Breast Cancer Prevention

Case Presentation

A 45-year-old female presents to your primary care office two days after learning that her 53-year-old sister has recently been diagnosed with breast cancer. She is distraught and asks you how common this is.

1. Regarding the incidence of breast cancer in the United States, which of the following is NOT true?

1. The cumulative risk for a woman being diagnosed with breast cancer by age 90 is approximately one in eight (12.5%).
2. Breast cancer is the most frequently diagnosed non-skin malignancy in U.S. women in 2011.
3. Only lung cancer is a larger cause of cancer mortality in women.
4. Approximately 20,000 new cases of breast cancer in men will have been diagnosed in 2011.
5. Data from the Surveillance, Epidemiology, and End Results Program show a decrease in breast cancer mortality of 1.9% per year from 1998 to 2007.

d. Correct.

Breast cancer is the most frequently diagnosed non-skin malignancy in U.S. women, and one in eight women will be diagnosed with breast cancer by age 90. Breast cancer will kill almost 40,000 women in 2011, and is second only to lung cancer as a cause of cancer mortality. Data from SEER has shown a 1.9% annual drop in breast cancer mortality.¹ It is estimated that 2,140 new cases of male breast cancer will have been diagnosed in 2011.²


Your patient mentions that her sister “may have had a drinking problem,” but states that she herself only drinks on weekends.

2. Regarding alcohol consumption and breast cancer risk, which of the following is true?

1. Randomized clinical trials have shown a causative effect from alcohol to the development of breast cancer.
2. The relative risk conferred by alcohol consumption does not differ based on the amount of alcohol consumed.
3. Drinking 3-6 glasses of wine per week has been shown to increase a woman’s risk of breast cancer by 15%.
4. Alcohol consumption between the ages of 18 and 40 does not appear to affect breast cancer risk if alcohol intake decreases after age 40.
5. Binge drinking has no relationship to future breast cancer risk.

c. Correct.
Data regarding alcohol intake and breast cancer risk comes from case-control, cohort, and observational studies. A British meta-analysis of 53 case-control and cohort studies showed a relative risk of breast cancer of 1.32 (95% CI, 1.19-1.45; P<.001) for women consuming 35g-44g of alcohol per day and 1.46 (95% CI, 1.33-1.61; P<.001) for those consuming at least 45g of alcohol per day. The relative risk of breast cancer increases by about 7% for each 10g (one drink) consumed per day.¹
Chen et al. have recently published results from the Nurses’ Health Study that included 105,986 patients from 1980-2008. With 2.4 million person-years of follow up, they have shown that even moderate drinking (3-6 glasses of wine per week) is associated with a 15% increased risk of breast cancer later in life. After controlling for cumulative alcohol intake, binge drinking was also associated with increased breast cancer risk. Alcohol intake both earlier and later in adult life was independently associated with risk.³





Your patient has a BMI of 30.

3. Which is the STRONGEST obesity-related predictor of breast cancer risk in postmenopausal women who do not take hormone replacement therapy?

1. Body weight.
2. Body mass index (BMI) at age 50.
3. Maximum BMI.
4. Postmenopausal weight change.
5. Waist and hip circumferences.

a. Correct.

A WHI observational study observed 85,917 women aged 50 to 79 years and collected information on weight history as well as known risk factors for breast cancer development. Among women who never used hormone replacement, increased breast cancer risk was associated with all of the following: increased body weight, BMI at study entry, BMI at age 50, maximum BMI, adult and postmenopausal weight changes, and waist and hip circumference. Body weight alone was the strongest predictor, with a RR of 2.85 (95% CI, 1.81-4.49) for women weighing more than 82.2kg compared to those weighing less than 58.7kg.⁴ It is uncertain, however, whether reducing weight would decrease a woman’s risk of developing breast cancer.¹


While collecting your patient’s obstetrical history, you learn that she has had three children but did not breastfeed more than a few months for each. She asks if this means she will get breast cancer.

