Breast cancer is a complex disease, resulting from the interaction of nonmodifiable factors such as an individual’s genome, age at menarche, menopause, and family history; along with modifiable risk factors such as environmental, hormonal, and lifestyle factors The goal of preventing breast cancer is to identify high-risk individuals who would benefit most from preventive therapies such as chemoprevention and risk-reducing surgeries. Chemoprevention can be defined as the use of natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer.1-5

In the United States, women who live to the age of 90 have a 1 in 8 chance of being diagnosed with breast cancer.6 In 2009, breast cancer will be the most frequently diagnosed nonskin malignancy in US women, with an estimated 192,370 cases and 40,170 deaths.7 Female breast cancer incidence rates decreased by 3.5% per year from 2001 to 2004. This decrease may reflect reduced use of hormone replacement therapy (HRT) and preventive strategies.

The Gail model8 estimates the probability that a woman who engages in annual mammographic screening will develop invasive or in situ ductal or lobular cancer over a particular age interval. The risk factors were adjusted simultaneously for the presence of the other risk factors, and only 6 factors were shown to be significant predictors of the lifetime risk of breast cancer:

1. 
   

   Current age

   
   
2. 
   

   Age at menarche

   
   
3. 
   

   Number of breast biopsies (pathologic diagnosis of atypical hyperplasia)

   
   
4. 
   

   Age at first live birth (or nulliparity)

   
   
5. 
   

   Family history of breast cancer in first-degree relatives

   
   
6. 
   

   Race

The model may be accessed at www.cancer.gov/bcrisktool. The average American woman’s Gail score is 0.3%, which represents her estimated risk for developing invasive breast cancer over the next 5 years; the lifetime risk for the average American woman is 10.1%. A previous diagnosis of atypical lobular or ductal hyperplasia nearly doubles the estimated risk.

The Breast Cancer Risk Assessment (BCRA) tool was updated from the results of the 2007 Women’s Contraceptive and Reproductive Experiences (CARE) study in addition to the NCI’s SEER program for more accurate risk assessment for African American women.9

The clinician’s role in identifying candidates for chemoprophylaxis should include a detailed assessment of familial breast cancer, the opportunity for genetic testing when appropriate, comprehensive quantitative risk assessment, and a specific management prescription.10 Clinicians should also address the risks and benefits of screening, prophylactic surgery when indicated, and risk reduction using approved chemopreventive agents. In addition to genetic susceptibility, hormonally linked adult reproductive and anthropometric risk factors have been well established in the etiology of pre- and postmenopausal breast cancers.11,12 The major steps in risk assessment of breast cancer include assessment of genetic susceptibility via genetic counseling, and quantitative risk assessment via the Gail model/BCRA tool. Women at lower risk of breast cancer qualify for routine surveillance, whereas high-risk women may qualify for chemoprevention in addition to routine and /or MRI surveillance.

Epidemiologic studies indicate that estrogen-mediated events are integral in the development of breast cancer13-15 and support the hypothesis that intact ovarian function is required to develop breast cancer. Oophorectomy or radiation-induced ovarian ablation can reduce the incidence of breast cancer by up to 75%.16 These observations suggest that estrogen antagonists may be instrumental in the primary prevention of breast cancer.

Chemoprevention may be recommended for certain women who are at increased risk of breast cancer based on the information cited in this chapter. Approximately 9 million women were eligible for tamoxifen chemoprevention based on criteria from the Breast Cancer Prevention Trial (BCPT).17 Of these 9 million, approximately 2.4 million might have derived a benefit from taking tamoxifen. An estimated 58,000 cases of invasive breast cancer would develop over the ensuing 5 years with that population, and based on the 49% risk reduction associated with tamoxifen in the BCPT, if all 2.4 million women had taken tamoxifen, 24,492 cases of breast cancer might have been prevented.

Hormones, especially estrogens, have been linked to breast cancer,18,19 with their role being attributed to their ability to stimulate cell proliferation. This cellular proliferation leads to the accumulation of random genetic errors that result in neoplastic transformation.15 According to this concept; chemoprevention of breast cancer is targeted to reduce the rate of cell proliferation through administration of hormonal modulators. Tamoxifen is a triphenylethylene compound, a potential fertility agent. Demethylation to the active metabolite, N-desmethyl tamoxifen, is the principal metabolic pathway in humans. Maximum serum concentration of N-desmethyl tamoxifen is observed within 12 to 24 hours after dosing; its serum half-life is approximately 12 days.20-23 Several mechanisms have been proposed regarding tamoxifen’s ability to prevent or suppress breast carcinogenesis.24-34

Raloxifene hydrochloride, like tamoxifen, is a selective estrogen receptor modulator (SERM) that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.35 It is a benzothiophene with characteristics similar to but distinct from the triphenlyethylene SERMs such as tamoxifen. It inhibits the growth of ER-dependent, dimethylbenzathracene-induced mammary tumors and reduces the occurrence of N-nitrosomethyl urea-induced mammary tumors in rats.

