While exemestane is not FDA-approved for prevention and no data directly comparing exemestane with tamoxifen or raloxifene, current NCCN prevention guidelines includes 25 mg/day as an option for postmenopausal women.6,10  In this study, exemestane was well tolerated, with  endocrine symptoms (hot flashes) and arthritis reported more often than with placebo. No difference was seen between exemestane and placebo in occurrence of osteoporosis, cardiovascular outcomes, or overall health-related quality of life, as reported by study participants.7

Currently, anastrozole is being studied in the phase 3 International Breast Cancer Intervention Study II (IBIS-II) for primary prevention of invasive breast cancer. The study has two separate treatment arms, where women with DCIS have been randomly assigned to either anastrozole or tamoxifen; and high-risk postmenopausal women with no history of disease are randomly assigned to anastrozole or placebo.12

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Results may provide a foundation for assessing whether or not there is a difference between the drugs in this class in terms of prevention. AIs have no endometrial effects or increased risk for thromboembolic events. However, they can decrease bone mineral density, increase fracture risk, and may have cardiovascular effects.4,12

The Future of Preventive Therapy

The costs and challenges of designing and carrying out prevention trials hamper the ability to identify effective and safe agents in this setting.4 Yet ample evidence exists for promising areas of research if appropriate surrogate endpoints, high-risk populations, or biomarkers for response can be identified for targeted prevention interventions. A well-validated surrogate endpoint from tamoxifen trials is mammographic breast density. Mammographic density is also the most powerful available predictive marker for breast cancer risk: more than 75% density increases risk 4- to 5-fold compared with lower density.

Women whose breast density decreased by 10% or more after 12 to 18 months on tamoxifen had a 63% risk reduction compared to women who experienced breast density decreased by less than 10% and had no benefit.12Identification of other surrogate endpoints or predictive biomarkers, whether specific to one agent or general to all, could reduce the time needed to identify and confirm a true prevention effect and make clinical trials more manageable.

A second issue is identification of populations likely to benefit from preventive therapy. In general, studies have shown that younger women derive less harm from available drugs than older women. Similarly, women at higher risk will derive more benefit. Younger women also stand to derive greater benefit from extended years of life. This suggests that the ideal prevention population is younger women at high risk, yet the challenge remains in engaging them in the prevention discussion.2

As described previously, the benefits of preventive therapy are largely limited to ER-positive disease. Unfortunately, the NCI risk tool cannot discriminate between a woman’s risk of developing ER-positive disease or ER-negative disease. A better risk model would be able to do so to spare those unlikely to benefit from treatment-related harm.2


Preventive therapy does no good if it is not used. Women cite concerns over adverse effects, skepticism that benefit outweighs risk, and dislike for taking daily medication as reasons not to initiate tamoxifen therapy.6 These barriers can be overcome with education and frank discussion between healthcare professionals and patients.27 Although patient stratification and additional therapy options increasingly tilt the balance toward benefit, a lack of knowledge among primary care providers and OB/GYNs, where women at risk but without cancer receive care, hampers efforts to expand breast cancer prevention.12