4. Regarding breastfeeding and breast cancer risk, which of the following is true?

1. The duration of breast-feeding for the first child has no impact on the risk of the mother subsequently developing breast cancer.
2. Twelve months of breast-feeding is estimated to confer a 4% reduction in the lifetime risk of breast cancer for the mother.
3. In the year 2000, less than 50% of babies born in the United States were ever breast-fed.
4. The number of children breast-fed has no impact on risk reduction for breast cancer in the mother

b. Correct.

As early as 1926, it was proposed that a breast never used for lactation is more likely to become cancerous. The overall evidence from case-control and cohort studies supports a reduction in risk with longer duration of breast-feeding, but the findings have varied substantially in the level of risk reduction. A pooled analysis from almost 50 studies in 30 countries reported an overall 4% reduction in risk per 12 months of breast-feeding for all parous women. It is estimated that if women in developed countries had the number of births and lifetime duration of breast-feeding as women in developing countries, the incidence of breast cancer could be reduced by 60%. In the United States in the year 2000 more than 60% of infants were ever breast fed, but only 27% were receiving breast milk at 6 months of age.^1,5




Your patient also tells you that she was a “late bloomer” and did not experience menarche until age 16. She wonders if this means something is “wrong with her hormones.”

5. Regarding endogenous hormone exposure and the risk of breast cancer, which of the following is NOT true?

1. Ovarian ablation may reduce the risk of breast cancer by as much as 75%.
2. White women who experience a first full term pregnancy before 20 years of age were half as likely to develop breast cancer as nulliparous women or women who have their first full-term pregnancy at age 35 years or older.
3. Women who experience menarche at age 11 years or younger had about a 50% greater chance of developing breast cancer than do women who experience menarche at age 14 years or older.
4. In the Nurses Health Study, the associations between age at first birth, menarche, and menopause and the development of breast cancer were observed only in women without a family history of breast cancer in a mother or sister.

c. Correct.

Ovarian ablation may reduce breast cancer risk by as much as 75% depending on age, weight, and parity, with the greatest reduction in young, thin, nulliparous women. Earlier pregnancy also reduced breast cancer risk: white women who experienced a first full term pregnancy before age 20 were half as likely to develop breast cancer as nulliparous women or those who had their first full term pregnancy at age 35 or older. There may be racial differences in these risk factors in African American women, which are currently being further explored. Another study showed that women who experience menarche at age 11 or younger were about 20% more likely to develop breast cancer than those who experienced menarche at age 14 or older. However, in the Nurses Health Study, the associations between age at first birth, menarche, menopause, and the development of breast cancer were observed only among women without a first-degree relative with breast cancer.¹




During the review of systems, it becomes apparent that your patient has been experiencing some menopausal symptoms, and asks if something “safe” can be prescribed to help with her severe unrelenting hot flushes and night sweats.

6. Regarding the Women’s Health Initiative combined estrogen-progestin hormone replacement therapy (HRT) trial, which of the following is FALSE?

1. It was stopped early after showing an increased breast cancer risk with combined estrogen-progestin therapy
2. The excess risk was observed in all subgroups of women for both invasive and in situ breast cancer.
3. Patients who developed cancer on combined HRT showed trends towards larger tumor size and higher incidence of lymph node metastases.
4. Extended follow up at 14 years showed increased breast cancer specific mortality.

b. Correct.

The WHI combined estrogen-progesterone trial included women aged 50-79 years who had intact uteri. They were randomly assigned to receive combined conjugated estrogen and continuous progestin (8,506 women) or were assigned to receive placebo (8,102) women. Breast cancer risk was increased (Hazard Ratio 1.24; 95% CI, 1.02-1.50) in the combined HRT group, causing early termination of the study. The excess risk was observed in invasive breast cancer, but not in situ cancers. Patients who did develop cancer in the combined HRT group showed trends towards both larger tumor size and higher incidence of lymph node positivity. An extended follow up at 14 years showed an even larger difference in breast cancer incidence in the HRT group and an increased breast cancer specific mortality (HR 1.95; 95% CI, 1.0-4.04; P=.049).^1,6



After explaining the increased risks of combined HRT, she asks "My sister takes only estrogen after her hysterectomy. What is her risk?”

