥ 35 years old because the utility of these agents in younger women is unknown [13]. For women aged ≥ 35 years who have completed childbearing, tamoxifen is still the standard of care [19][20]. Tamoxifen is the most studied agent and the only one indicated for premenopausal women, while all four agents may be prescribed for postmenopausal women [13].
Women who could benefit most from chemoprevention with endocrine therapy are those who “have been diagnosed with atypical (ductal or lobular) hyperplasia or lobular carcinoma in situ (LCIS) or have an estimated 5-year risk (according to the National Cancer Institute Breast Cancer Risk Assessment Tool) of at least 3%, a 10-year risk (according to the International Breast Intervention Study [IBIS]/Tyrer-Cuzick Risk Calculator) or have at least 5%, or a relative risk of at least four times the population risk for their age group if they are age 40 to 44 years or at least two times the population risk for their age groups if they are age 45 to 69 years” [19].
In 1992, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1 Study) following the observation that using tamoxifen for adjuvant therapy reduced the incidence of contralateral breast cancer [21]. The study randomized 13,388 women at increased risk for breast cancer to receive a placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for five years. Increased risk was defined by age ≥ 60, or between 35 and 59, with a Gail model 5-year score > 1.66% or a previous history of lobular carcinoma in situ. After a median follow-up of 54.6 months, the results showed that tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided p < 0.00001) and noninvasive breast cancer by 50% (two-sided p < 0.002). The incidence of estrogen receptor-positive (ER+) tumors was reduced by 69%, but no difference was observed in the occurrence of estrogen receptor-negative (ER-) tumors [21]. Tamoxifen administration increased the rates of endometrial cancer (RR 2.53; 95% CI 1.35–4.97) and pulmonary embolism in women aged ≥ 50 years (RR 3.19; 95% CI 1.12–11.15) [21]. After seven years of follow-up, the benefit remained for both invasive (RR 0.57; 95% CI 0.46–0.70) and noninvasive breast cancer (RR 0.63; 95% CI 0.45–0.89) [22].
Along this line, the first International Breast Cancer Intervention Study (IBIS-I) reported the risk reduction of invasive breast cancer with tamoxifen use as well [23]. This study randomized 7254 patients between 35 and 70 years old with a high risk for breast cancer to receive tamoxifen or a placebo for five years [23]. Increased risk for breast cancer was defined by age, family history, high-risk histology, or an estimated 10-year risk higher than 5%. Tamoxifen decreased breast cancer occurrence by 32% (95% CI 8–50, p = 0.013) [23]. In addition, at a median follow-up of 8 years, tamoxifen use reduced the incidence of all types of invasive breast cancer (RR 0.73; 95% CI 0.58–9.91, p = 0.004) [24].
The Royal Marsden Hospital study was a pilot randomized placebo-controlled trial that included healthy women with an increased risk of developing breast cancer based on strong family history (between October 1986 and June 1993). The study aimed to evaluate the efficacy of tamoxifen 20 mg/day for up to 8 years in reducing breast cancer incidence [25][26]. This study allowed women to continue or initiate hormone replacement therapy (HRT). No difference in breast cancer incidence between the groups was observed at 20-year follow-up (HR 0.78; 95% CI 0.58–1.04; p = 0.10). Of note, the incidence of ER+ tumors was significantly lower in the tamoxifen arm (HR 0.61; 95% CI 0.43–0.86; p = 0.005) [27].
The Italian Tamoxifen Prevention Study randomized 5408 healthy women—between 35 and 70 years old—who had undergone a previous hysterectomy to receive tamoxifen or placebo for five years. No difference in breast cancer incidence was observed in the overall study population at a median follow-up of 46, 81.2, and 109.2 months, respectively [28][29][30]. In the study population, however, only 13% (n = 702) of women could be considered at increased risk for breast cancer based on reproductive and hormonal characteristics. At 11 years of follow-up, in the subgroup analysis for the higher-risk women, the breast cancer rates were statistically reduced by tamoxifen (RR 0.24; 95% CI 0.1–0.59) [29].
Raloxifene is a second-generation SERM with similar anti-estrogenic effects and less endometrial stimulation than tamoxifen [13]. The placebo-controlled randomized Multiple Outcomes of Raloxifene Evaluation (MORE) trial evaluated the efficacy of raloxifene in reducing the risk of fracture in postmenopausal women with osteoporosis [31]. The authors randomized 7705 postmenopausal patients between 31 and 80 years to receive a placebo, or raloxifene 60 mg/day, or raloxifene 120 mg/day for three years. Raloxifene decreased the risk of vertebral fractures and increased bone mineral density in the femoral neck and spine [31]. After a median follow-up of 40 months, the relative risk of developing invasive breast cancer was 0.24 (95% CI 0.13–0.44). Raloxifene reduced only the incidence of ER+ breast cancer (RR 0.1; 95% CI 0.04–0.24). However, raloxifene increased the incidence of deep venous thromboses and pulmonary emboli but not the risk of endometrial cancer [31].
