BREAST CANCER PREVENTION

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• In the United States, breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women
• Based on current incidence rates, 12.4% of women born in the United States today will develop breast cancer at some time during their lives
• The incidence of breast cancer is highest in white women for most age groups, but African-American women have higher incidence rates before 40 years of age and higher breast cancer mortality rates than women of any other racial/ethnic group in the United States at every age

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• Risk factors for breast cancer include:
• Increasing age
• Physical inactivity
• Race (In the United States, breast cancer is diagnosed more often in white women)
• Personal history of certain benign breast diseases or breast cancer (e.g. atypical hyperplasia)
• Early menstruation
• Late menopause
• Never pregnant or first pregnancy after 30
• Use of oral contraceptives (possible risk factor, data is inconclusive)
• Family history of breast cancer
• Presence of certain inherited genetic changes (ex. BRCA mutations)
• History of radiation therapy to the chest
• Long-term use of combined hormone replacement therapy (see hormone replacement therapy)
• History of taking diethylstilbestrol (DES)
• Increased breast density
• Alcohol use
• Obesity after menopause [1, 3]

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• Breast cancer risk tools
• National Institute of Health breast cancer risk assessment tool (Gail model)
• Estimates 5-year risk and lifetime risk of developing invasive breast cancer up to age 90
• Not for women with a history of any breast cancer, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), BRCA mutations, or those who have received previous radiation therapy to the chest for treatment of Hodgkin lymphoma
• Breast Cancer Surveillance Consortium risk assessment tool
• Estimates both five-year and ten-year breast cancer risk
• Not for women < 35 years old or ≥ 75 years old and/or any of the following: history of breast cancer or of ductal carcinoma in situ (DCIS), breast augmentation, or mastectomy
• BRCA risk tools
• Breast Cancer Genetics Referral Screening Tool
• Tool helps identify women who may have a strong genetic (hereditary) risk for breast and ovarian cancer due to their family history
• Can help determine which women are appropriate for BRCA testing
• BRCA Exchange
• Site that gives risk estimates for breast cancer, ovarian cancer, and other diseases based on BRCA variant types
• NOTE: BRCA testing results must be available in order to get estimates

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• Overview
• BRCA1 and BRCA2 are two genes found in all people. Certain mutations in these genes are associated with an increased risk of breast and ovarian cancer.
• Genetic testing that can identify the harmful mutations has been available for years. Testing is expensive, and the results can have a number of implications that go beyond identifying risk for breast or ovarian cancer.

• BRCA mutations and risk of breast cancer
• In the general population, 12.3% of women will develop breast cancer over their lifetime and 2.8% will die from it
• In the general population, 1.4% of women will develop ovarian cancer over their lifetime and 1.0% will die from it
• The overall incidence of harmful BRCA mutations in the general population is 1 in 300 - 500 women (0.2% - 0.3%)
• For BRCA1 and BRCA2 carriers, the cumulative risk of breast cancer to age 80 years is around 70%
• For BRCA1 carriers, the cumulative risk of ovarian cancer to age 80 years is around 44%
• For BRCA2 carriers, the cumulative risk of ovarian cancer to age 80 years is around 17%
• For women who have been diagnosed with breast cancer and are BRCA carriers, the cumulative risk of contralateral breast cancer 20 years after diagnosis is 40% for BRCA1 carriers and 26% for BRCA2 carriers [4]

• Risk factors for harmful BRCA mutations
• Family member with diagnosis of breast cancer before age 50
• Family member who developed breast cancer in both breasts
• Family member who had more than one primary breast cancers (cancer that started from 2 distinct sites)
• History of both breast and ovarian cancer in the family or same person
• Breast cancer present in one or more male family members
• Ashkenazi Jewish background
• "Triple negative" breast cancer diagnosed before the age of 60

• Whom to screen for BRCA mutations
• There are several online screening tools that can help identify women who should be screened for BRCA mutations. One of the tools that is easy to use is the Breast Cancer Genetics Referral Screening Tool (B-RST). It is available at the link below.
• If possible, the family member with breast or ovarian cancer should be screened first
• Breast Cancer Genetics Referral Screening Tool

