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Abstract

The development of pharmacologic agents for the prevention of breast cancer is a significant milestone in medical and laboratory research. Despite these advances, the endorsement of preventive options has become challenging and complex, as physicians are expected to counsel and tailor their recommendations using a personalized approach taking into account medical comorbidities, degree of risk and patient preferences. This article provides a comprehensive overview of the major breast cancer prevention trials, review of the pharmacologic options available for breast cancer prevention, and strategies for integrating chemoprevention of breast cancer in high-risk women into clinical practice.

Keywords

aromatase inhibitor breast cancer prevention breast cancer risk chemoprevention Gail Model high-risk women raloxifene tamoxifen

Over the past decade, there have been new advances in understanding the influence of estrogen in the pathogenesis of breast cancer [1]. A majority of breast cancers in women aged 50–64 years are estrogen receptor positive [101], and adjuvant endocrine therapy used in the treatment of hormone receptor-positive breast cancer has resulted in improved disease-free survival [2]. The two classes of endocrine therapy are selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). Major advances have also been made in the use of these pharmacologic agents to decrease the risk of developing breast cancer in high-risk patients. Studies have reported a decline in breast cancer incidence rates, and factors contributing to this decline are not completely elucidated, but are speculated to possibly be due to an uptake in chemopreventive medication use, declining menopausal hormone therapy use, and the engagement of more women in healthy lifestyle behaviors [3,4].

Healthcare providers are strategically positioned to be proactive in the identification and counseling of high-risk individuals. An ongoing provider–patient relationship allows for an approach to risk assessment and management that is integrated into an overall care plan. Consideration of breast cancer risk in the context of medical history and with acknowledgment of the patient's stated values allows for construction of an individualized strategy that emphasizes shared decision-making and allows for a personalized approach to counseling. The goal of this approach is to improve acceptance, tolerance, and compliance with chemoprevention strategies [5].

Individual risk assessment is a key first step in any chemoprevention strategy, and risk calculation tools are available to assist providers in determining eligibility for chemoprevention. Promoting pharmacologic interventions to reduce the risk of breast cancer among healthy, asymptomatic women who have been identified to be at increased risk can be challenging. In order to provide a balanced assessment of benefit and risk, providers must be knowledgeable about available chemoprevention medications and have a good understanding of the side-effect profiles (quality of life vs potentially life-threatening) of each medication. The negative quality of life-related side effects associated with chemoprevention medications may be perceived to outweigh benefits, and some women may be reluctant to initiate treatment [6].

Breast cancer risk factors & risk calculation tools

The first step in constructing an individualized treatment plan is to obtain a detailed medical and family history. Hormonal and nonhormonal risk factors are associated with an increased risk of developing breast cancer. Hormonal risk factors include early age of menarche, late-onset menopause, nulliparity and late age of first parity. Nonhormonal risk factors include alcohol consumption and postmenopausal obesity. A history of breast biopsies, specifically atypical lobular or ductal hyperplasia, or lobular carcinoma in situ (LCIS) are associated with a greater than fourfold increased risk of breast cancer during a 15–20-year period [7]. A family history of breast cancer in a first-degree relative and extremely dense breast tissue are additional risk factors; each are associated with a twofold increase in breast cancer risk in women aged 40–49 years [8].

Risk assessment is challenging and further limited by the fact that very few tools are currently available to providers. The Gail Model is the most well-known tool to date that has been validated and utilized in determining eligibility for chemoprevention [9,102]. The major chemoprevention trials in the USA incorporated risk assessment with the Gail Model in determining eligibility for participation in these trials. The Gail Model is a computerized tool that incorporates age, family history and, specifically, the number of first-degree relatives diagnosed with breast cancer, number of prior breast biopsies, presence of atypical hyperplasia, age at menarche, age of first live birth and race into the risk calculation. The model provides a well-calibrated estimate of individual risk, but because the distribution of projected risks in cases overlaps the distribution of risk in women who do not develop breast cancer, the model has limited discriminatory accuracy and cannot identify which women will and will not develop breast cancer. The limitations of the Gail Model result from inclusion of only maternal first-degree relatives in the input data on family history with no inclusion of the age of the affected relatives. This can lead to an underestimation or overestimation of risk [10]. The model is not appropriate for use in women with a BRCA mutation, previous history of breast cancer, LCIS, ductal carcinoma in situ (DCIS), history of thoracic radiation for Hodgkin's lymphoma, and certain other women [102]. Investigators who designed the BCPT for tamoxifen, included women aged 60 years and older, and younger women with a 5-year absolute risk of invasive breast cancer of 1.66%, the risk of an average 60-year-old women. The value of 1.66% has since become regarded as a level of ‘high risk,‘ but as discussed below, there is no one level of risk that determines whether a woman should take tamoxifen to prevent breast cancer. This required level of risk depends on the individual risk of other health outcomes and personal values that may be affected by the intervention.

