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Risk Reducing Medications

6 September 2019


The US Preventative Services Task Force (USPSTF) and the American Society of Clinical Oncology (ASCO) have both released updated recommendations on the use of medications (tamoxifen, raloxifene, anastrozole and exemestane) to reduce the risk of estrogen-receptor positive breast cancer in women who are considered to be at high risk for the disease. The use of these medications to reduce breast cancer risk is commonly known as “chemoprevention.” Tamoxifen, anastrozole and exemestane are also used in the treatment of estrogen receptor positive breast cancer. Summaries of the statements and links to the manuscripts and associated publications are provided at the end of this post.

Risk assessment may be performed using a variety of online calculators that take into account age, menstrual and pregnancy history, family history and prior breast biopsies – especially biopsies that show atypical hyperplasia or lobular carcinoma in situ (LCIS). Some models also take into account body mass index and breast density. These models tend to perform well in populations of women, but are not as accurate as predicting the likelihood of breast cancer development in an individual woman. The models calculate 5-year and lifetime breast cancer risks. The “average” woman has a 5-year risk of approximately 1% and lifetime risk of approximately 10-12%. The early studies evaluating risk-reducing medications considered a 5-year risk of 1.66% or greater as “high risk” (lifetime risk over 20% is also considered “high risk”). Both the USPSTF and ASCO statements focus on women age 35 and older with a 5-year risk of 3% or higher. 

The USPSTF and ASCO recommendations are similar. For women at high risk of developing breast cancer (3% or greater 5-year calculated risk OR high risk due to combination of factors – see below), it is recommended that patients consider the use of a risk-reducing medication, taking into account side effects of the medications and an individual patient’s medical condition and preferences. Both guidelines specifically do NOT recommend the use of risk-reducing medications in women who are not at elevated risk for the development of breast cancer. 

The risk factor combinations that convey increased risk and should prompt consideration of risk-reducing medications include:

From the USPSTF Statement:

  • Age 65 or older with one 1st degree relative with breast cancer
  • Age 45 or older with more than one 1st degree relative with breast cancer or one 1st degree relative who developed breast cancer before age 50
  • Age 40 or older with atypical hyperplasia or lobular carcinoma in-situ, or with a 1st degree relative with bilateral breast cancer 

From the ASCO Statement:

  • 1st degree relative with breast cancer diagnosed before age 45
  • Two 1st degree relatives with breast cancer diagnosed at any age
  • A 1st and 2nd degree relative with breast cancer

The USPSTF statement acknowledges that women with BRCA mutations and those who have received chest wall radiation at a young age are at increased risk, but it was felt that there was insufficient evidence to recommend chemoprevention in these patients. These women are included in the ASCO statement in the Clinical Considerations section of the manuscript.

Risk assessment and the decision to use risk-reducing medications is a challenging and at times confusing topic. Many studies report that the use of risk-reducing medications in high risk women can result in a 50% or greater reduction in the likelihood of developing invasive breast cancer compared with placebo. However, as the JAMA editorial by Drs. Pace and Keating notes, the absolute reduction in risk for an individual woman could be very low – less than 1 percentage point. They noted that over 100 high-risk women would need to be treated to prevent one breast cancer. Obviously when multiplied by the large number of women that might be impacted by these guidelines (noted to be approximately 10 million women in the US in the JAMA editorial by Drs. Daly and Ross) there is the potential to make a significant impact on the incidence of breast cancer. None of these medications have been shown to improve breast cancer-related survival rates in high-risk women. 

Many of the early studies that determined the effectiveness of these medications in reducing risk defined “high risk” as a 1.66% or greater 5-year risk. However, both USPSTF and ASCO recommend using the 3% or greater level of 5-year risk as it was felt that these women at the highest level of risk are most likely to benefit from the medications, and that this benefit will be more likely to outweigh potential harms. But even these women may be more likely to NOT develop breast cancer.

In deciding on a medication, tamoxifen may be used in pre- or post-menopausal women. Raloxifene, anastrozole and exemestane are only for use in post-menopausal women.