7. Regarding the Women’s Health Initiative Estrogen-Alone Trial, which of the following is TRUE?

1. It evaluated the use of estrogen-only HRT in women with intact uteri.
2. Estrogen-only preparations are safe in women who have had a hysterectomy as well as those who have intact uteri.
3. This trial was stopped early because of an increased risk of breast cancer in the HRT group.
4. The incidence of breast cancer was lower in the group receiving estrogen-only HRT at 6.8 years of follow up.
5. Over the extended follow up period (10.7 years), there were increased risks of coronary heart disease, deep vein thrombosis, stroke, hip fracture, and colorectal cancer.

d. Correct.

The Women’s Health Initiative Estrogen-Alone Trial was a randomized control only for women who had had a hysterectomy. This is because unopposed estrogen therapy increases the risk of uterine cancer. This trial was stopped early due to an increased risk of stroke in the HRT group and no evidence of benefit as measured by a global index of risks and benefits. After an average 6.8 years of follow-up, the incidence of breast cancer was slightly lower in the HRT group, but this difference was not statistically significant. (HR=.77; 95% CI, 0.59-1.01)¹ Over the extended follow up period of 10.7 years, the decreased risk of breast cancer persisted (HR=.75; 95% CI, 0.51-1.09) and there was neither an increased or decreased risk of coronary heart disease, DVT, stroke, hip fracture, or colorectal cancer between the estrogen only HRT group and placebo.⁷



Your patient’s sister was told that she would need to take tamoxifen to treat her breast cancer, and your patient has brought a printed web page discussing the various indications for tamoxifen.

8. Which of the following statements regarding the Breast Cancer Prevention Trial (BCPT, also known as NSABP P-1) is FALSE?

1. It was a randomized controlled trial that assigned 13,388 patients at elevated risk for breast cancer to receive tamoxifen 20mg daily for five years or placebo.
2. It was closed early after showing a 49% reduction in the incidence of breast cancer for the group receiving tamoxifen.
3. There was no reduction in the incidence of noninvasive breast cancers.
4. A reduction in fractures was observed in the tamoxifen treated group.
5. An increase in endometrial cancer and thrombotic events was noted in women aged 50 years and older.
6. No overall mortality benefit was seen for tamoxifen prevention after seven years of follow up.

c. Correct.

The BCPT (NSABP P-1) showed a reduction in the incidence of both invasive and noninvasive breast cancers. There were 31 cases of noninvasive cancers in the tamoxifen treated group versus 59 in the placebo group. All of the other above statements regarding the BCPT are correct.^1,8,9


She asks if you will prescribe tamoxifen for her.

9. Which of the following statements regarding management recommendations for chemoprevention of breast cancer is FALSE?

1. The Food and Drug administration has approved the use of tamoxifen for breast cancer risk reduction in women who are 35 years or older and have a 5-year risk of 1.66% or more as determined by the Gail model.
2. The American Society of Clinical Oncology Working Group has advised that patients with the risk of an average 60 year-old white North American female be offered tamoxifen chemoprevention.
3. Premenopausal women at increased risk for the development of breast cancer derive the greatest net benefit because of the absence of increased risks for either thromboembolic events or uterine cancer in this group.
4. Despite having been shown to offer a similar breast cancer risk reduction to tamoxifen, raloxifene has significant safety disadvantages compared to tamoxifen and is not currently recommended for chemoprevention.

d. Correct.