Major randomized clinical prevention trials: SERMs

Based on the results of a number of large, randomized controlled trials, the US FDA has approved the use of SERMs, tamoxifen and raloxifene for reducing the risk of developing invasive breast cancer in women who are identified as high risk [11 –13]. All primary prevention trials were conducted in women with no prior diagnosis of breast cancer, thromboembolic event or those who were pregnant. The inclusion for individual trials was based on assessment of breast cancer risk and the criteria used to define high risk varied by trial [14]. The definition of high risk includes women who have a Gail Model risk assessment of at least 1.66% (5-year predicted risk of breast cancer), high-risk breast biopsy results (atypical hyperplasia or LCIS) or breast cancer diagnosed in one or more first-degree relatives [14].

The first trial to demonstrate the beneficial effects of tamoxifen in breast cancer prevention was the National Surgical Adjuvant Breast and Bowel Project (NSABP) BCPT P-1. Initiated in 1992, this trial investigated premenopausal and postmenopausal women who were identified to be at high risk for the development of breast cancer by randomizing them to either placebo or 20 mg of tamoxifen for 5 years. The initial results demonstrated a statistically significant reduction in the risk of estrogen receptor-positive breast cancer (relative risk [RR] 0.31; 95% CI: 0.22–0.45) [11]. Reanalysis after 7 years of follow-up confirmed a persistence of the significant reduction in estrogen receptor-positive breast cancers (RR: 0.38; 95% CI: 0.28–0.50) [13]. The major side effects of tamoxifen use seen in this trial included endometrial cancer (RR: 3.28; 95% CI: 1.87–6.03), pulmonary embolism (RR: 2.15; 95% CI: 1.08–4.51), deep vein thrombosis (RR: 1.44; 95% CI: 0.91–2.30) and stroke (RR: 1.42; 95% CI: 0.97–2.08) [13].

The IBIS-I study, also initiated in 1992, included premenopausal and postmenopausal women in a double-blind, randomized controlled trial comparing tamoxifen 20 mg per day to placebo for 5 years. Women from the UK, Australia and New Zealand were recruited [15]. Since the most recent reporting, this trial has demonstrated findings similar to the NSABP BCPT P-1. At 96 months of follow-up, there was a statistically significant decrease in invasive breast cancer in the treatment arm of the trial (RR: 0.73; 95% CI: 0.58–0.91; p = 0.004) and the benefit was observed for up to 10 years after patients were randomized for inclusion in the study. The active phase of the trial was 5 years. Occurrence of deep venous thrombosis was similar to the NSABP trial, but occurred only during the active phase of the trial [16].

Raloxifene is a SERM with tissue-specific effects that differ from tamoxifen. Raloxifene has estrogen-agonist activity on bone and exerts a positive effect on lipid profiles, but demonstrates an estrogen-antagonistic effect on both breast tissue and the endometrium [17]. The efficacy of raloxifene in the treatment of osteoporosis has been demonstrated in a number of trials [18,19]. The MORE was a multicenter, randomized, double-blind trial of postmenopausal women with osteoporosis and not at increased risk for breast cancer, who were randomized to receive raloxifene or placebo to determine the effect on the main outcome measure of newly diagnosed breast cancer. After a median follow-up of 40 months, the raloxifene group demonstrated a 76% reduction in the risk of invasive breast cancer [20]. In contrast to tamoxifen, treatment with raloxifene was not associated with an increased risk of endometrial cancer [20].

The CORE trial was a continuation study of the MORE trial and it also demonstrated a marked decrease in the incidence of invasive breast cancer in women who continued four additional years of raloxifene therapy. The women who received raloxifene had a 59% reduction (HR: 0.41; 95% CI: 0.240–0.710) in risk compared with those who took placebo. A combined 8-year follow-up of participants in MORE/CORE trials demonstrated a 66% reduction (HR: 0.34; 95% CI: 0.220–0.500) in the risk of invasive breast cancer [21].