The Continuing Outcomes Relevant to Evista (CORE) trial evaluated the impact of 4 additional years of raloxifene on the incidence of invasive breast cancer in 4011 women enrolled in the MORE trial [32]. Raloxifene reduced the 4-year incidence of invasive breast cancer by 59% (HR 0.41; 95% CI 0.24–0.71) and invasive ER+ breast cancer by 61% (HR 0.34; 95% CI 0.18–0.66), without impacting the occurrence of ER- tumors [32]. In addition, raloxifene did not increase the risk of endometrial events or thromboembolism (RR 2.17; 95% CI 0.83–5.70) [32].
The Raloxifene Use for The Heart (RUTH) trial randomized postmenopausal women with a high risk for coronary heart disease to receive raloxifene or placebo [33][34]. According to the Gail model, 40% of the study participants had an increased risk for breast cancer. After a median follow-up of 5.6 years, raloxifene reduced the incidence of invasive breast cancer by 44% (95% CI 0.38–0.83) and decreased the occurrence of ER+ tumors by 55% (95% CI 0.28–0.72) but did not decrease the risk of noninvasive breast cancer and cardiovascular events [34].
The NSABP STAR trial (P-2 Study) compared the efficacy of tamoxifen versus raloxifene to reduce breast cancer incidence. A total of 19,747 postmenopausal women aged > 35 years with high risk for invasive breast cancer, based on the modified Gail model or with a personal history of LCIS, were randomized to receive tamoxifen 20 mg/day or raloxifene 60 mg/day for five years. The efficacy was similar (RR 1.02; 95% CI 0.82–1.28); however, thromboembolic events and cataracts occurred less frequently in the raloxifene group (RR 0.70; 95% CI 0.54–0.91 and RR 0.79; 95% CI 0.68–0.92, respectively) [35].
Other SERMs have shown a reduction in the incidence of invasive breast cancer in postmenopausal women with osteoporosis. Arzoxifene [36] reduced invasive breast cancer incidence by 56% (95% CI 0.26–0.76, p< 0.001) and lasofoxifene [37] by 79% (95% CI 0.08–0.55).
A meta-analysis with individual participant data from nine prevention trials assessed the efficacy of chemoprevention with four SERMs (tamoxifen, raloxifene, arzoxifene, and lasofoxifene) in reducing all breast cancers’ incidence during ten years of follow-up. The analysis evaluated data from 83,399 women during a median follow-up of 65 months. Breast cancer incidence decreased by 38% (HR 0.62; 95% CI 0.56–0.69), while the frequency of thromboembolic events increased with all SERMS (OR 1.73; 95% CI. 1.47–2.05, p<0.0001), and vertebral fractures reduced by 34% (HR 0.66, 95% CI 0.59–0.73) [14].
Aromatase inhibitors have also been evaluated for primary prevention in women with an increased risk for breast cancer. The MAP.3 randomized, placebo-controlled, double-blind trial randomized 4560 postmenopausal women ≥ 35 years old with moderately increased risk for breast cancer to receive a placebo or exemestane. Women eligible for the study were ≥60 years old, had a Gail 5-year score > 1.66%, had prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or had a history of ductal carcinoma in situ with mastectomy. During a median follow-up period of 3 years, the annual incidence of invasive breast cancer decreased in patients receiving exemestane compared with placebo (HR 0.35; 95% CI 0.18–0.70, p = 0.002). The frequency of skeletal fractures, cardiovascular events, or deaths related to treatment were similar [17].
The international, double-blind, randomized, placebo-controlled IBIS-II trial assessed the efficacy and safety of anastrozole for preventing breast cancer in 3864 postmenopausal women at increased risk [38]. The study randomized 1920 women to receive anastrozole 1 mg/day and 1944 a placebo for five years. After a median follow-up of 5 years, anastrozole use decreased the incidence of breast cancer (HR 0.47; 95%CI 0.32–0.68, p < 0.0001); the reduction occurred mainly in high-grade tumors compared with intermediate- or low-grade tumors [38]. The use of anastrozole was associated with a 54% reduction in invasive ER+ breast cancer (HR 0.46; 95% CI 0.33–0.65, p < 0.0001) and a 59% decrease in ductal carcinoma in situ (HR 0.41; 95% CI 0.22–0.79, p = 0.0081), mainly in participants with ER+ tumors (HR 0.22; 95% CI 0.78–0.65, p < 0.0001). No significant difference was observed in overall deaths (HR 0.96; 95% CI 0.69–1.34, p = 0.82) or deaths for breast cancer. In addition, breast cancer incidence showed a significant continuing reduction in long-term follow-up [18].
A meta-analysis of six studies evaluated the efficacy and acceptability of breast cancer prevention agents in 50,927 women at above-average risk of developing breast cancer. Tamoxifen use reduced breast cancer risk compared to placebo (HR 0.68; 95% CI 0.62–0.76) but increased the risk of severe toxicity (RR 1.28; 95% CI 1.12–1.47), particularly endometrial cancer and thromboembolism. Aromatase inhibitor use reduced the risk of breast cancer by 53% (RR 0.47; 95% CI 0.35–0.63) but increased the risk of severe toxicity by 18% (RR 1.18; 95% CI 1.09–1.28), especially hot flashes, diarrhea, and arthralgia [15].
