A proactive approach to identifying individual women at increased risk for breast cancer is required: women benefit from genetic testing, high-risk breast imaging surveillance, preventive endocrine therapy interventions, and lifestyle education.
Breast cancer risk assessment includes: age, age at menarche, age at first childbirth, breast cancer history in first-degree relatives, history of breast biopsies, and history of atypical hyperplasia.
Risk management begins with a thorough history and utilization of the Gail model for risk assessment.
The US Preventive Services Task Force guidelines state that an estimated 5-year risk of at least 3% is considered to be substantial risk, and endocrine therapy should be recommended for eligible women unless a contraindication to ET outweighs the benefits.
Women with an estimated relative risk of at least 4 times the population risk for their age if 40 to 44 years old, or 2 times their age if 45 to 69 years old, are at high risk for breast cancer and should receive appropriate risk reduction counseling.
These above estimates confer essentially the same risk as a calculated 5-year risk of 3% or more, a 10-year risk of 5% or more, or a lifetime risk of 20% or more.
Increased risk defined as 1.66%, which equates to the 5-yer risk of an average 60 year old North American white women.
For a woman with a 5 year risk of greater than 1.6%, a history of lobular or ductal cancer in situ (DCIS), atypical hyperplasia, a family member with BRA gene mutation, a women with a first-degree relative with breast cancer should be considered for individual management of risk for breast cancer.
Atypical ductal hyperplasia confers a future risk of breast cancer to either breast of approximately 1% to 2% per year or approximately 25% to 30% at 25 years of follow-up: benefit of ET is imperative in this population.
Women with a combination of lifestyle and reproductive risk factors such as obesity, older age, early menarche, nulliparity or late age of first parity (age ≥30 years), prolonged combined menopausal hormone therapy (>3 years of use after the expected age of the onset of menopause), and increased breast density are eligible for endocrine therapy counseling.
It is estimated that less than 4% of eligible women accept use of endocrine therapy to prevent BC.
The age range to consider initiating ET is 35 to 70 years.
Women with known genetic variants conferring an increased risk of breast cancer, such as BRCA 1/2 are at the highest risk for breast cancer.
Patients with BRCA 1 and BRCA 2 need aggressive management.
BRCA mutation carrriers have a 50-85% lifetime risk of developing breast cancer.
Prophylactic mastectomy and oophorectomy decreases risk of breast cancer in BRCA positive patients by 90%.
Antagonism of estrogen carcinogenic effects is the dominant pharmacologic approach in breast cancer
Women who received mantle chest irradiation , for Hodgkin’s disease, between the ages of 10 and 30 years have a substantial increase in breast cancer risk.
If a family history screening is positive, patients should be referred for genetic counseling and consideration of genetic testing.
A strong family history for breast cancer includes: a close relative, first or second degree, with breast cancer diagnosed before age 45 years, 2 first-degree relatives with breast cancer diagnosed at any age, multiple affected relatives over several generations on the same side of the family, bilateral breast cancer, or male breast cancer.
Chemoprevention of breast cancer focused mainly on the selective estrogen receptor modulators tamoxifen and raloxifene.
In the National Surgical Adjuvant Breast and Bowel Project P-1 study,16 5 years of standard therapy with tamoxifen 20 mg/d decreased the risk of invasive estrogen receptor–positive breast cancer by approximately 50% in high-risk women, by 86% in those with atypical hyperplasia, and by 56% in those with LCIS.
The IBIS-I breast cancer prevention trial reported an extended long-term benefit after completion of 5 years of tamoxifen treatment.
Recently, a study of tamoxifen 5 mg/d vs placebo in patients with atypical hyperplasia or ductal carcinoma in situ by DeCensi et al found a 50% decreased risk of invasive cancer with fewer adverse effects than standard-dose tamoxifen.
In a small prospective study, tamoxifen reduced breast cancer occurrence by approximately 60% in BRCA2 variant carriers but did not reduce breast cancer occurrence in BRCA1 carriers, possibly because breast cancers that develop in BRCA1 carriers tend to be hormone receptor negative.