For both raloxifene and tamoxifen, minor differences in SERM–ligand interaction with specific amino acids produce different intrinsic estrogen actions. The tamoxifen-ER complex is more estrogen-like in vitro, reflecting more estrogen-like action in uterus. In contrast, the raloxifene-ER complex is much less estrogen-like and has fewer estrogen-like properties in uterus.

Four prospective studies evaluating tamoxifen for reducing the risk of invasive breast cancer have been published: the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT, P-1),36,37 the Royal Marsden Hospital Tamoxifen Chemoprevention Trial,38-40 the Italian Tamoxifen Prevention Study,41-43 and the International Breast Intervention Study I (IBIS-I).44,45 See Tables 10-1 and 10-2.

Breast Cancer Prevention Trial (BCPT, P-1)

The National Cancer Institute in collaboration with NSABP launched the BCPT P-1,36 a randomized, placebo-controlled, double-blind clinical trial in 1992. The primary aim of the trial was to evaluate the effectiveness of 20 mg/day of tamoxifen (versus placebo) taken orally for 5 years for the prevention of invasive breast cancer in high-risk women. Secondary aims of the trial assessed osteoporotic fractures and cardiovascular disease in women on tamoxifen compared to the control group.

Eligible participants were 60 years or older, or 35 to 59 years of age with a 5-year predicted risk of breast cancer of at least 1.66% as indicated by the Gail model, or had a history of lobular carcinoma in situ (LCIS). The trial was terminated after a median follow-up time was 54.6 months when an interim analysis showed that statistical significance was achieved in a number of study end points. This decrease was only evident in estrogen receptor-positive breast cancers, with no significant change seen in estrogen receptor-negative tumors. The median follow-up time at the end point was 48 months, at which time a 49% (p < 0.00001) decreased risk of invasive breast cancer in the total study population was documented, with the greatest benefit seen in women of ages 60 and older. Overall, a total of 264 invasive cases were documented; 175 cases occurred in the placebo group, compared with 89 cases in the tamoxifen group (risk ratio, 0.51; 95% confidence interval [CI], 0.39–0.66; p < 0.00001). There was a 50% reduction in the rate of noninvasive breast cancer in women taking tamoxifen. The relative risks (RR) for invasive breast cancer reduction were 0.56 for women less than 50 years of age; 0.49 for women 50 to 59 years of age; and 0.45 for women 60 years of age and older.

After 7 years of follow-up in BCPT,46 the cumulative rate of invasive breast cancer was reduced 43% in the tamoxifen group and the cumulative rate of noninvasive breast cancer was reduced 37%. The BCPT revealed that substantial net benefit accrues for women with a diagnosis of either LCIS or atypical hyperplasia who take tamoxifen. Among women with a history of LCIS, the reduction in risk was 46% (RR, 0.54; 95% CI, 0.27–1.02). Among women with a history of atypical hyperplasia, the reduction in risk was 75%; tamoxifen continued to reduce the occurrence of ER-positive tumors by 62%, but no difference was seen in the occurrence of ER-negative tumors.

Secondary outcomes in the BCPT included osteoporotic fractures and cardiovascular events. Tamoxifen is known to have estrogen agonist–like effects on both mineral density and serum cholesterol levels in postmenopausal women.47,48 Women in the tamoxifen group had a 32% reduction in hip, spine, and distal radius fractures. Most fractures (89%) occurred in women aged 50 years or older and tamoxifen reduced fractures in this group by 29%.

Adverse outcomes related to tamoxifen were significantly higher in women over the age of 50 when compared to their younger counterparts. Women on tamoxifen were found to have twice the incidence of pulmonary embolism compared to those on placebo. While incidences of deep vein thrombosis, stoke, and transient ischemic attack were not statistically significant, there was a higher incidence in women on tamoxifen, and thus the concern lies for development of these events in women on tamoxifen.