The US Preventive Services Task Force conducted a systematic review (46 studies) to evaluate medication use for the risk reduction of primary breast cancer in women [16]. In placebo-controlled trials, tamoxifen (RR 0.69; 95% CI 0.59–0.84), raloxifene (RR 0.44; 95% CI 0.24–0.80), exemestane, and anastrozole (RR 0.45; 95% CI 0.26–0.70) decreased the incidence of invasive breast cancer but did not reduce breast cancer-specific and all-cause mortality [16].
Tamoxifen, raloxifene, and aromatase inhibitors were associated with acute, long, and late adverse effects that differed between medications. Raloxifene was associated with a reduced incidence of vertebral fractures compared with tamoxifen (RR 0.61; 95% CI 0.53–0.73). Thromboembolic events occurred more frequently in patients receiving tamoxifen (RR 1.93: CI 95% 1.33–2.68) and raloxifene (RR 1.56: CI 95% 1.11–2.60) compared with placebo. In addition, tamoxifen increased the risk of endometrial cancer (RR 2.25; 95% CI 1.17–4.41) and cataracts (RR1.22: CI 95% 1.08–1.48) compared to the placebo. Vasomotor and musculoskeletal events varied by medication [16].
Concerns about the burden of adverse effects of chemoprevention raised doubts regarding the use of chemoprevention, considering the benefit overestimated, especially for healthy women [39]. In addition, the fear of side effects is a significant reason for the poor adherence to chemoprevention for breast cancer risk reduction [40][41]. However, the success of preventive therapy in reducing breast cancer incidence depends on adherence to therapy and the adequate uptake of chemopreventive agents.
A systematic review including 24 articles with 21,423 women reported a pooled uptake of 16.3% (95% CI 13.6–19.0) of breast cancer prevention agents. In addition, the uptake of preventive agents was significantly higher in patients treated in trials (25.2%; 95% CI 18.3–32.2) than in routine care (8.7%; 95% CI 6.8–10.9, p < 0.001) [42].
A study evaluated whether chemoprevention uptake differs among women according to the presence of risk factors for breast cancer. The results showed that women aged ≥ 50 were more likely to use chemoprevention than women younger than 50 (28% versus 11%, p < 0.001). Moreover, the presence of risk factors for breast cancer increased chemoprevention uptake only in women aged ≥ 50 [43].
Whether improving the safety profile of chemoprevention might increase the uptake of preventive agents and consequently decrease breast cancer mortality is unknown.
Studies with low-dose tamoxifen have shown lower toxicity than and similar efficacy to higher doses [44]. A study randomized 500 women with intraepithelial neoplasia (atypical hyperplasia, LCIS or DCIS) to receive low-dose tamoxifen (5 mg/day) or placebo for three years [44]. The low-dose tamoxifen group showed half of the neoplastic breast events (DCIS or invasive cancer) that the placebo group did after a median follow-up of five years. Additionally, these results were consistent with the effect of 20 mg/day of the NSABP-B24 subgroup analysis of hormone-sensitive DCIS (HR 0.58; 95% CI 0.24–0.81); patient adherence to the treatment was similar in both groups [45].
At a median follow-up of 9.7 years, patients assigned to low-dose tamoxifen had a significant 42% reduction in neoplastic breast events (in situ or invasive); the annual rate per 1000 person-years was 11.3 for patients with tamoxifen versus 19.5 with placebo (HR 0.58, 95% CI 0.35–0.95; log-rank p = 0.03). In addition, the incidence of contralateral breast cancer was decreased by 64% for patients with tamoxifen (HR 0.36; 95% CI 0.14–0.92; p = 0.025). The number needed to be treated with tamoxifen to prevent one case of a breast event was 22 in five years and 14 in ten years. Low-dose tamoxifen reduced recurrence by 50% (HR 0.50; 95% CI 0.28–0.91; p = 0.02) in the DCIS cohort, the subgroup representing 70% of the overall population. Low-dose tamoxifen did not increase the risk of serious adverse effects, including deep venous thrombosis and endometrial cancer. Therefore, low-dose tamoxifen represents an alternative for women diagnosed with intraepithelial neoplasia [46].
Current agents prescribed for chemoprevention decreased breast cancer diagnoses, primarily the incidence of ER+ breast cancers. This selective benefit might be because the available agents target the hormonal pathways, while other factors trigger the progression of ER-negative breast cancer. Moreover, triple-negative breast cancers are more aggressive and have inferior survival than ER-positive tumors [47]. Chemoprevention did not decrease breast cancer-related mortality [17]. However, different from the screening programs, mortality is not the primary goal of chemoprevention, while decreasing breast cancer incidence may avoid a cancer diagnosis and aggressive therapies, besides reducing healthcare costs [11][39].
The E3N cohort assessed the association between breast cancer risk and low-dose aspirin or clopidogrel use in postmenopausal women [48]. Among 62,512 women followed during nine years, the authors identified 2864 breast cancer cases. A transient higher breast cancer risk was observed during the third year of low-dose aspirin use compared with never use (HR 1.49, 1.08–2.07), followed by a lower risk (HR 0.72, 0.52–0.99). Clopidogrel ever use was associated with a higher breast cancer risk (HR 1.3, 1.02–1.68), restricted to ER- tumors (3.07, 1.64–5.76, p = 0.01). The authors concluded that antiplatelet drugs are not good pharmacologic candidates for breast cancer prevention [48].