Tamoxifen is associated with a small to moderate increased risk of venous thromboembolism events.
There is a higher risk of thromboembolism in older women, 4-7 events per 1000 over 5 years.
Tamoxifen is associated with menstrual
irregularities..
Women taking tamoxifen should report any abnormal vaginal symptoms: bloody discharge, spotting, and leukorrhea.
Tamoxifen is a teratogen; therefore, contraception is strongly recommended for premenopausal women.
Tamoxifen is associated with an increased risk of endometrial cancer in postmenopausal women (3.05 cancers per 1000 women older than 50 years treated with tamoxifen vs 0.76 cancers per 1000 women older than 50 years receiving placebo).
Premenopausal women treated with tamoxifen had no increased risk of uterine cancer or cataracts.
Vision changes with tamoxifen are rare and include cataracts; therefore, yearly eye examinations are recommended.
Up to 80% of women taking tamoxifen experience vasomotor symptoms and 30% of cases can be severe.
Caution is advised with concurrent use of a strong CYP2D6-inhibiting selective serotonin reuptake inhibitor (eg, paroxetine and fluoxetine); citalopram and venlafaxine may be more favorable options.
Common adverse effects : Hot flashes (up to 80%, 30% severe, night sweats; vaginal discharge, vaginal dryness; weight gain; muscle cramps ;Joint pain (20%-50%)
Complications: Increased risk of DVT/PE, stroke, uterine cancer, cataracts, decreased bone density.
Contraindications to tamoxifen use:
History of DVT/stroke; hypercoagulable condition; endometrial hyperplasia with atypia/endometrial cancer; current/planned pregnancy. personal history of DVT/stroke, hypercoagulable condition, premenopausal osteoporosis and/or severe bone loss, Postmenopausal/advanced age, obesity, immobility, recent surgery, and tobacco use may result in a thrombotic risk.
Tamoxifen selectively blocks estrogen in the breasts but acts like estrogen in other tissues such as bone and uterus.
Tamoxifen is US Food and Drug Administration–approved for breast cancer risk reduction in premenopausal and postmenopausal women older than 35 years with a BCRAT 5-year risk of more than 1.7%.
In the National Surgical Adjuvant Breast and Bowel Project P-1 study,16 5 years of standard therapy with tamoxifen 20 mg/d decreased the risk of invasive estrogen receptor–positive breast cancer by approximately 50% in high-risk women, by 86% in those with atypical hyperplasia, and by 56% in those with LCIS.
No studies to date have found a survival benefit with tamoxifen.
In a a study of tamoxifen 5 mg/d vs placebo in patients with atypical hyperplasia or ductal carcinoma in situ there was a 50% decreased risk of invasive cancer with fewer adverse effects than standard-dose tamoxifen.
Tamoxifen reduces breast cancer occurrence by approximately 60% in BRCA2 variant carriers but did not reduce breast cancer occurrence in BRCA1 carriers.
Breast cancers that develop in BRCA1 carriers tend to be hormone receptor negative.
Tamoxifen is associated with a small to moderate increased risk of venous thromboembolism events.
Thromboembolism occurs with a higher risk in older women (4-7 events per 1000 over 5 years) with tamoxifen use.
Menstrual irregularities can occur, and women taking tamoxifen.
Any new vaginal symptoms or persistent bleeding requires a gynecologic evaluation.
Tamoxifen is a teratogen; therefore, contraception is strongly recommended for premenopausal women.
The addition of oral hormonal contraception may further increase thrombotic risk, whereas certain intrauterine devices have less thrombotic risk.
Tamoxifen is associated with an increased risk of endometrial cancer in postmenopausal women.
Premenopausal women treated with tamoxifen have no increased risk of uterine cancer or cataracts, as seen in the National Surgical Adjuvant Breast and Bowel Project P-1 study.
Vision changes associated with tamoxifen are rare and include cataracts; therefore, yearly eye examinations are recommended.
Up to 80% of women taking tamoxifen experience vasomotor symptoms and 30% of cases can be severe.
