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Medications to Reduce Breast Cancer Risk

15 January 2019

The US Preventative Services Task Force (USPSTF) has released draft recommendations for the use of medications to reduce the risk of breast cancer development in women who are at increased risk. The draft document, which is open for public comment until February 11, 2019, is an update of their 2013 recommendation – the conclusions are similar, and the current document now includes aromatase inhibitors. The recommendations apply to women at high risk (see next 2 paragraphs) and do not apply to women with a current or previous diagnosis of invasive breast cancer or ductal carcinoma in situ (DCIS). 

Various factors are taken into account when assessing breast cancer risk. Family history is certainly important, but other factors such as age at first menstrual cycle, age at first pregnancy, and prior biopsies showing abnormal cellular changes (such as atypical hyperplasia and lobular carcinoma in situ) and impact risk. Weight gain after menopause, breast density, and sedentary lifestyle also contribute to increased risk. Various risk assessment calculators can be used to estimate a woman’s risk of developing breast cancer. Unfortunately, risk assessment is not an exact science – we have a long way to go in terms of predicting whether an individual woman will or will not develop breast cancer.

An “average” woman’s risk of developing breast cancer over 5 years is approximately 1.0 – 1.5%, and 8-12% over her lifetime. Women are considered to be “high risk” if their 5-year risk is greater than 1.7-(although the USPSTF uses 3%) and if the lifetime risk is 20% or greater. In these patients, we often utilize supplemental imaging such as MRI and/or ultrasound in addition to mammography, and these patients are candidates for taking risk-reducing medications. The medications used to reduce risk are also used for breast cancer treatment: tamoxifen, raloxifene, and the aromatase inhibitors (anastrozole, exemestane, and letrozole).

The USPSTF reviewed available data and concluded with “moderate certainty” that there is a “moderate net benefit” from taking risk reducing medications in women who are at increased risk. In addition, they noted that the potential harms of the medications outweigh any potential benefit in women who are notat increased risk. As these medications either block the estrogen receptor in the breast (tamoxifen and raloxifene) or diminish estrogen production (aromatase inhibitors) they will only reduce the risk of estrogen receptor positive breast cancer. 

Compared to placebo, tamoxifen reduces the likelihood of invasive breast cancer development by 7 events per 1000 women over 5 years. Raloxifene results in 9 per 1000 fewer invasive breast cancers, and aromatase inhibitors result in 16 per 1000 fewer invasive cancers. The benefit increases as a woman’s level of risk increases. Tamoxifen can be used in premenopausal women, but raloxifene and the aromatase inhibitors are only used in postmenopausal women. The report noted that aromatase inhibitors are primarily used to treat breast cancer, and are not currently FDA approved for risk reduction.

All of the medications have the potential for side effects, which the USPSTF considered to be “small to moderate”. Both tamoxifen and to a lesser extent, raloxifene, can increase the risk of blood clots – this risk is greater in older women. Tamoxifen can increase the risk of endometrial cancer and cataract development, and both medications can increase the likelihood of hot flashes. Both medications can reduce the risk of some types of fractures. Aromatase inhibitors can be associated with hot flashes, gastrointestinal symptoms, musculoskeletal pains, possible cardiovascular events (primarily stroke) and may increase fracture risk.

Most trials utilized the medications for 3-5 years for risk reduction.  The report notes that the benefits of tamoxifen continue at least 8 years after discontinuation of therapy, and the risk of tamoxifen-associated blood clots and endometrial cancer return to baseline after treatment has ended. They noted insufficient data on length of protection for raloxifene or the aromatase inhibitors. 

The USPSTF did identify research needs and gaps, including how to better identify individuals at increased risk, racial disparities, and that longer follow up of patients using raloxifene and aromatase inhibitors for risk reduction is needed. In addition, as there are multiple risk assessment models, more work needs to be done to determine which is “best” – different models may be more appropriate depending on specific clinical factors. 

Not addressed in the USPSTF document is that fact that many patients who are at high risk, as well as those who have been diagnosed with breast cancer, discontinue medication early (or do not start at all) due to side effects. An abstract presented at the December SABCS conference compared 5mg of tamoxifen (usual dose is 20mg) to placebo in high risk woman and found similar reduction in breast cancer development with fewer side effects. Lower dosing could be one answer, but more effective mediations with fewer side effects would certainly be welcome by all.

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Body Fat, BMI, and Breast Cancer

10 December 2018

Being overweight after menopause is associated with an increased risk of breast cancer. But a new study suggests that our traditional measure of overweight, the body mass index (BMI) may not tell the whole story.

A recent study, published in JAMA Oncology, performed detailed body composition analysis on 3000 women who were of normal BMI. They found that among these women, those with increased levels of body fat (especially in the truncal area – “belly fat”) had higher risks of estrogen receptor positive (ER+) breast cancer compared to women with lower body fat levels. In addition, the women with higher body fat levels also had higher levels of inflammatory markers as well as other metabolic abnormalities. 