The FDA has approved tamoxifen for breast cancer risk reduction in women who are 35 years or older and have a 5 year risk of 1.66% or more as determined by the Gail model. (www.cancer.gov/bcrisktool) The American Society of Clinical Oncology Working Group has also advised offering tamoxifen to patients with a 1.66% 5-year risk, which is the risk of the average, 60 year-old white, North American female. However, the group (and others) has noted that the greatest clinical benefit is observed when tamoxifen was given to younger, premenopausal women, women without a uterus, and in women with a higher risk of breast cancer. Raloxifene 60mg orally daily for five years offers an acceptable and similarly effective alternative to tamoxifen for the reduction of breast cancer risk in high risk postmenopausal women and is associated with lower risks of both benign and malignant uterine events as well as significantly less thromboembolic toxicity.¹⁰


After referral to a medical breast specialist for risk calculation and consideration of tamoxifen chemoprevention, your patient asks if there is anything else she could take to reduce her risk.

10. Which of the following statements regarding diet and vitamins and breast cancer is FALSE?

1. In a randomized controlled trial as part of the WHI enrollment, the group that reduced fat intake by 10% for approximately 8 years of follow was shown to have a slightly lower incidence of invasive breast cancer.
2. Fruit and vegetable consumption has been linked to the prevention of breast cancer.
3. There are no specific micronutrients, including beta carotene, Vitamin E, folic acid, vitamin B6, or vitamin B12 that have been shown to reduce breast cancer risk.
4. Fenretinide is a Vitamin A analog that has been shown to reduce breast carcinogenesis in preclinical trials, but a randomized trial showed no significant differences in the incidence of breast cancer, nonbreast malignancies, or all-cause mortality.

b. Correct.

A randomized dietary modification study was undertaken among 48,835 women in the WHI study. The goal fat reduction was 20% but the intervention group was able to reduce fat consumption by 10% on average. At 8.1 years of follow up, the incidence of invasive breast cancer was slightly lower in the fat reduction group (HR 0.91, 95% CI, 0.83-1.01). A pooled analysis of eight cohort studies investigating fruit and vegetable consumption showed little evidence of a reduction in breast cancer based on increased fruit and vegetable consumption. No randomized trials have examined the effect of fruit and vegetable consumption on breast cancer.¹
Beta-carotene, Vitamin E, folic acid, vitamin B6, and vitamin B12 have all been investigated as supplements to reduce breast cancer risk. None of these have shown a reduction. Fenretinide is a Vitamin A analog that has been shown to reduce breast carcinogenesis in preclinical trials, but a phase III Italian randomized trial using a 5 year intervention with fenretinide versus no treatment showed no statistically significant differences in the incidence of breast cancer, nonbreast malignancies, or all-cause mortality.¹




Key Points

1. There may be no “safe” level of alcohol intake with regards to breast cancer risk. Even moderate alcohol consumption has been tied to an increased risk of breast cancer, although risk does increase with heavier and more frequent drinking.
2. Body weight, BMI, and adult weight changes have all been associated with an increased risk of breast cancer. A low fat diet may decrease the risk (likely by decreasing weight), but no other specific dietary modifications (fruits / vegetables, vitamins) have been conclusively shown to reduce risk.
3. In general, increased lifetime endogenous estrogen exposure (early menarche and late menopause) is associated with increased breast cancer risk, as is delayed childbirth, which is a worldwide trend.
4. Extended use of combined HRT (estrogen plus progesterone) is best avoided for breast cancer prevention.
5. Tamoxifen 20mg daily for five years is approved for breast cancer risk reduction in women who are 35 years or older and have a 5 year risk of 1.66% or more as determined by the Gail model. The greatest clinical benefit is observed when tamoxifen was given to younger, premenopausal women, women without a uterus, and in women with a higher risk of breast cancer. Raloxifene 60mg orally daily for five years offers an acceptable alternative to tamoxifen for the reduction of breast cancer risk in high risk postmenopausal women.