The NSABP P-2 trial, also called the STAR trial, was a head-to-head study of tamoxifen and raloxifene for the primary prevention of breast cancer. Women enrolled in this study had an increased risk of breast cancer, and 19,747 postmenopausal women were randomized to receive either tamoxifen 20 mg per day or raloxifene 60 mg per day for a period of 5 years. At the end of 5 years, no difference in breast cancer incidence between the two groups was found (RR: 1.02; 95% CI: 0.821–0.280) [12] and there was a slight decrease in the incidence of endometrial cancer in the raloxifene arm of the study, although it did not reach statistical significance (RR: 0.62; 95% CI: 0.353–1.080). This trial was limited by the fact that there was no placebo arm. An updated analysis of the trial was published in 2010 after a median post-treatment follow-up of 81 months. With the longer follow-up data, a statistically significant difference emerged for invasive breast cancer risk reduction in favor of tamoxifen (RR: 1.24; 95% CI: 1.051–0.470), but the difference in the noninvasive breast cancer remained statistically nonsignificant (RR: 1.22; 95% CI: 0.951–0.590). In addition, the difference in endometrial cancer risk reached statistical significance in favor of raloxifene (RR: 0.55; 95% CI: 0.360–0.830) [22].

AIs & the MAP.3 trial

Adjuvant endocrine therapy with AIs is part of the armamentarium for the treatment of hormone receptor-positive invasive breast cancer. Studies with AIs in the adjuvant setting have demonstrated an increase in disease-free survival [23] and a decreased risk of contralateral breast cancer [24]. In the ATAC trial, the efficacy data demonstrated a significant reduction in the risk of contralateral breast cancer in the Arimidex® (AstraZeneca, London, UK) versus the tamoxifen group (overall response: 0.42; 95% CI: 0.220–0.790) [25]. This study provided strong support to evaluate the role of AIs for primary prevention of breast cancer. The mechanism of action of AIs involves blocking the aromatase enzyme, which is responsible for the conversion of androstenedione and testosterone to estrone and estradiol, respectively, in adipose tissue and muscle. This results in a profound suppression of estrogen synthesis and subsequent lowering of estrogen levels in the breast and peripheral tissue [26].

The MAP.3 trial is the largest randomized, double-blind Phase III trial evaluating the benefits of exemestane for breast cancer prevention [27]. This study, conducted by the National Cancer Institute of Canada Clinical Trials Group across the USA, Spain and France was published in June 2011. The study demonstrated that exemestane reduced the risk of breast cancer by 65% compared with placebo (RR: 0.35; 95% CI: 0.180–0.700; p = 0.002) among postmenopausal women who were at increased risk of developing breast cancer. Approximately 4500 women were enrolled in the study who met the eligibility criteria of at least one of the following risk factors: age >60 years; 5-year Gail Model risk score >1.66%; prior atypical ductal or lobular hyperplasia or LCIS; or DCIS with prior unilateral mastectomy. The median age was 62.5 years and median Gail risk score was 2.3%. One of the limitations of this study was the short median follow-up of 3 years. In addition, there were a small number of cancers detected; 11 invasive breast cancers in the exemestane and 32 in the placebo group (65% RR; 95% CI: 0.180–0.700).

Participants in both groups experienced hot flashes, fatigue, night sweats, insomnia and arthralgia, with symptoms predictably slightly more common on exemestane. There was no difference between the two groups in the self-reported overall health-related quality-of-life symptoms. With regard to serious adverse events, bone fractures, osteoporosis, hypercholesterolemia and cardiovascular events were essentially equal in both study arms. The projected figure, described as the number needed to treat to prevent one case of breast cancer with exemestane, was 94 over 3 years and 26 over 5 years. The number needed to treat to prevent one case of breast cancer with tamoxifen or raloxifene was 95 over 5 years. Exemestane has not yet been approved by the FDA for breast cancer prevention, and it would be considered off-label use for primary breast cancer prevention if prescribed as outlined recently [27].

Despite evidence that treatment with exemestane did not result in more clinical fractures or diagnoses of osteoporosis than placebo in the MAP.3 trial, serial dual-energy x-ray absorptiometry scans might be warranted in patients started on exemestane, given concerning findings from the bone substudy of the MAP.3 trial indicating that the bone volumetry (measured by high-resolution peripheral quantitative computed tomography) and density (measured by dual-energy x-ray absorptiometry) were significantly negatively impacted in the exemestane versus placebo group [28]. All MAP.3 trial participants were taking vitamin D and calcium supplementation.