Metformin is an oral glucose-lowering agent used in first-line therapy for type 2 diabetes mellitus [49]. A systematic review and meta-analysis selected 11 independent studies to evaluate the impact of metformin on cancer incidence and mortality. The study reported 4042 cancer events and 529 cancer deaths in patients with diabetes. Patients using metformin had the relative risk reduced by 31% (95% CI 0.61–0.79) compared to other antidiabetic drugs. This inverse relation was notable for pancreatic and hepatocellular cancer but not for colon, breast, and prostate cancer [50][51][52]. This observation led to further investigations in primary breast cancer patients as prevention. According to this, the NCT01905046 trial has been designed to evaluate the role of metformin hydrochloride in reducing breast cancer occurrence in patients with atypical hyperplasia or in situ breast cancer [53].
Veronesi et al. evaluated the efficacy of the retinoic acid derivative fenretinide in reducing second primary breast cancers [54]. The study randomized 2972 patients with surgically removed breast cancer to receive fenretinide 200 mg/day for five years or a placebo. Results showed no benefit in preventing second primary breast cancer [54]. At a median follow-up of 14.6 years, a subgroup analysis showed a decreased risk of second breast cancer only in premenopausal women (HR 0.62; 95% CI 0.46–0.83) [55].
A meta-analysis assessed the effect of vitamin D supplementation in reducing breast cancer risk in 19,137 females. The analysis described no effect on breast cancer risk reduction (RR 1.04: 95% CI 0.84–1.28, p = 0.71) [56].
Two randomized clinical trials assessed the efficacy of alendronate and zoledronic acid in breast cancer risk reduction [57]. The Fracture Intervention Trial (FIT) randomized 6459 women aged between 55 and 81 years to receive alendronate or a placebo, with a mean follow-up of 3.8 years. The HORIZON-PFT (The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial) randomly assigned 7765 women between 64 and 89 years old to receive annual intravenous zoledronic acid or a placebo for a mean follow-up of 2.8 years. Notwithstanding, neither alendronate nor zoledronic acid decreased the risk of postmenopausal breast cancer [57].
Preclinical studies assessed the role of various natural compounds in preventing breast cancer, including curcumin [58], genistein [59], resveratrol [60], and epigallocatechin gallate (EGCG) [61]. In vitro studies have shown that the flavonoid quercetin may enhance tamoxifen-induced antiproliferative effects [62]. However, further clinical studies are necessary to address the safety and efficacy of these compounds in breast cancer prevention, isolated or combined with other agents.

2.2. Chemoprevention for Hereditary Breast Cancer

For women carrying BRCA1 and BRCA2 P/LP germline variants, the cumulative breast cancer risks to age 80 are estimated at 72% and 69%, respectively [63]. The gold standard for primary breast cancer prevention remains bilateral mastectomy, and the annual screening with magnetic resonance imaging and mammography enables earlier detection [64][65]. Data on the efficacy of tamoxifen, raloxifene, and aromatase inhibitors on breast cancer primary prevention in women carrying BRCA1 or BRCA1 and BRCA2 P/LP germline variants are scarce.
The first evidence of breast cancer risk reduction with tamoxifen in healthy BRCA1 and BRCA2 germline variant carriers came from a subgroup analysis of the P-1 trial. The P-1 study evaluated the efficacy of tamoxifen (versus placebo) for reducing breast cancer incidence in 13,388 women at increased risk for breast cancer. Of 288 patients who developed breast cancer after being enrolled in the study, 19 (6.6%) carried BRCA1 P/LP (n = 8) or BRCA2 P/LP (n = 11) germline variants [66]. Tamoxifen did not decrease breast cancer incidence among healthy patients with BRCA1 germline variants. Of eight patients with BRCA1 germline variants who developed breast cancer, five had tamoxifen, and three received a placebo (RR 1.67; 95% CI, 0.32–10.7). Regarding BRCA2 germline variant carriers, of 11 patients with breast cancer, 3 received tamoxifen and 8 had a placebo (RR 0.38; 95% CI, 0.06–1.56). The subgroup analysis of the P-1 trial that assessed chemoprevention with tamoxifen in BRCA1 and BRCA2 germline variant carriers has limitations regarding the small number of patients. If the number of patients with BRCA2 germline variant was higher, the observed risk ratio could be statistically significant. In addition, the study was not designed to address tamoxifen chemoprevention specifically in BRCA1 and BRCA2 germline variant carriers. Again, it is unclear if prevention started before 35 years of age in patients with BRCA1 germline variants could have different results. The role of prophylactic bilateral salpingo-oophorectomy in breast cancer reduction is known and is most evident in younger women [67]. However, it is unknown if tamoxifen enhances this benefit. In addition, these findings may be related to the greater likelihood of developing ER+ tumors in BRCA2 germline variant carriers compared with BRCA1 germline variant carriers.
Although the evidence for chemoprevention with tamoxifen for primary breast cancer in BRCA germline variant carriers is controversial, studies have shown that tamoxifen reduces the occurrence of contralateral breast cancer [64]. According to a meta-analysis, treatment with tamoxifen for a first breast cancer reduced the risk of a second breast cancer in BRCA1 and BRCA2 germline variant carriers by 44% (HR 0.56; 95% CI 0.41–0.76), 0.47 (95% CI 0.37–0.60) for BRCA1 and 0.39 (95% CI 0.28–0.54) for BRCA2 germline variant carriers [68].
