The prevention of disease has become an increasingly important focus in the past two decades for patients, their health care providers, and insurers.^1–3 Worldwide, scientists and population health experts are uncovering the impact that genetics and the environment, individually and in combination, have on the development of particular diseases. Heart disease has historically been the leading cause of death in the United States and remains a focus for primary prevention through pharmacologic (aspirin, statins) and lifestyle interventions (tobacco cessation, weight loss, diet modification).^4,5 Cancer however was a “close second” as a cause for death in the United States in 2010 and is expected to surpass heart disease as the primary cause for mortality in the next decade.⁶ Cancer prevention, therefore is positioned to become an important adjunct to primary cancer therapy.

The use of surgery for disease prevention and for oncologic disease prevention in particular is less common than medical or lifestyle interventions. For those with a known genetic aberration that can cause a future malignancy, surgery can be used to reduce the incidence of colon cancer in patients with familial adenomatous polyposis, the incidence of thyroid cancer in patients with multiple endocrine neoplasia, and the incidence of breast cancer in patients with BRCA1 and 2 and other high-risk genetic mutations.^7,8 The latter is expected to increase in utilization, over the next 5 to 10 years based on a number of influential factors, including increased public awareness, and availability of genetic testing and reconstruction options.^9–11 For breast cancer prevention, there are two surgical options that are utilized: ovarian removal in the pre- or perimenopausal setting which provides an estimated 50% reduction in the development of breast cancer, and prophylactic mastectomy which provides an estimated 90% reduction in risk.¹² For those individuals who want to avoid or postpone prophylactic surgery, however, medical and lifestyle modification interventions offer an alternative approach for breast cancer risk reduction.

Foremost in a discussion on surgical or nonsurgical breast cancer risk reduction is defining the population at risk. Determining future breast cancer risk requires consideration of both genetic and nongenetic factors. Individuals who have inherited mutations in highly penetrant breast cancer susceptibility genes, such as BRCA1 and 2, PALB2 and PTEN (65% to 85% lifetime risk), CDH1, STK11 (35% to 50% lifetime risk), and others that are less penetrant such as CHEK and p16 have the greatest future breast cancer risk.^13–15 Some women with extensive family histories of breast cancer will test negative for a known genetic mutation and yet remain at high risk for the future development of breast cancer. Utilization of genetic models such as BRCAPRO and the Claus model may help determine the estimated percentage lifetime risk of a breast malignancy for these individuals.^16,17 For women without a suspected mutation, the Gail model is the most commonly used general risk assessment tool and includes the hormonal risk factors of onset age of menses, age of menarche, and first live birth in addition to a limited family history and history of prior breast biopsy.¹⁸ The Tyrer–Cuzick model is another model that includes genetic factors and a range of nongenetic factors, but this model has not been as thoroughly validated as the Gail risk tool.¹⁹ Interrelated to a patient’s genetic background are risk factors such as breast density and findings of atypical changes on breast biopsy, each of which are known to increase a woman’s lifetime risk to approximately 20% or greater.^20,21 It can be assumed based on current models which are incorporating single nucleotide polymorphisms (SNPs) and breast density into existing risk models²² that future risk assessment models will also incorporate lifestyle factors. This will allow patients to better understand their breast cancer risk affording them the opportunity to evaluate and potentially adopt nonsurgical approaches to risk reduction.

In this chapter, evidence for pharmacologic preventive therapy or chemoprevention with selective estrogen receptor modulators (SERMs) and aromatase inhibitors will be discussed, along with current guidelines for their use. Additionally reviewed will be the ongoing research and growing evidence for use of other medical risk-reducing agents, including metformin, bisphosphonates, and statins. Lastly, evidence for breast cancer risk reduction with lifestyle interventions including exercise programs, weight management, limited alcohol consumption, tobacco cessation, and dietary changes is described.

Selective Estrogen Receptor Modulators

In 1896, Dr George Beatson described the first use of ovariectomy to treat a premenopausal woman with advanced breast cancer.²³ Over the next 118 years multiple basic scientific investigators and clinicians have unraveled the complex interactions of hormonal pathways and receptors to delineate the importance of estrogen stimulation and manipulation on the development and treatment of breast malignancies. Over 30 years ago, tamoxifen, a drug developed as a selective estrogen receptor modulator and oral contraceptive, was proven to prevent the induction of mammary cancer in laboratory cell lines and rodent models.²⁴ After subsequent human study in women with breast cancer and those at future risk, tamoxifen was the first agent approved by the Food and Drug Administration (FDA) for use as preventive therapy in women with elevated risk for breast cancer.²⁵ Its mechanism targets estrogen receptor positive (ER+) breast cancers. Tamoxifen, a trans isomer, competes with estradiol for estrogen receptor protein, conferring antiestrogenic effects in target tissues. Randomized controlled clinical trials have demonstrated the efficacy of tamoxifen versus placebo at reducing the risk of invasive breast cancer by 26% to 43% over approximately 7 to 8 years of follow-up. These trials included National Surgical Adjuvant Breast and Bowel Project (NSABP)-P1 study and International Breast Cancer Intervention Study (IBIS) I trial.^26,27 Both trials found no significant reduction in risk of ER negative breast cancers. The IBIS-1 trial was recently updated and 5 years of Tamoxifen use confirmed as a long term prevention agent with risk reduction from 12.3% in the placebo group to 7.8% in the Tamoxifen treated group over an average follow-up of 16 years. This equates to 22 women needed to treat over 5 years to prevent 1 breast cancer in 20 years.²⁸The Italian Randomized Tamoxifen Prevention Trial demonstrated similar trends that were not statistically significant.²⁹ The Royal Marsden Breast Cancer Prevention Trial only demonstrated significant ER+ breast cancer risk reduction with tamoxifen in the follow-up period after 8 years of treatment (Table 70-1).³⁰ None of the aforementioned studies have however shown an improvement in breast cancer-specific survival with chemoprevention.