There is insufficient evidence to recommend CYP2D6 testing when prescribing tamoxifen for risk-reduction purposes.
Caution is advised with concurrent use of a strong CYP2D6-inhibiting selective serotonin reuptake inhibitor (eg, paroxetine and fluoxetine); citalopram and venlafaxine may be more favorable options.
Raloxifene has antiestrogen effects in the breasts and is used only in postmenopausal women for breast cancer risk reduction.
In the NSABP Study of Tamoxifen and Raloxifene,21 postmenopausal women with a mean 5-year BCRAT risk of 4.03% were randomly assigned to either tamoxifen or raloxifene: no difference in risk reduction between the drugs in patients with invasive cancer, but there were fewer noninvasive cancers in the tamoxifen arm.
The raloxifene arm had fewer cases of uterine cancer and fewer thrombotic events: there is no increased risk of endometrial cancer.
Raloxifene can increase bone strength and is approved for the prevention and treatment of osteoporosis.
It is associated with an increased risk of venous thromboembolism but less than that for tamoxifen.
Low-dose tamoxifen for breast cancer risk reduction in radiation-induced cancer survivors was effective in reducing established biomarkers of risk, including breast density.
Aromatase inhibitors (AIs), are effective in reducing estrogen by blocking the enzyme aromatase, which is responsible for the peripheral conversion of androgens to estrogen.
AIs substantially decrease the risk of breast cancer in postmenopausal women.
In the MAP.3 study24 of more than 4500 patients, exemestane 25 mg/d substantially decreased the risk of breast cancer by 65%: The IBIS-II trial25 reported that anastrozole 1 mg/d also decreased breast cancer risk, with similar adverse effects to exemestane.
AIs decrease bone mineral density; however, prevention trials report no increase in fractures.
Common adverse effects associated with ET include hot flashes, vaginal dryness, joint pain, and osteoporosis risk.
Women with an intact uterus who are using local vaginal estrogen therapy do not require progesterone.
Joint pain decreases the quality of life for about 30% of women taking AIs.
Baseline monitoring of bone mineral density is recommended before initiating AI therapy in postmenopausal women.
Bone mineral density testing should be offered every 1 to 2 years, depending on fracture risk.
Women identified as being at high risk for invasive breast cancer: strong family history, combination of hormonal or reproductive risk factors, or history of a high-risk pathologic lesion, should be offered ET.
The benefits of risk reduction therapy almost always outweigh the arms for patients with atypical hyperplasia, both ductal and lobular, and lobular carcinoma in situ.
Estimates of breast cancer risk range from 4-5 fold increased risk with atypical hyperplasia, and 8-10 fold increased risk in patients with lobular carcinoma in situ.
Both tamoxifen and raloxifene halve the risk of breast cancer and reduce the risk of osteoporotic fractures.
Tamoxifen breast cancer risk reduction benefits have long-term durability even after the drug is discontinued.
Long-term studies reveal breast cancer risk reduction is greater with tamoxifen them with raloxifene, with raloxifene maintaining 75% of the benefits of tamoxifen after discontinuation of treatment.
Aromatase inhibitors have shown even a greater breast cancer risk reduction then tamoxifen and raloxifene in women at increased risk of developing breast cancer (70%).
Aromatase inhibitors can cause hot flashes, arthralgias, my allergies and decreased bone mineral density.
Only 25% of women eligible for breast cancer risk reduction oral therapy are on such agents.
BRCA mutation carriers who do not undergo prophylactic mastectomy have significant benefit from prophylactic oophorectomy and the use of tamoxifen, especially for BRCA 2 mutation patients.
Endocrine therapy preventive breast cancer may be used earlier in women with atypical hyperplasia, LCIS, previous mantle irradiation, or known high-risk breast cancer genetic variants.
Tamoxifen
Raloxifene
Aromatase inhibitors (exemestane/anastrozole)
Tamoxifen selectively blocks estrogen in the breasts but acts like estrogen in other tissues such as bone and uterus.