The randomized, double-blinded, placebo-controlled phase III French Liber Trial evaluated chemoprevention with aromatase inhibitors in postmenopausal women carrying BRCA1 or BRCA2 P/LP germline variants. The study compared the treatment with letrozole 2.5 mg/day for five years (n = 84) versus a placebo (n = 86) in decreasing breast cancer incidence [69]. The study population comprised postmenopausal women aged between 40 and 70, healthy or with unilateral breast cancer diagnosed five or more years earlier. After a median follow-up of 72.7 months, the 5-year invasive breast cancer-free survival did not differ between the two groups (92% for placebo and 91% for letrozole; HR 0.83; 95% CI 0.3–2.3, p = 0.73) in the overall population. Similar results were described in women with or without breast cancer and BRCA1 or BRCA2 carriers. Limitations included the small number of patients (170 of 270 expected) and the high dropout rate.
The uptake of chemoprevention agents is low among women carrying BRCA1 and BRCA2 P/LP germline variants. Metcalfe et al. examined differences in the uptake of preventive practices (screening with mammography and MRI, prophylactic mastectomy, prophylactic oophorectomy, and chemoprevention with tamoxifen) by 2677 women with BRCA1 and BRCA2 P/LP germline variants from nine countries. Approximately half of the women at risk for breast cancer did not opt for preventive measures and relied solely on regular screening. On the other hand, 1531 (57.2%) women opted to undergo a bilateral prophylactic oophorectomy. Among the 1383 women who did not have breast cancer, 248 (18%) underwent a prophylactic bilateral mastectomy. For those who did not choose to have a prophylactic mastectomy as a preventive option, only 76 women (5.5%) decided to take tamoxifen and 40 (2.9%) raloxifene for breast cancer risk reduction. The uptake of the different preventive options varied among different countries. Women from the US were the most likely to take tamoxifen or raloxifene (12.4%), while no women from Norway, Italy, Netherlands, or France reported using these drugs. Among women without breast cancer, those who had undergone an oophorectomy had a higher tamoxifen usage rate (15.6%) compared with those who had not undergone a prophylactic oophorectomy (1.7%) [70].


  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  2. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33.
  3. Vegunta, S.; Bhatt, A.A.; Choudhery, S.A.; Pruthi, S.; Kaur, A.S. Identifying women with increased risk of breast cancer and implementing risk-reducing strategies and supplemental imaging. Breast Cancer 2022, 29, 19–29.
  4. Heer, E.; Harper, A.; Escandor, N.; Sung, H.; McCormack, V.; Fidler-Benaoudia, M.M. Global burden and trends in premenopausal and postmenopausal breast cancer: A population-based study. Lancet Glob. Health 2020, 8, e1027–e1037.
  5. Colditz, G.A.; Willett, W.C.; Hunter, D.J.; Stampfer, M.J.; Manson, J.E.; Hennekens, C.H.; Rosner, B.A. Family history, age, and risk of breast cancer. Prospective data from the Nurses’ Health Study. JAMA 1993, 270, 338–343.
  6. Slattery, M.L.; Kerber, R.A. A comprehensive evaluation of family history and breast cancer risk. The Utah Population Database. JAMA 1993, 270, 1563–1568.
  7. Apostolou, P.; Fostira, F. Hereditary breast cancer: The era of new susceptibility genes. Biomed. Res. Int. 2013, 2013, 747318.
  8. Chlebowski, R.T. Factors that modify breast cancer risk in women. In UpToDate; Post, T., Ed.; UpToDate: Waltham, MA, USA, 2023.
  9. Parkin, D.M.; Boyd, L.; Walker, L.C. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br. J. Cancer 2011, 105, S77–S81.
  10. Bellhouse, S.; Hawkes, R.E.; Howell, S.J.; Gorman, L.; French, D.P. Breast Cancer Risk Assessment and Primary Prevention Advice in Primary Care: A Systematic Review of Provider Attitudes and Routine Behaviours. Cancers 2021, 13, 4150.
  11. Pruthi, S.; Mussallem, D.M.; Cornell, L.F.; Klassen, C.L.; Kling, J.M. Reducing Breast Cancer Incidence and Mortality: Rethinking an Approach to Risk Assessment and Prevention. JCO Oncol. Pract. 2021, 17, 717–719.
  12. Franceschini, G.; Di Leone, A.; Terribile, D.; Sanchez, M.A.; Masetti, R. Bilateral prophylactic mastectomy in BRCA mutation carriers: What surgeons need to know. Ann. Ital. Chir. 2019, 90, 1–2.
  13. National Comprehensive Cancer Network. Breast Cancer Risk Reduction (Version 1.2023). Available online: (accessed on 30 November 2022).
  14. Cuzick, J.; Sestak, I.; Bonanni, B.; Costantino, J.P.; Cummings, S.; DeCensi, A.; Dowsett, M.; Forbes, J.F.; Ford, L.; LaCroix, A.Z.; et al. Selective oestrogen receptor modulators in prevention of breast cancer: An updated meta-analysis of individual participant data. Lancet 2013, 381, 1827–1834.