Comparison of side effects

Women at increased risk of breast cancer who are considering a chemoprevention drug must engage in a thorough discussion with their healthcare provider about the risks and benefits of the available agents to allow for informed decision-making. Table 1 summarizes current chemoprevention medications in use, protective benefits, side effects and associated adverse events [11,15,22,27,29 –31].

Table 1.

Endocrine therapies for breast cancer chemoprevention.

Endocrine therapies	Timing of use (pre- vs postmenopausal)	Benefits (decreased risk)	Side effects	Adverse event (increased risk)
SERMs
Tamoxifen	Pre- and postmenopausal	Invasive and noninvasive breast cancer Fractures (50+ age group)	Vasomotor symptoms Vaginal discharge, itching/irritation, bleeding/spotting Bladder problems (incontinence) Leg cramps	Endometrial adenocarcinoma Thromboembolic events Cataracts Stroke (All risks above are for 50+ age group only)
Raloxifene	Postmenopausal	Invasive and noninvasive breast cancer (75% of the effectiveness of tamoxifen) Osteoporosis/fractures	Dyspareunia Musculoskeletal problems Weight gain	Thromboembolic events Cataracts Stroke (All risks above are lower with raloxifene than tamoxifen and occur in the 50+ age group only)
AIs
Exemestane	Postmenopausal	Invasive and noninvasive breast cancer	Hot flashes Fatigue Insomnia Diarrhea Nausea Arthralgia Arthritis Vaginal atrophy	Osteoporosis

AI: Aromatase inhibitor; SERM: Selective estrogen receptor modulator.

Data taken from [11,15,22,27,29 –31].

A recent review found less than a third of primary care physicians surveyed from 2002–2004 prescribed tamoxifen because of a perception of an unfavorable risk:benefit ratio [32]. A study by Day et al., as part of the NSABP P-1, reviewed the health-related quality-of-life outcomes showing that sexual function, interest, arousal and orgasm were problematic for women among the tamoxifen group compared with placebo, with the overall sexual activity rates being similar among the two groups [29,33]. With regards to physical and mental health or depressive symptoms from patient-reported outcomes in the STAR trial comparing tamoxifen and raloxifene, no significant difference was found [30].

Data on the toxicity profile of the AIs are largely derived from adjuvant therapy trials in women treated for breast cancer. The ATAC trial compared anastrozole with tamoxifen alone and in combination, and found a better side-effect profile for anastrozole, when compared with tamoxifen alone with a lower incidence of endometrial cancer, thromboembolic events, vaginal bleeding, vaginal discharge, hot flashes and cerebrovascular events (all p < 0.05) [24]. In the Breast International Group 19–8 trial, hot flashes were also reduced for those taking letrozole (incidence 32.8%) compared with those taking tamoxifen (37.3% incidence) [31,34]. When exemestane was compared with placebo in the MAP.3 trial, cardiovascular events (4.7 vs 4.9%, respectively), fractures (6.7 vs 6.4%, respectively) and other cancers (1.9 vs 1.7%, respectively) did not show a statistically significant difference [27,35]. However, there was a higher incidence of hot flashes, arthritis, fatigue, insomnia, nausea and diarrhea in those taking exemestane compared with placebo [35]. Several studies have shown almost half of patients taking AIs have musculoskeletal complaints [31].