Women in the tamoxifen arm of the trial were found to have a 3.3 times greater risk of developing invasive endometrial carcinoma than women in the placebo arm. Of the 70 cases of endometrial cancer (17 in the placebo group and 53 in the tamoxifen froup) 67 cases were International Federation of Gynecology and Obstetrics (FIGO) stages 0 or 1 and thus had excellent clinical prognoses with treatment.

An increase of 21% in the development of cataracts was seen in women who were free of cataracts at initiation of the trial. The number of cataract surgeries was also increased by 39% in women taking tamoxifen. Vasomotor symptoms, mainly hot flashes, were reported by 46% of women on tamoxifen and only 29% of women in the placebo arm; whereas an increase in vaginal discharge was reported in 29% of women taking tamoxifen and 13% of women taking placebo. Tamoxifen was not associated with an increased risk of developing depressive symptoms comparing the tamoxifen and placebo groups in the BCPT.49,50

Royal Marsden Hospital (RMH) Tamoxifen Chemoprevention Trial

RMH Tamoxifen Chemoprevention Trial was a randomized, placebo-controlled clinical trial initiated in 1986 and the aim of this trial was to assess whether tamoxifen (20 mg/day for up to 8 years) would prevent breast cancer in healthy women at increased risk of breast cancer based on family history.38-40 Eligible women were ages 30 years to 70 years with least one first-degree relative younger than 50 years with breast cancer, one first-degree relative with bilateral breast cancer, or one affected first-degree relative of any age and another affected first- or second-degree relative. Women were allowed to use HRT during the trial. In initial reports, a total of 70 invasive and noninvasive breast cancers occurred among the women in this trial, and the frequency of breast cancer was the same for women receiving tamoxifen or placebo.38,51 After a median follow-up 13 years, the trial reported a statistically significant decrease in ER–positive tumors.52

Italian Tamoxifen Prevention Trial

The Italian Tamoxifen Prevention Trial was a randomized, placebo-controlled, double-blind clinical trial, initiated to evaluate the effectiveness of tamoxifen in preventing breast cancer.41 The primary aim of this trial was to evaluate the effectiveness of 20 mg/day of tamoxifen orally for 5 years in preventing the occurrence of breast cancer versus placebo in healthy women, with the primary end points being reduction in the incidence of, and mortality from, breast cancer. Because of the potential side effect of endometrial cancer, the study was restricted to women between the ages of 35 and 70 and who had undergone a hysterectomy. More than 5400 women were randomized into either the tamoxifen 20 mg/day or the placebo group. The trial was ended prematurely because of a 26.3% dropout rate for women already randomized.

In a subgroup analysis,41 women are at increased risk for ER-positive breast cancer. This group included women taller than 160 cm (the median height of the group), with at least one functioning ovary, who had menarche when they were no older than 13 years, and who had no full-term pregnancy before 24 years of age. This group of 702 women (13% of the trial population) was classified as high risk. Tamoxifen reduced the incidence of breast cancer in the high-risk group, but it had no effect in the low-risk group.

After 11 years of follow-up, in the group defined as “high risk” with at least one functioning ovary, there was a 77% reduction in the incidence of breast cancer.42 This trial demonstrated that appropriate selection of women at high-risk for developing hormone receptor-positive breast cancer led to benefit from tamoxifen intervention. The update after 11 years of follow-up also confirmed the finding that tamoxifen in addition to estrogen replacement therapy is protective against breast cancer development, although this approach is not used in North America.

International Breast Cancer Intervention Study I (IBIS-I)

The IBIS-I trial was a randomized, placebo-controlled study, with design and outcomes similar to that of BCPT, initiated in 1992 to evaluate whether tamoxifen reduced the risk of invasive breast cancer in women at increased risk.44 The primary aim of the trial was to evaluate the effectiveness of 20 mg/day of tamoxifen (versus placebo) orally for 5 years in preventing the occurrence of both invasive and in situ breast cancer in women deemed at high risk. Selection criteria for the trial’s high-risk patients required that women aged 45 to 70 have at least a 2-fold RR, women aged 40 to 44 needed at least a 4-fold RR, and women aged 35 to 39 years of age had at least a 10-fold RR of developing breast cancer.53 Risk factors involved in determining the RR of breast cancer development included family history, history of LCIS, history of atypical hyperplasia, benign breast biopsies, and nulliparity, and the primary end point was the incidence of breast cancer including ductal carcinoma in situ (DCIS).