  15. Mocellin, S.; Goodwin, A.; Pasquali, S. Risk-reducing medications for primary breast cancer: A network meta-analysis. Cochrane Database Syst. Rev. 2019.
  16. Nelson, H.D.; Fu, R.; Zakher, B.; Pappas, M.; McDonagh, M. Medication Use for the Risk Reduction of Primary Breast Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2019, 322, 868–886.
  17. Goss, P.E.; Ingle, J.N.; Alés-Martínez, J.E.; Cheung, A.M.; Chlebowski, R.T.; Wactawski-Wende, J.; McTiernan, A.; Robbins, J.; Johnson, K.C.; Martin, L.W.; et al. Exemestane for Breast-Cancer Prevention in Postmenopausal Women. N. Engl. J. Med. 2011, 364, 2381–2391.
  18. Cuzick, J.; Sestak, I.; Forbes, J.F.; Dowsett, M.; Cawthorn, S.; Mansel, R.E.; Loibl, S.; Bonanni, B.; Evans, D.G.; Howell, A. Use of anastrozole for breast cancer prevention (IBIS-II): Long-term results of a randomised controlled trial. Lancet 2020, 395, 117–122.
  19. Visvanathan, K.; Fabian, C.J.; Bantug, E.; Brewster, A.M.; Davidson, N.E.; DeCensi, A.; Floyd, J.D.; Garber, J.E.; Hofstatter, E.W.; Khan, S.A.; et al. Use of Endocrine Therapy for Breast Cancer Risk Reduction: ASCO Clinical Practice Guideline Update. J. Clin. Oncol. 2019, 37, 3152–3165.
  20. Gillman, A.S.; Helmuth, T.; Koljack, C.E.; Hutchison, K.E.; Kohrt, W.M.; Bryan, A.D. The Effects of Exercise Duration and Intensity on Breast Cancer-Related DNA Methylation: A Randomized Controlled Trial. Cancers 2021, 13, 4128.
  21. Fisher, B.; Costantino, J.P.; Wickerham, D.L.; Redmond, C.K.; Kavanah, M.; Cronin, W.M.; Vogel, V.; Robidoux, A.; Dimitrov, N.; Atkins, J.; et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. 1998, 90, 1371–1388.
  22. Fisher, B.; Costantino, J.P.; Wickerham, D.L.; Cecchini, R.S.; Cronin, W.M.; Robidoux, A.; Bevers, T.B.; Kavanah, M.T.; Atkins, J.N.; Margolese, R.G.; et al. Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl. Cancer Inst. 2005, 97, 1652–1662.
  23. Cuzick, J.; Forbes, J.; Edwards, R.; Baum, M.; Cawthorn, S.; Coates, A.; Hamed, A.; Howell, A.; Powles, T. First results from the International Breast Cancer Intervention Study (IBIS-I): A randomised prevention trial. Lancet 2002, 360, 817–824.
  24. Cuzick, J.; Forbes, J.F.; Sestak, I.; Cawthorn, S.; Hamed, H.; Holli, K.; Howell, A. Long-term results of tamoxifen prophylaxis for breast cancer--96-month follow-up of the randomized IBIS-I trial. J. Natl. Cancer Inst. 2007, 99, 272–282.
  25. Powles, T.; Eeles, R.; Ashley, S.; Easton, D.; Chang, J.; Dowsett, M.; Tidy, A.; Viggers, J.; Davey, J. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998, 352, 98–101.
  26. Powles, T.J.; Jones, A.L.; Ashley, S.E.; O’Brien, M.E.; Tidy, V.A.; Treleavan, J.; Cosgrove, D.; Nash, A.G.; Sacks, N.; Baum, M.; et al. The Royal Marsden Hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res. Treat. 1994, 31, 73–82.
  27. Powles, T.J.; Ashley, S.; Tidy, A.; Smith, I.E.; Dowsett, M. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J. Natl. Cancer Inst. 2007, 99, 283–290.
  28. Veronesi, U.; Maisonneuve, P.; Costa, A.; Sacchini, V.; Maltoni, C.; Robertson, C.; Rotmensz, N.; Boyle, P. Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998, 352, 93–97.
  29. Veronesi, U.; Maisonneuve, P.; Rotmensz, N.; Bonanni, B.; Boyle, P.; Viale, G.; Costa, A.; Sacchini, V.; Travaglini, R.; D’Aiuto, G.; et al. Tamoxifen for the prevention of breast cancer: Late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J. Natl. Cancer Inst. 2007, 99, 727–737.
  30. Veronesi, U.; Maisonneuve, P.; Sacchini, V.; Rotmensz, N.; Boyle, P. Tamoxifen for breast cancer among hysterectomised women. Lancet 2002, 359, 1122–1124.
  31. Ettinger, B.; Black, D.M.; Mitlak, B.H.; Knickerbocker, R.K.; Nickelsen, T.; Genant, H.K.; Christiansen, C.; Delmas, P.D.; Zanchetta, J.R.; Stakkestad, J.; et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999, 282, 637–645.
  32. Martino, S.; Cauley, J.A.; Barrett-Connor, E.; Powles, T.J.; Mershon, J.; Disch, D.; Secrest, R.J.; Cummings, S.R. Continuing outcomes relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J. Natl. Cancer Inst. 2004, 96, 1751–1761.