Individualizing therapy

After the FDA's approval of tamoxifen for chemoprevention in 1998 and raloxifene in 2007, there were high expectations from the research community that these medications would be practice changing and their use would contribute to a significant decrease in breast cancer incidence [36,37]. Despite FDA approval and widespread evidence of benefit and safety from large clinical studies, data on the use of chemoprevention for breast cancer show that women at high risk for breast cancer are not receiving adequate treatment. A 2010 National Health Interview Survey estimates the prevalence of the use of chemoprevention for primary breast cancers among women in the USA to be 20,598 (95% CI: 518–114,864) for women aged 35–79 years using tamoxifen and 96,890 (95% CI: 41,277–192,391) for women aged 50–79 years using raloxifene [38]. This is well below 1% of the population. Although chemoprevention with tamoxifen was poorly accepted in 2000 [39], the use of tamoxifen in 2000 was ten-times more prevalent than in 2010. Since then, a shift was noted in the use of chemoprevention from tamoxifen to raloxifene, mainly after 2007, when raloxifene became FDA approved for this indication [38]. This is likely due to the favorable risk profile of raloxifene and the increased knowledge and comfort level that primary care providers have with using raloxifene for the prevention and treatment of osteoporosis. Although primary care providers are strategically positioned to address chemoprevention, they are often uncomfortable recommending medications that have historically belonged to the armamentarium of medical oncologists. Knowledge gaps about risk and benefits of these medications may influence confidence in the ability to counsel patients and may also contribute to reluctance to prescribe [40]. In addition, women are reluctant to use chemoprevention, mainly due to fear of adverse effects, which are perceived as outweighing the benefits of breast cancer reduction [38,39]. However, interventions to educate women on this issue have led to less adoption of chemoprevention [41]. Indeed, a recent survey of 712 women at high risk for breast cancer addressed the interest in tamoxifen and raloxifene after receiving a web-based decision aid versus a control group [6]. At 3-months follow-up, 55% decided against chemoprevention, 8% looked for additional information, 2% spoke to their doctor about it, 0.5% started raloxifene and no one started tamoxifen. Participants were not particularly worried about these medications but did not perceive significant benefits from taking them. Similar results were seen in a decision-aid study on the benefits of tamoxifen, based on the results from the BCPT [42]. It was previously shown that presenting a treatment as having potential side effects leads to aversion to it [43] and that avoidance of complications leads to biased healthcare decisions [38].

Although a woman may be at high risk for breast cancer, it is important to remember that for an asymptomatic individual, a decision to initiate therapy associated with side effects that may negatively impact quality of life is difficult. Adding to this reluctance is the exposure to conflicting information about chemoprevention in the media, which tends to exaggerate side effects and fear of potential adverse events, such as uterine cancer, stroke and venous thromboembolism, which are, in reality, relatively rare occurrences [44].

Furthermore, in women who have decided to initiate chemoprevention, the compliance with these medications is less than ideal. In trials of chemoprevention, adherence to tamoxifen and raloxifene ranged from 60 to 80% [45]. Exemestane is also associated with a 30% discontinuation rate [46]. Side effects are the most common reason for discontinuation of these medications. Baseline predictors of poor adherence are current smoking, heavy alcohol use and younger age, whereas higher education, white race and higher risk for breast cancer are associated with better compliance [47,48].

Adherence to chemoprevention therapy needs to be encouraged in clinical practice. Adherence can be improved by providing a supportive environment for patients, providing them with information on managing side effects and continuing to inform patients about effectiveness supported by scientific evidence of the medication in reducing breast cancer risk.

Assessing individual risk & benefit

To help discern the benefits and the risks of these medications and to guide medical providers in counseling individual patients, Freedman et al. constructed a risk:benefit ratio of tamoxifen versus placebo or raloxifene versus placebo for different categories of increased breast cancer risk in women 50 years of age and older [49]. To calculate this index, the authors assigned weights to pertinent health outcomes, such as invasive breast cancer, hip fracture, endometrial cancer, stroke, pulmonary embolism, in situ breast cancer, deep venous thrombosis, Colles fracture, hip fracture and cataracts. Incidence of these outcomes (using the Women's Health Initiative study baseline rates), and the RR of these outcomes in women treated with tamoxifen or raloxifene (from the BCPT and STAR trials, respectively), were used in the computation of this index, taking into consideration the weight of each item.

As can be seen in Figures 1 & 2, raloxifene was beneficial for all groups by age, breast cancer risk and uterus status, except for older women in the lower categories of increased risk. By contrast, the risk:benefit ratio of tamoxifen in women above the age of 50 years was strongly influenced by the presence or absence of the uterus. In women without a uterus, the evidence for benefit from tamoxifen was similar to that of raloxifene, whereas in women with an intact uterus, there was no benefit with tamoxifen except for the younger group (50–59 years) with a 5-year risk of breast carcinoma of ≥4.5% [49].

Figure 1.

Risk/benefit indices for tamoxifen and raloxifene chemoprevention by level of 5-year projected risk of invasive breast cancer for white non-Hispanic women with a uterus, by age group.

Figure 2.

Risk/benefit indices for tamoxifen and raloxifene chemoprevention by level of 5-year projected risk of invasive breast cancer for white non-Hispanic women without a uterus, by age group.