• Interventions for BRCA mutation carriers
• 1. Early, more frequent, intensive breast and ovarian cancer screening
• No trials have evaluated intensive screening outcomes specifically in women with BRCA mutations
• For breast cancer screening, MRI has been shown to be more sensitive than mammography (MMG) in this high-risk population:
• Sensitivity: MRI - 71-77%, MMG - 40%
• Specificity: MRI - 81-90%, MMG - 93-95%
• For ovarian cancer screening, ultrasound and blood levels of cancer antigen CA-125 have the following yields:
• Sensitivity: CA-125 - 71%, Ultrasound - 43%
• Specificity: CA-125 - 99%, Ultrasound - 99%
• 2. Use of Selective Estrogen Receptor Modifiers (SERMs) (tamoxifen and raloxifene)
• SERMS reduce the risk of breast cancer
• Unfortunately, they do not reduce the risk of estrogen receptor-negative cancers which make up 78% of breast cancers associated with BRCA1 mutations and 23% associated with BRCA2 mutations
• 3. Risk-reducing surgery - breast removal (mastectomy) and ovary/fallopian tube removal (salpingo-oophorectomy)
• Mastectomy has been shown to reduce the risk of breast cancer by 85-100%
• Salpingo-oophorectomy reduces the risk of ovarian cancer by 69 - 100%, and breast cancer by 37 - 100% [3]

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• Overview
• The recommendations below are for women who are not BRCA positive or have not undergone BRCA testing. See whom to screen for BRCA mutations above for recommendations on BRCA screening.

• USPSTF 2019 recommendations
• Risk-reducing medications (tamoxifen, raloxifene, exemestane, or anastrozole) should be offered to women ≥ 35 years old who are at increased risk for breast cancer and at low risk for adverse medication effects
• Only tamoxifen should be used in premenopausal women
• The USPSTF does not endorse any single risk prediction tool or risk threshold for what defines "increased risk," but they do give the following examples:
• Age ≥ 65 years with 1 first-degree relative with breast cancer
• Age ≥ 45 years with more than 1 first-degree relative with breast cancer or 1 first-degree relative who developed breast cancer before age 50 years
• Age ≥ 40 years with a first-degree relative with bilateral breast cancer
• Presence of atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a prior biopsy
• The guidelines do not specify what constitutes "low risk" for adverse medication effects. A set of tables was published in 2011 that can help estimate the risk/benefit of therapy with tamoxifen and raloxifene (see risk/benefit estimation below).

• NCCN 2020 recommendations
• Offer risk-reducing medications (tamoxifen, raloxifene, exemestane, or anastrozole) to women who have a lifetime risk ≥ 20% based on a risk-prediction model (see risk assessment tools) and a life expectancy ≥ 10 years (use ePrognosis calculator to estimate life expectancy)
• Only tamoxifen should be used in premenopausal women
• Postmenopausal women should have a BMD before starting therapy, and women with a low baseline BMD should use raloxifene over exemestane or anastrozole
• A set of tables was published in 2011 that can help estimate the risk/benefit of therapy with tamoxifen and raloxifene (see risk/benefit estimation below).
• Contraindications to tamoxifen and raloxifene include:
• History of DVT or PE
• History of stroke or TIA
• Known thrombophilia
• Pregnancy or desire to become pregnant [5]

• Risk/benefit estimation for tamoxifen and raloxifene
• In 2011, a group of tables was published in the Journal of Clinical Oncology that can help determine which women have a favorable benefit/risk ratio when taking tamoxifen or raloxifene
• The tables use a woman's 5-year projected risk of invasive breast cancer (see NCI risk assessment tool), age, race (black, white, hispanic), and hysterectomy status (uterus vs none) to project whether the benefits of raloxifene/tamoxifen therapy outweigh the risks
• The tables are available at the link below. There are six tables grouped by race and hysterectomy status.
• Risk/benefit tables for raloxifene and tamoxifen
• Fig 1 - White non-Hispanic women with a uterus
• Fig 2 - White non-Hispanic women without uterus
• Fig 3 - Black women with uterus
• Fig 4 - Black women without uterus
• Fig A1 - Hispanic women with uterus
• Fig A2 - Hispanic women without uterus

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• Overview
• There are two medications in the U.S. that have been approved to prevent breast cancer in women at high risk - tamoxifen (Nolvadex®) and raloxifene (Evista®)
• Both drugs are members of a class of drugs called SERMs (Selective Estrogen Receptor Modulator). SERMs act as both agonists (stimulate) and antagonists (block) at estrogen receptors. Their action at the receptor depends on the tissue where the receptor is located. See SERM activity table for more.
• Both raloxifene and tamoxifen block estrogen receptors in breast tissue making them effective at preventing certain types of breast cancer [2]

• Breast cancer prevention
• Tamoxifen and raloxifene are both approved for the primary prevention of breast cancer. Tamoxifen is also approved for the secondary prevention of breast cancer and as an adjuvant treatment for active breast cancer.
• For primary prevention, tamoxifen and raloxifene are indicated to reduce the risk of breast cancer in women who are at high risk. Tamoxifen was compared to placebo in the Breast Cancer Prevention Trial (BCPT) and was found to reduce the relative risk of breast cancer by about 50%. Raloxifene was compared to tamoxifen in the STAR trial and was found to be equally effective. Both studies are summarized below.