  33. Barrett-Connor, E.; Mosca, L.; Collins, P.; Geiger, M.J.; Grady, D.; Kornitzer, M.; McNabb, M.A.; Wenger, N.K. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med. 2006, 355, 125–137.
  34. Grady, D.; Cauley, J.A.; Geiger, M.J.; Kornitzer, M.; Mosca, L.; Collins, P.; Wenger, N.K.; Song, J.; Mershon, J.; Barrett-Connor, E. Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J. Natl. Cancer Inst. 2008, 100, 854–861.
  35. Vogel, V.G.; Costantino, J.P.; Wickerham, D.L.; Cronin, W.M.; Cecchini, R.S.; Atkins, J.N.; Bevers, T.B.; Fehrenbacher, L.; Pajon, E.R., Jr.; Wade, J.L., 3rd; et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006, 295, 2727–2741.
  36. Cummings, S.R.; McClung, M.; Reginster, J.-Y.; Cox, D.; Mitlak, B.; Stock, J.; Amewou-Atisso, M.; Powles, T.; Miller, P.; Zanchetta, J.; et al. Arzoxifene for prevention of fractures and invasive breast cancer in postmenopausal women. J. Bone Miner. Res. 2011, 26, 397–404.
  37. LaCroix, A.Z.; Powles, T.; Osborne, C.K.; Wolter, K.; Thompson, J.R.; Thompson, D.D.; Allred, D.C.; Armstrong, R.; Cummings, S.R.; Eastell, R.; et al. Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J. Natl. Cancer Inst. 2010, 102, 1706–1715.
  38. Cuzick, J.; Sestak, I.; Forbes, J.F.; Dowsett, M.; Knox, J.; Cawthorn, S.; Saunders, C.; Roche, N.; Mansel, R.E.; von Minckwitz, G.; et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): An international, double-blind, randomised placebo-controlled trial. Lancet 2014, 383, 1041–1048.
  39. Prasad, V.; Diener-West, M. Primary chemoprevention of breast cancer: Are the adverse effects too burdensome? CMAJ 2015, 187, E276–E278.
  40. Ropka, M.E.; Keim, J.; Philbrick, J.T. Patient decisions about breast cancer chemoprevention: A systematic review and meta-analysis. J. Clin. Oncol. 2010, 28, 3090–3095.
  41. Serrano, D.; Lazzeroni, M.; Bonanni, B. Cancer chemoprevention: Much has been done, but there is still much to do. State of the art and possible new approaches. Mol. Oncol. 2015, 9, 1008–1017.
  42. Smith, S.G.; Sestak, I.; Forster, A.; Partridge, A.; Side, L.; Wolf, M.S.; Horne, R.; Wardle, J.; Cuzick, J. Factors affecting uptake and adherence to breast cancer chemoprevention: A systematic review and meta-analysis. Ann. Oncol. 2016, 27, 575–590.
  43. Flanagan, M.R.; Zabor, E.C.; Stempel, M.; Mangino, D.A.; Morrow, M.; Pilewskie, M.L. Chemoprevention Uptake for Breast Cancer Risk Reduction Varies by Risk Factor. Ann. Surg. Oncol. 2019, 26, 2127–2135.
  44. DeCensi, A.; Puntoni, M.; Guerrieri-Gonzaga, A.; Caviglia, S.; Avino, F.; Cortesi, L.; Taverniti, C.; Pacquola, M.G.; Falcini, F.; Gulisano, M.; et al. Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia. J. Clin. Oncol. 2019, 37, 1629–1637.
  45. Allred, D.C.; Anderson, S.J.; Paik, S.; Wickerham, D.L.; Nagtegaal, I.D.; Swain, S.M.; Mamounas, E.P.; Julian, T.B.; Geyer, C.E., Jr.; Costantino, J.P.; et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: A study based on NSABP protocol B-24. J. Clin. Oncol. 2012, 30, 1268–1273.
  46. Lazzeroni, M.; Puntoni, M.; Guerrieri-Gonzaga, A.; Serrano, D.; Boni, L.; Webber, T.B.; Fava, M.; Briata, I.M.; Giordano, L.; Digennaro, M.; et al. Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study. J. Clin. Oncol. 2023, 41, 3116–3121.
  47. Chlebowski, R.T.; Aragaki, A.K.; Pan, K. Breast Cancer Prevention: Time for Change. JCO Oncol. Pract. 2021, 17, 709–716.
  48. Cairat, M.; Al Rahmoun, M.; Gunter, M.J.; Severi, G.; Dossus, L.; Fournier, A. Antiplatelet Drug Use and Breast Cancer Risk in a Prospective Cohort of Postmenopausal Women. Cancer Epidemiol. Biomark. Prev. 2021, 30, 643–652.
  49. Heckman-Stoddard, B.M.; DeCensi, A.; Sahasrabuddhe, V.V.; Ford, L.G. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia 2017, 60, 1639–1647.
  50. DeCensi, A.; Puntoni, M.; Goodwin, P.; Cazzaniga, M.; Gennari, A.; Bonanni, B.; Gandini, S. Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis. Cancer Prev. Res. 2010, 3, 1451–1461.