Subsequent to these clinical trials, additional studies compared the relative effectiveness of tamoxifen versus another SERM, raloxifene. The Study of Tamoxifen and Raloxifene (STAR) NSABP-P2 Trial,³¹ provided evidence that led to raloxifene becoming FDA approved for breast cancer risk reduction in postmenopausal women. The STAR trial demonstrated that raloxifene was 76% as effective as tamoxifen at reducing risk of ER+ breast cancer.³¹ Raloxifene has demonstrated a more favorable side-effect profile, compared to tamoxifen, with regard to lower risks of deep vein thrombosis, cataracts, uterine cancer, and benign uterine hyperplasia.³¹

Raloxifene has also been approved for the treatment and prevention of osteoporosis in postmenopausal women. It can serve as dual therapy for both breast cancer risk reduction and osteoporosis prevention. Additionally, raloxifene was tested in comparison to placebo in Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial,³² Continuing Outcomes Relevant to Evista (CORE) trial,³³ and Raloxifene Use for The Heart (RUTH) trial.³⁴ In these trials, the risk of invasive breast cancer was reduced by 25% to 59% over 4 to 8 years (see Table 70-1).

Newer SERMs, including lasofoxifene and arzoxifene, have been introduced through the Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) trial^35,36 and the GENERATIONS trial,^37,38 respectively. In the PEARL trial, lasofoxifene significantly reduced the risk of ER+ cancer by 83% over 5 years and demonstrated a favorable side-effect profile in postmenopausal women with osteoporosis.^35,36 In the GENERATIONS trial, arzoxifene reduced the risk of ER+ breast cancer in postmenopausal women with low bone mass or osteoporosis by 70% over 4 years.^37,38 Both trials were placebo controlled and the comparative effectiveness of lasofoxifene and arzoxifene to tamoxifen or raloxifene has not yet been assessed. Neither lasofoxifene nor arzoxifene are FDA approved for use in breast cancer prevention. In 2009 the manufacturer of arzoxifene, Eli Lilly and Company, reported that after reviewing the overall clinical profile of arzoxifene in light of currently available treatments, the company would not pursue further regulatory review.³⁹ A meta-analysis of all four SERMS published in 2013 analyzed data for 83,399 women with a median follow-up of 65 months and identified a 38% reduction in breast cancer incidence with a significant increase in incidence of thromboembolic events.⁴⁰ Again noted in this analysis is the lack of survival endpoints for any of the SERM trials.

All SERMs present patients with the risk of side effects, including hot flashes, mood changes, cataracts, venous thromboembolic events, and endometrial carcinoma. In the updated IBIS-1 trial the 5 women died of endometrial cancer in the Tamoxifen treated group versus none in the placebo group.²⁸ Prescribing physicians should discuss the risks, signs, and symptoms of serious adverse effects with patients and monitor them throughout the course of therapy. Side effects of SERMs can make adherence to therapy difficult for some patients.^41,42 Adherence to primary preventive therapy with tamoxifen has been reported to be as low as 41%.^26,43 Various adjunct treatments have been proposed to help patients manage symptoms and side effects. Desvenlafaxine was shown to be an effective, nonhormonal treatment for vasomotor symptoms in postmenopausal women in two randomized, double-blind, placebo-controlled trials.^44,45 Venlafaxine, a related serotonin-norepinephrine reuptake inhibitor, demonstrated superior efficacy when compared to clonidine for the treatment of hot flashes in breast cancer survivors enrolled in a double-blind, randomized phase III study.⁴⁶ Other reportedly effective therapies for vasomotor symptoms in postmenopausal women include selective serotonin reuptake inhibitors (SSRIs) and gabapentin.⁴⁷ Trials studying the use of soy phytoestrogens,⁴⁸ acupuncture,⁴⁹ and hypnotherapy⁵⁰ have not demonstrated statistically significant effects in improving vasomotor symptoms. Physicians that prescribe SERMs for preventive therapy should discuss before treatment the potential side effects that may become barriers to medication adherence, and offer effective adjuncts as indicated for symptom management.

Aromatase Inhibitors

Exemestane was the first aromatase inhibitor to demonstrate clinical efficacy as a breast cancer risk-reducing therapy for postmenopausal women. Evidence from the National Cancer Institute of Canada Clinical Trials Group MAP.3 trial of exemestane versus placebo demonstrated an approximate 65% reduction in postmenopausal invasive breast cancers over a 3-year period in women with a median Gail model risk score of 2.3%.⁵¹ The reported side effects of exemestane have been minimal, which confers a possible advantage to this therapy over tamoxifen and raloxifene. However, there is also potential for bone loss, requiring bone density monitoring and vitamin D supplementation for women who choose this preventative therapy. The IBIS II trial provided similar outcomes in a prospective international randomized trial of anastrazole versus placebo.⁵² In this trial the overall risk reduction in all breast cancer events was 53% with a 50% reduction in invasive breast cancers and 70% reduction in DCIS.

Other aromatase inhibitors that have potential to become effective preventive strategies include letrozole and anastrozole. Both have undergone evaluation in prospective clinical trials for which results are pending (NCT00673335, NCT00579826, NCT00256217).⁵³

Table 70-1 provides a summary of evidence for the use of the currently FDA-approved SERMs and aromatase inhibitor preventive agents.

Additional Experimental Pharmacologic Prevention Agents