• RCT
  BCPT - Tamoxifen vs Placebo for the Primary Prevention of Breast Cancer in High-Risk Women, J Natl Cancer Inst (1998) [PubMed abstract]
• Design: Randomized placebo-controlled trial (N=13,388; length = 5 years) in women who were at increased risk of breast cancer (defined as ≥ 60 years old, 5-year estimated risk of ≥ 1.66%, or history of lobular carcinoma in situ)
• Treatment: Tamoxifen 20 mg once daily vs Placebo
• Primary outcome: Occurrence of invasive breast cancer over time
• Results:
• Invasive breast cancer (cumulative cases/1000 women): Tamoxifen - 22, Placebo - 43 (RR 0.51, p<0.00001)
• Findings: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.

• RCT
  STAR trial - Raloxifene vs Tamoxifen for the Primary Prevention of Breast Cancer in High-Risk Women, JAMA (2006) [PubMed abstract]
• Design: Randomized controlled trial (N=19,747; length = 5 years) in women with an average estimated 5-year risk of breast cancer of 4.03%
• Treatment: Raloxifene 60 mg once daily vs Tamoxifen 20 mg once daily
• Primary outcome: Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events
• Results:
• Invasive breast cancer (cases/1000 women-years): Raloxifene - 4.41, Tamoxifen - 4.3 (RR 1.02, 95%CI [0.82 - 1.28])
• Findings: Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs.

• Osteoporosis
• Raloxifene is FDA-approved to treat and prevent osteoporosis in postmenopausal women (see osteoporosis medications for more). Tamoxifen is not approved for osteoporosis, but in trials, it has been shown to have a positive effect on fracture incidence in postmenopausal women. Its effect in premenopausal women is unknown.

• Risks
• Tamoxifen and raloxifene therapy have been associated with an increased risk of several life-threatening conditions including venous thromboembolism (DVT and PE) and stroke. Tamoxifen has also been associated with an increased risk of uterine malignancies and cataracts.
• In general, the risks are small. Incidence rates from studies are presented in the tables below. In most cases, the risks were not found to be statistically significant when compared to placebo, but the studies were likely underpowered for these outcomes.

• Data expressed as cases/1000 women/year
• Data is from the BCPT trial

Tamoxifen Risks (cases/1000 women/year)
Outcome	Tamoxifen	Placebo
Endometrial adenocarcinoma	2.20	0.71
Uterine sarcoma	0.17	0.04
Stroke	1.43	1.0
Pulmonary embolism	0.75	0.25
Deep vein thrombosis	1.26	0.79
Cataract	25.41	22.51

• Data expressed as % of women with outcome/year
• Data is from the RUTH trial [PMID 16837676]

Raloxifene Risks (% of women with outcome/year)
Outcome	Raloxifene	Placebo
Death from stroke	0.22	0.15
Stroke	0.95	0.86
Pulmonary embolism	0.14	0.09
Deep vein thrombosis	0.24	0.18

• Contraindications
• Raloxifene
• History of venous thromboembolism including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis
• Pregnancy and nursing
• Tamoxifen (when taken for primary prevention)
• History of venous thromboembolism including deep vein thrombosis and pulmonary embolism
• Women requiring concomitant coumarin-type anticoagulant therapy
• Pregnancy and nursing

• Reference: Tamoxifen Package Insert
• Data is from the BCPT trial

Tamoxifen side effects
Side effect	Tamoxifen	Placebo
Hot flashes	80%	68%
Vaginal discharges	55%	35%
Vaginal bleeding	23%	22%
Mood changes	11.6%	10.8%
Infection/sepsis	6.0%	5.1%
Constipation	4.4%	3.2%
Hair loss	5.2%	4.4%
Skin changes	5.6%	4.7%

• Reference: Raloxifene Package Insert
• Side effects that occurred with a difference between placebo of < 1% are not included

Raloxifene side effects
Side effect	Raloxifene	Placebo
Joint pain	15.5%	14%
Flu syndrome	13.5%	11.4%
Hot flashes	9.7%	6.4%
Leg cramps	7%	3.7%
Uterine disorders (not defined)	3.3%	2.3%

• Metabolism and drug interactions
• Tamoxifen
• Tamoxifen is metabolized to its active form by the CYP2D6 enzyme. The activity of the CYP2D6 enzyme varies between individuals with some people having very active enzymes (rapid metabolizers) and others having reduced enzyme activity (poor metabolizers). In addition, a number of widely prescribed drugs, particularly antidepressants, are strong CYP2D6 inhibitors. These issues have raised theoretical concerns that poor metabolizers and patients taking certain medications may get a reduced benefit from tamoxifen while patients who are rapid metabolizers may experience more side effects. Observational studies that have looked at these issues have had mixed results.
• Because tamoxifen is an important drug in breast cancer prevention, the issue has garnered much attention. Several consortiums have been established to review the data and make recommendations for patients based on CYP2D6 metabolizer status and concomitant CYP2D6 inhibitors. Links to recommendations and studies are provided below.
• Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy
• Recommendations for tamoxifen based on CYP2D6 genotypes
• Tamoxifen and antidepressant studies
• CYP2D6 Genotype and Tamoxifen Outcomes, J Clin Oncol (2020) [PubMed abstract]


• Raloxifene
• Raloxifene is not metabolized by CYP enzymes. See raloxifene for more.