Tamoxifen is US Food and Drug Administration–approved for breast cancer risk reduction in premenopausal and postmenopausal women older than 35 years.
Among the various endocrine treatments, which include tamoxifen, raloxifene, anastrozole, and exemestane, tamoxifen is the only one available for premenopausal women aged 35 years and older.
Combined data indicates that five years of tamoxifen therapy offered at the overall reduction in breast cancer incidence of 30-40% compared with placebo (Cusick J et al).
International Breast Cancer Intervention Study (IBIS-1), a double blind, placebo controlled trial of females with increased risk of breast cancer, randomized 7,154 women aged 35-70 years, to tamoxifen vs placebo for 5 years: associated with a 26% reduction in incidence of estrogen receptor positive breast cancer, and for individuals that received treatment for 5 years and beyond the rate of estrogen receptor breast cancer was 44% lower in the tamoxifen arm (median 96 months).
The benefits of the aromatase inhibitor anastrozole for breast cancer prevention in high-risk postmenopausal women extend well beyond the five-year treatment period, according to long-term data from the International Breast Cancer Intervention Study II (IBIS-II) Prevention trial.
After a median follow-up of five years, showed a 61% reduction in new breast cancers (from 4.6% with placebo to 1.8% with anastrozole).
Long-term data show there continues to be a 36% reduction in new cancers in years five to 12 .
Anastrozole as the preferred therapy for breast cancer prevention in high-risk postmenopausal women.
Royal Marsden study of 2,471 women at high risk for breast cancer compared tamoxifen for 8 years to placebo revealed at 20 years (median 13 years), a 39% reduction in invasive estrogen receptor positive breast cancer for the tamoxifen group.
NSABP (National Surgical Adjuvant Breast and Bowel Project) B14 trial of 1150 women who received 5 years of tamoxifen and were free of recurrence randomized to continued treatment with tamoxifen or to placebo for a planned total course of 10 years.
NSABP (National Surgical Adjuvant Breast and Bowel Project) B14 trial was stopped early: due to significant advantages in disease free survival and distant disease free survival observed inpatients who stopped tamoxifen at 5 years (92% vs. 86%), and overall survival was better in the group treated with tamoxifen for just 5 years, albeit not statistically significant.
Use of breast cancer prevention drugs have demonstrated greater breast cancer risk reduction in women with atypical hyperplasia and lobular carcinoma in situ.
Italian Tamoxifen Prevention Study (ITPS) a randomized and controlled study of hysterectomized women, allowed to take hormone replacement therapy and followed for 81 months did not show reduction in breast cancer in the tamoxifen group compared to control group: reanalysis of high risk of women that did not have oophorectomy had a decreased risk of breast cancer by 82% n the tamoxifen group compared to the placebo group.
In the Multiple Outcomes of Raloxifene Evaluation (MORE), trial to test the effect of these drugs on bone health showed in postmenopausal women to be associated with a 76% decrease in the risk of invasive breast cancer (Cummings SR et al).
The National Surgical Adjuvant Breast and Bowel Project P-1 trial indicated that Tamoxifen significantly reduced the number of invasive breast cancers by 49%, as compared with placebo (Fisher B et al).
Breast Cancer Prevention Trial revealed that women with atypical hyperplasia and lobular carcinoma in situ obtained greater risk reduction with tamoxifen than other women with high risk.
The Study of Tamoxifen and Raloxifene (STAR) trial showed no difference in the therapeutic effect of these drugs in women with atypical hyperplasia and LCIS while on treatment.
The USPSTF recommends prescribing risk reducing medications such as tamoxifen, raloxifine, aromatase inhibitors to women who are increased for breast cancer and are at low risk for adverse medication effects.
Anastrozole 1 mg per day, tamoxifen 20 mg, raloxifene 60 mg, and exemestane 25 mg have been shown to reduce breast cancer incidence in trials when prescribed once per day for five years to postmenopausal women at increased risk.The USPSTF does not recommend the use of risk reducing medications for breast cancer in women not at increased risk.