A similar risk:benefit index of tamoxifen versus placebo and decision-aid tables, applicable to a broader age category of premenopausal and postmenopausal women at high risk for breast cancer, were created by Gail et al. in 1999 [50], based on the results from the BCPT. The decision-making tool developed by Gail et al. is shown in Figure 3 [50].

Figure 3.

Tool for decision-making regarding the risk/benefits of tamoxifen in women at high risk for breast cancer (in a theoretical population of 40-year-old women with an intact uterus and a projected 5-year risk of breast cancer of 2%).

For premenopausal women, there is a strong benefit from tamoxifen in all categories of increased breast cancer risk, and the likelihood of serious adverse events is very low, based on the results from the BCPT trial [11]. In this group of younger women, there was also evidence of increased thromboembolic events (RR: 0.76 for stroke, 2.03 for pulmonary embolism and 1.39 for deep vein thrombosis), although not statistically significant. Overall, in younger women, the baseline risk of these adverse events in the absence of tamoxifen is very low and is the reason for which the benefits of tamoxifen outweigh the risks in this population. For those with a very high risk for breast cancer, such as biopsy-proven atypical hyperplasia or LCIS, tamoxifen should be recommended.

Raloxifene would be the preferred choice for postmenopausal women with an intact uterus. However, in making this recommendation, one has to be aware that tamoxifen was shown to have a persistent effect for up to 20 years in breast cancer risk reduction [16,51], whereas there is no long-term data with raloxifene, which is thought to have a shorter duration of action and to be less potent than tamoxifen in the adjuvant treatment setting [22,52,53]. In postmenopausal women without a uterus, tamoxifen and raloxifene have a similar risk:benefit ratio, and either can be offered with the caveats presented above.

Of some concern is the use of tamoxifen in women taking selective serotonin reuptake inhibitors (SSRIs), in particular fluoxetine and paroxetine. These medications inhibit the CYP2D6 enzyme, responsible for the conversion of tamoxifen to its major active metabolite, endoxifen [54,55]. By contrast, the selective norepinephrine uptake inhibitors (SNRIs), such as venlafaxine and desvenlafaxine, do not interfere with this enzyme. Although controversy remains regarding the CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant breast cancer treatment setting, this correlation seems to be nonexistent in the prevention setting. Indeed, Goetz et al. performed a nested case–control study of patients in the NSABP P-1 and P-2 studies [56]. There was no correlation between the CYP2D6 genotype (extensive or poor metabolizer) or the use of a potent CYP2D6 inhibitor, such as an SSRI, and breast cancer occurrence for women in receiving either tamoxifen or raloxifene. In general, it is not common practice to switch from current treatment with SSRIs to SNRIs for the patient being treated with tamoxifen in whom antidepressant treatment is contemplated. However, the use of an SNRI as a first line of therapy might be reasonable.

AIs appear to have a more favorable risk:benefit ratio than SERMs, with the exception of osteoporosis and fractures. However, a recent meta-analysis of trials comparing AIs with tamoxifen in the adjuvant setting has shown an increase in cardiovascular events with prolonged AI use and a nonstatistically significant increased risk of death without recurrence [57]. The cardiovascular concern was not reproduced in the MAP.3 trial in which exemestane was compared with placebo, possibly reflecting the favorable cardiovascular profile of tamoxifen in studies comparing AIs and tamoxifen. Given the more favorable risk:benefit ratio and the fewer side effects of AIs compared with SERMs, this class of medication may appear more attractive to postmenopausal women at high risk for breast cancer. The decision should depend on the race, breast cancer risk, age, uterus status and comorbidities. The discussion should be ongoing as breast cancer risk can change over time, keeping in mind the patient's values, but also stressing the safety and benefits of these interventions.

Guidelines for breast cancer chemoprevention

Based on results from the major breast cancer prevention studies, the American Society of Clinical Oncology generated guidelines for consideration to use chemoprevention in women at increased risk for breast cancer [58]. The guidelines were supported by evidence which demonstrated that for women at increased risk for breast cancer, treatment with tamoxifen in women 35 years of age and older (20 mg per day for 5 years) has been shown to have a persistent effect in breast cancer risk reduction of at least 10 years after completion of therapy, and should be considered for chemoprevention. In postmenopausal women with an intact uterus, raloxifene (60 mg per day for 5 years), may be considered for women at increased risk for breast cancer.