This suggests that maintaining a healthy weight may not be enough. Muscle mass declines with age, so even if weight is stable, there is a slow but steady increase in body fat. Regular exercise can certainly help to maintain muscle mass and it also helps decrease the level of inflammatory markers. 

The authors note that more study is needed to better understand the links between body fat and breast cancer, but it is very clear that there is no way around it – exercise is essential for good health.

Additional Information:
NBC News: Belly fat increases risk of breast cancer despite normal BMI
CNN – Body fat levels linked to breast cancer risk in post-menopausal women

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Hormonal Contraceptives and Breast Cancer Risk

10 December 2017

A study published in the New England Journal of Medicine has shown that birth control pills and other forms of hormone based contraception (such as some intrauterine devices (IUDs) are associated with an increased risk of breast cancer. We’ve thought that the pills currently in use, which have much lower doses of estrogen and progesterone compared to older formulations, did not have a significant impact on breast cancer risk. However, the study showed a small but increased rate of breast cancer developing in those using birth control pills and IUDs.

The large study (1.8 million women), performed in Denmark, evaluated the breast cancer risk in women under the age of 50. The breast cancer risk associated with hormonal birth control is small – out of 100,000 women, there was an increase of 13 breast cancers per year (68 / year in the hormonal contraception group and 55 per year in the non-users). Most of the cases that occurred in this study were in women in their 40s. In women under the age of 35, the increased risk was 2 cases per 100,000 women.  As limitation of the study is that it did not take into account other breast cancer risk factors such as breast feeding history, alcohol intake, and exercise patterns. Breast cancer risk increased with duration of contraceptive therapy. It is important to note that as this was an observational study, it cannot conclusively be stated that hormonal contraception causes breast cancer – only that it is associated with an increased risk.

The increased risk needs to be balanced against the potential benefits of hormonal contraceptive therapy, such as preventing unwanted pregnancy, control of heavy bleeding especially during the perimenopausal period, and reduction in the subsequent risk of ovarian, endometrial and (possibly) colorectal cancers. Potential risks of long term hormonal contraception include an increased incidence in blood clots (especially in women who are overweight and/or smokers) and stroke.

Patients should evaluate their risk tolerance, breast cancer risk factors, and the risks and benefits of hormonal contraception in their individual case. As expected, the media coverage on the story is variable – HealthNewsReview.org did a good job of evaluating the media coverage and summarizing the important points of the study.

Additional Information:
NEJM Editorial
NPR – Even Low Dose Contraceptives Slightly Increase Breast Cancer Risk 
NY Times – Birth Control Pills Still Linked to Breast Cancer Risk
NY Times – Birth Control and Breast Cancer – Putting the Risk into Perspective

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Are False Alarms Cause for Alarm?

5 December 2015

Approximately 60% of women undergoing annual screening mammography over a 10 year period will be called back for additional views. Often these are in women with dense breast tissue, which can make it more challenging to read mammograms. Many of these callbacks are false alarms, also known as false positives – the abnormality may resolve with additional views, it may be found to be a benign lesion (such as a fluid filled cyst), or a biopsy may be performed and the pathology is found to be benign.

In a study published in the journal Cancer Epidemiology, Biomarkers, and Prevention, researchers found that false positive mammograms are associated with an increased likelihood of eventually developing breast cancer. Using data from the Breast Cancer Surveillance Consortium, they noted that women who had a false positive mammogram with additional imaging or biopsy recommendation had a higher likelihood of developing breast cancer compared to women with a normal mammogram. For every 1,000 women who had a true negative mammogram, 3.9 developed breast cancer over a 10 year period (average follow up 5.4 years). For those requiring additional imaging, 5.5 / 1000 developed breast cancer over 10 years, and in those who underwent a biopsy 7 / 1000 eventually developed breast cancer. It is important to note that the absolute risk of developing a breast cancer in the case of a false positive mammogram was very low – less than 1%.

The group of women with the highest rate of breast cancer development were those with dense breast tissue who underwent a biopsy. This is not surprising, as we know that breast density increases the risk of breast cancer, and the number of prior breast biopsies is factored into risk assessment models such as the Gail and Tyrer-Cusik models.

At this point, it is not recommended that women who have a false positive mammogram undergo any specific additional imaging such as MRI (unless recommended based on the mammogram). A false positive mammogram is one risk factor, but it needs to be evaluated in the context of other breast cancer risk factors, such as increasing age, family history, obesity, and alcohol intake.

Additional Information:
Dr. Margaret Polaneczky blog post
Breast Screening Decisions – screening mammogram decision tool for women age 40-49
ASCO Post Commentary
NPR False Alarm Mammograms
HNR False Positive Mammograms and Cancer Risk

 

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