Breast cancer risk and prevention

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.

Most studies define the use of chemo prevention breast cancer drugs when there is a 3% chance of developing breast cancer in the next five years.
The risk is determined by family history, reproductive factors, patient’s age, age at which she began menstruation.

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.

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 may reduce breast cancer risk by 16 cases per thousand women over five years.
As noted the medication best studied for breast cancer prevention and endocrine therapy include selective estrogen receptor modulators and aromatase inhibitors, but there is no known survival benefit for this approach.
The benefits of breast cancer prevention measures is in its reduction in morbidity by preventing breast cancers.

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. 



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.

There are two classes of medications used for breast cancer risk reduction: selective estrogen receptor modulators (SERMs), , which include tamoxifen and raloxifene and aromatase inhibitors which include anastrozole and exemestane.
SERMs Have the strongest evidence supporting their effectiveness in preventing breast cancer.: The absolute reduced reduction which SERMs as 7-9 fewer invasive breast cancers for every 1000 women treated over five years compared with women who were not treated.

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. 

Comparing raloxifene with tamoxifen at six years, the drugs were not significantly different in the in relation to relative risk, however at the 9.7 years relaxing was associated with a higher risk of invasive cancer, but a lower risk of overall mortality.
Raloxifene has a lower incidence of thromboembolism than tamoxifen.
Tamoxifen has an increased risk of uterine cancer.
Raloxifene is not associated with an increased risk of uterine cancer. 
Tamoxifen causes more menstrual  abnormalities, sexual dysfunction come and vaginal  discharge then raloxifene.
SERMs increase bone density and their use is associated with a decrease risk of fracture in post menopausal women.

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.

The choice of preventive medication is guided by individual patient characteristics including: menopause status, prior hysterectomy, and comorbidities.
Tamoxifen is the only medication approved for use in pre-menopausal women.
In postmenopausal women tamoxifen or raloxifene are  the first line options.
Raloxifine is associated with lower rates of harm, but Tamoxifen has strong evidence of long-term benefit and may be preferred in some women who have had a hysterectomy because they are no longer at risk for endometrial cancer.
Aromatase inhibitors are considered for patients with postmenopausal status with elevated venous thromboembolism risk who are not at high risk for osteoporosis.
The recommended duration of treatment with preventative medication is five years.
The WHI dietary modification study looked at the effects of dietary fat and 48,835 patients assigned to a low-fat dietary pattern or usual diet with the end point of primary breast cancer incidence: there was no statistical significant difference in breast cancer incidence, but they were statistically significant decrease incidence of breast cancer mortality.
In the WHI diet modification study there was a reduced incidence of ER positive, PR negative breast cancers and a 20% reduction in deaths from breast cancer in the dietary intervention group.
In a metaanalysis of four randomized prevention trials, tamoxifen reduced the 10 year cumulative incidence of invasive breast cancer by 33% and reduced the incidence of ER positive cancers by 44%, whereas for ER negative cancers a non-significant 13% increase in incidence was seen.
To date selective estrogen receptor modulators tamoxifen and raloxifene, and the aromatase inhibitors exemestane in anastrozole reduce the incidence of primary ER positive, progesterone receptor positive breast cancers but there is no evidence for a survival advantage for primary prevention, and no reduction in deaths from breast cancer.
Long-term follow up of tamoxifen prevention trials show reduction in breast cancer incidence, but numerically more deaths from breast cancer were seen in the tamoxifen group.
The WHI randomized trial of CEE found there was a significantly reduced incidence of poor prognosis ER positive, PR negative breast cancers in postmenopausal women with prior hysterectomy.
WHI showed CEE reduced risk of breast cancer by 40% in postmenopausal women ages 50 through 59 with prior hysterectomy.
Women with a high body mass index have a higher risk for  post menopausal breast cancers and higher risk for recurrent cancer.
Obesity with the metabolic syndrome is associated with the highest risk of breast cancer.
The quality of food and glycemic index may be a modifiable risk factor for breast cancer development.
The WHI noted a benefit from exercise in postmenopausal women having a beneficial effect on breast cancer prevention.
Breast cancer incidence goes up with increased alcohol intake.

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