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• Overview
• Aromatase is an enzyme involved in the production of estrogen in both premenopausal and postmenopausal women. Aromatase inhibitors block aromatase and cause a decrease in estrogen levels of 85 - 95%. Aromatase inhibitors are approved for the treatment of breast cancer in postmenopausal women.
• Two aromatase inhibitors, exemestane (Aromasin®) and anastrozole (Arimidex®), have been studied in the prevention of breast cancer and are recommended as possible agents to be used for breast cancer prevention by the USPSTF and NCCN. Neither drug is FDA-approved to prevent breast cancer.

• RCT
  MAP.3 study - Exemestane vs Placebo for Prevention of Breast Cancer in Moderate-risk Postmenopausal Women, NEJM (2011) [PubMed abstract]
• Design: Randomized placebo-controlled trial (N=4560 | length = median of 2.9 years) in postmenopausal women ≥ 35 years old with at least one of the following: Gail 5-year risk score greater than 1.66%; prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy
• Treatment: Exemestane 25 mg once daily vs Placebo
• Primary outcome: Incidence of invasive breast cancer
• Results:
• Primary outcome: Exemestane - 0.19%/year, Placebo - 0.55%/year (p=0.002)
• Findings: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life

• RCT
  IBIS-II trial - Anastrozole vs Placebo for Prevention of Breast Cancer in High-risk Postmenopausal Women, Lancet (2014) [PubMed abstract]
• Design: Randomized placebo-controlled trial (N=3864 | length = median of 5 years) in postmenopausal women 40 - 70 years old at high risk for breast cancer (average 10-year risk by the Tyrer-Cuzick model was 7.7%)
• Treatment: Anastrozole 1 mg once daily vs Placebo
• Primary outcome: Histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ)
• Results:
• Primary outcome: Anastrozole - 2%, Placebo - 4% (p <0.0001)
• Findings: Anastrozole eff ectively reduces incidence of breast cancer in high-risk postmenopausal women. This fi nding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer.

• Only side effects that occurred at an incidence greater than placebo are listed
• Data from MAP.3 study

Side effects of Exemestane (Aromasin®) in the MAP.3 study
Side effect	Exemestane (N=2240)	Placebo (N=2248)
Hot flashes	40%	32%
Joint pain	30%	27%
Fatigue	23%	21%
Sweating	22%	19%
Vaginal dryness	16%	15%
Heartburn	15%	13%
Arthritis	11%	9%
Mood disorder	11%	10%
Insomnia	10%	8%
Nausea	7%	5%
Extremity pain	7%	5%
Fracture	6.7%	6.4%
Diarrhea	5%	3%
Malignancy besides breast cancer	1.9%	1.7%
New osteoporosis	1.7%	1.3%

• Only side effects that occurred at an incidence greater than placebo are listed
• Data from IBIS II trial

Side effects of Anastrozole (Arimidex®) in the IBIS II study
Side effect	Anastrozole (N=1920)	Placebo (N=1944)
Hot flashes	57%	49%
Joint pain	51%	46%
Vaginal dryness	19%	16%
Fracture	9%	8%
Joint stiffness	7%	5%
Pain in hand or foot	9%	8%
Hypertension	5%	3%
Dry eyes	4%	2%

• Precautions
• Pregnancy or desire to become pregnant - DO NOT USE
• Premenopausal women - DO NOT USE
• Reduction in BMD - aromatase inhibitors lower estrogen levels which can have a negative effect on bone health. Use caution in susceptible individuals. The NCCN recommends checking a BMD before initiating risk-reducing therapy in postmenopausal women. Women with low baseline bone density should avoid aromatase inhibitors.
• Cardiovascular disease - a higher incidence of ischemic cardiovascular events has been seen in some studies involving aromatase inhibitors. Use caution in susceptible patients.
• Cholesterol - cholesterol elevations have been seen in some patients [2]

• Drug interactions
• Anastrozole (Arimidex®)
• No known significant interactions
• Exemestane (Aromasin®)
• CYP3A4 strong inducers - exposure may be decreased. [2]

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• 1 - National Cancer Institute website
• 2 - Manufacturer's package insert
• 3 - USPSTF website
• 4 - PMID 28632866 - Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers, JAMA (2017)
• 5 - NCCN website