  51. Franciosi, M.; Lucisano, G.; Lapice, E.; Strippoli, G.F.; Pellegrini, F.; Nicolucci, A. Metformin therapy and risk of cancer in patients with type 2 diabetes: Systematic review. PLoS ONE 2013, 8, e71583.
  52. Noto, H.; Goto, A.; Tsujimoto, T.; Noda, M. Cancer risk in diabetic patients treated with metformin: A systematic review and meta-analysis. PLoS ONE 2012, 7, e33411.
  53. U.S. National Library of Medicine. Metformin Hydrochloride in Preventing Breast Cancer in Patients With Atypical Hyperplasia or In Situ Breast Cancer; U.S. National Library of Medicine: Bethesda, MD, USA, 2023.
  54. Veronesi, U.; De Palo, G.; Marubini, E.; Costa, A.; Formelli, F.; Mariani, L.; Decensi, A.; Camerini, T.; Del Turco, M.R.; Di Mauro, M.G.; et al. Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J. Natl. Cancer Inst. 1999, 91, 1847–1856.
  55. Veronesi, U.; Mariani, L.; Decensi, A.; Formelli, F.; Camerini, T.; Miceli, R.; Di Mauro, M.G.; Costa, A.; Marubini, E.; Sporn, M.B.; et al. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann. Oncol. 2006, 17, 1065–1071.
  56. Li, Z.; Wu, L.; Zhang, J.; Huang, X.; Thabane, L.; Li, G. Effect of Vitamin D Supplementation on Risk of Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front. Nutr. 2021, 8, 655727.
  57. Hue, T.F.; Cummings, S.R.; Cauley, J.A.; Bauer, D.C.; Ensrud, K.E.; Barrett-Connor, E.; Black, D.M. Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer: Results From the Randomized Clinical Trials of Alendronate and Zoledronic Acid. JAMA Intern. Med. 2014, 174, 1550–1557.
  58. Guneydas, G.; Topcul, M.R. Antiproliferative Effects of Curcumin Different Types of Breast Cancer. Asian Pac. J. Cancer Prev. 2022, 23, 911–917.
  59. Bouker, K.B.; Hilakivi-Clarke, L. Genistein: Does it prevent or promote breast cancer? Environ. Health Perspect. 2000, 108, 701–708.
  60. Vervandier-Fasseur, D.; Latruffe, N. The Potential Use of Resveratrol for Cancer Prevention. Molecules 2019, 24, 4506.
  61. Romano, A.; Martel, F. The Role of EGCG in Breast Cancer Prevention and Therapy. Mini Rev. Med. Chem. 2021, 21, 883–898.
  62. Xu, Z.; Zhao, D.; Zheng, X.; Huang, B.; Xia, X.; Pan, X. Quercetin exerts bidirectional regulation effects on the efficacy of tamoxifen in estrogen receptor-positive breast cancer therapy: An in vitro study. Env. Toxicol. 2020, 35, 1179–1193.
  63. Kuchenbaecker, K.B.; Hopper, J.L.; Barnes, D.R.; Phillips, K.A.; Mooij, T.M.; Roos-Blom, M.J.; Jervis, S.; van Leeuwen, F.E.; Milne, R.L.; Andrieu, N.; et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017, 317, 2402–2416.
  64. Kotsopoulos, J. BRCA Mutations and Breast Cancer Prevention. Cancers 2018, 10, 524.
  65. Sénéchal, C.; Reyal, F.; Callet, N.; This, P.; Noguès, C.; Stoppa-Lyonnet, D.; Fourme, E. Hormonotherapy for breast cancer prevention: What about women with genetic predisposition to breast cancer? Bull. Cancer 2016, 103, 273–281.
  66. King, M.C.; Wieand, S.; Hale, K.; Lee, M.; Walsh, T.; Owens, K.; Tait, J.; Ford, L.; Dunn, B.K.; Costantino, J.; et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001, 286, 2251–2256.
  67. Wang, Y.; Song, Z.; Zhang, S.; Wang, X.; Li, P. Risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 or BRCA2 mutation carriers: A systematic review and meta-analysis. Eur. J. Surg. Oncol. 2022, 48, 1209–1216.
  68. Xu, L.; Zhao, Y.; Chen, Z.; Wang, Y.; Chen, L.; Wang, S. Tamoxifen and risk of contralateral breast cancer among women with inherited mutations in BRCA1 and BRCA2: A meta-analysis. Breast Cancer 2015, 22, 327–334.
  69. Pujol, P.; Roca, L.; Lortholary, A.; Lasset, C.; Dugast, C.; Berthet, P.; Tennevet, I.; Fricker, J.-P.; Nathalie, C.-B.; Gesta, P.; et al. Five year letrozole versus placebo in BRCA1/2 germline mutations carriers: Final results of LIBER, a double-blind randomized phase III breast cancer prevention trial. J. Clin. Oncol. 2020, 38, 1534.
  70. Metcalfe, K.A.; Birenbaum-Carmeli, D.; Lubinski, J.; Gronwald, J.; Lynch, H.; Moller, P.; Ghadirian, P.; Foulkes, W.D.; Klijn, J.; Friedman, E.; et al. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int. J. Cancer 2008, 122, 2017–2022.
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