These guidelines reflect expert consensus based on best available evidence to assist physicians in the decision-making process about currently accepted approaches to management and treatment of high-risk women. The guidelines provide literature updates and discussion on the comparative efficacy, risks, benefits and side-effect profiles of the available pharmacologic options. Organizations with published chemoprevention guidelines include the US Preventive Services Task Force [59,60], National Comprehensive Cancer Network [61], American Society of Clinical Oncology [58] and Canadian Task Force on Preventive Health Care [62].

The purpose of establishing and implementing chemoprevention guidelines is to ensure that high-risk women are appropriately counseled and educated about their options. Risk assessment and risk communication are also important essential components of the educational effort of these guidelines. The common goal is that integration of pharmacologic options into clinical practice will allow high-risk women to benefit from breast cancer prevention strategies.

Conclusion

Over the past decade there have been significant advances involving clinical trials and research evaluating pharmacologic agents for breast cancer prevention. Both SERMs and AIs have been shown to reduce breast cancer risk among women at increased risk for breast cancer. The decision-making process and individual counseling regarding chemoprevention medication use is complex. Providers are challenged to tailor and personalize pharmacologic therapies based on individual breast cancer risk and knowledge regarding risks and benefits of the available options. In addition to considering the risk:benefit ratio, any decision should consider potential side effects of these medications.

The efficacy of the antiestrogen therapies has been demonstrated, but more research is needed on the optimal duration of therapy, as well as the optimal age at which to initiate treatment. It is essential that future research target the identification of biomarkers that will aid in risk prediction and response to pharmacologic therapy to enable more women who are at increased risk for breast cancer to benefit from chemoprevention and reduce the incidence of breast cancer worldwide.

Future perspective

Research endeavors support the development of new methods or models that will accurately identify high-risk women who are most likely to benefit from chemoprevention. A risk assessment or calculation tool that, for example, incorporates biomarkers, tissue histology and breast density, may be more accurate in estimating the true individual risk rather than a population risk. Such risk assessment models would result in a personalized approach to minimizing risk and maximizing benefit. If an individual is prescribed a bisphosphonate for treatment of osteoporosis, a bone mineral density scan or bone biomarkers are available for monitoring the efficacy of the drug. In the area of chemoprevention, imaging tests or biomarkers are not yet available to assess drug efficacy or benefit.

Good evidence is lacking on available chemoprevention options for BRCA carriers. The NSABP P-1 trial determined that tamoxifen in BRCA2 carriers was associated with a nonsignificant decrease in breast cancer risk [63]. A randomized chemoprevention trial in France for BRCA mutation carriers is underway that is comparing anastrozole versus placebo. The International Breast Cancer Intervention Study (IBIS-II) began recruitment in 2003 and was closed in January 2012; the results are pending [103]. This study addresses the ability of anastrozole to reduce the incidence of invasive breast cancer in postmenopausal women at increased risk for breast cancer and women with DCIS. Over 6000 women have been enrolled on this study, which includes a bone substudy component of 1000 women [103]. The NSABP B-35 is another clinical trial comparing anastrozole with tamoxifen in postmenopausal women with DCIS undergoing lumpectomy with radiation on preventing subsequent occurrence of breast cancer [104]. The study has completed accrual and results are pending.

A study involving BRCA carriers that will evaluate letrozole versus placebo for breast cancer prevention is underway [64]. A study being conducted by the University of Arizona (USA) is the first study to include four arms with de-escalating doses of letrozole given for 6 months that will evaluate the incidence of breast cancer [105]. This study includes a biomarker assessment utilizing random periareolar fine-needle aspiration to assess changes in proliferation pre- and postdrug intervention. New research is being conducted on the role of metformin, a commonly used medication for treating Type 2 diabetes mellitus, to decrease breast cancer risk. The preclinical evidence indicates that metformin works by reducing the growth of breast cancer cells and may also have unique antitriple negative breast cancer effects [65].

Acknowledgements

The authors sincerely thank G Hebl from Mayo Clinic Grant and Publication Support Services for her editorial assistance.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Therapeutic preventive options to reduce risk of breast cancer include selective estrogen receptor modulators and aromatase inhibitors.

Individual risk assessment and risk communication are important first steps in determining chemoprevention strategy.

Clinical decision tools exist to calculate benefit and risks of the chemoprevention drugs and guide providers in medication selection.

In the area of chemoprevention, biomarkers to assess response to pharmacotherapy are not yet available.

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