Both statements acknowledge the potential side effects that may occur with use of these medications. Some of the more common potential side effects include uterine cancer (tamoxifen), blood clots (tamoxifen and raloxifene), bone / joint / muscle pains and bone loss (anastrozole and exemestane) and hot flashes (all medications). Generally, risk-reducing medications are used for 5 years although raloxifene may be used for longer periods of time as it is often used as a treatment for osteoporosis. The risk reduction appears to last approximately 8-10 years after the medication is stopped, and many studies report that side effects tend to improve shortly after medications are discontinued. The ASCO statement notes that 3 years of risk-reducing therapy may be effective. The paper also discusses a recent study that evaluated the use of low dose (5 mg as opposed to the usual 20mg)  tamoxifen versus placebo in high risk women. There was an approximately 50% reduction in the risk of invasive breast cancer among patients who took the low dose of tamoxifen – similar risk reduction to what is seen with the full 20mg dose.

Both statements mentioned other ways that risk can be reduced, including adoption of a healthy lifestyle (exercise, alcohol limitation, and weight management). Challenges in the use of risk assessment models and in discussing risk reducing medications include limited time and lack of patient decision aids. More data is needed on the risks and benefits of the medications in some patient populations. 

It is hoped that ongoing research evaluating the use of polygenic risk scores (a form of genetic testing) will add more insight to an individual’s level of risk in the (hopefully) near future. Drs. Daly and Ross noted in their editorial that “In the new era of precision medicine, there is a realization that one size fits all is no longer acceptable for most treatments.” and that “More efficient and sophisticated tools to more precisely quantify each individual’s benefit / risk for a variety of chemoprevention drugs may ultimately translate into precision medicine for breast cancer prevention.” Physicians and patients will certainly welcome more precise, tailored information to help guide the decision-making process for women who are at high risk for breast cancer.

USPSTF Recommendation: Medications to Reduce the Risk of Breast Cancer
ASCO Guideline Update: Use of Endocrine Therapy for Breast Cancer Risk Reduction

If access to any of the references articles is desired, please email me:  contact at drattai dot com and I will be happy to provide a copy.

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USPSTF Update on BRCA Testing

23 August 2019

Earlier this week, the United States Preventative Services Task Force (USPSTF) released an updated recommendation for genetic testing for BRCA 1 and 2 mutations. Their previous guideline, released in 2013, recommended risk assessment and consideration of testing in women with a family history of breast and/or ovarian cancer. The current guidelines add consideration for ancestry and personal history of breast, ovarian, fallopian tube or peritoneal cancer (BRCA-associated cancers for the purpose of this post). Under the Affordable Care Act, private insurers follow USPSTF recommendations, often with no out-of-pocket cost to the patient.

The BRCA 1 and 2 genes are involved in DNA repair. Mutations in these genes may impact the ability of a cell to repair DNA damage resulting in an increased risk of certain cancers. In women, the most common BRCA-associated cancers are breast and ovarian cancer. In men, the most common BRCA-associated cancers are prostate, breast and pancreatic cancers as well as melanoma. The abnormal genes can be inherited from the mother or father.  Mutations in BRCA 1 and 2 genes have been identified in every racial and ethnic group with a prevalence ranging from 1 in 40 to 1 in 500. The Ashkenazi Jewish population has the highest mutation prevalence.  Not everyone that inherits an abnormal gene will develop the cancer – the risk and type of cancer depend on the specific mutation and many other factors. Mutations in the BRCA genes account for approximately 5-10% of breast cancers and approximately 15% of ovarian cancers.

The updated USPSTF recommendation applies only to women (they did not address genetic testing in men) and only applies to the BRCA 1 and 2 genes, which are the most common genes associated with hereditary breast and ovarian cancer. 

The current guideline recommends a 3-step process. In patients who have a personal or family history of BRCA-associated cancers or a hereditary susceptibility (Ashkenazi Jewish) the task force recommends:

  • Use of a validated tool to determine likelihood of a genetic mutation
  • Referral of patients with a high likelihood of carrying a genetic mutation for genetic counseling
  • Genetic testing if the results would impact medical decision making

It is important to note that they are not stating that all Ashkenazi Jewish women, or that all women with a personal or family history of breast or ovarian cancer be tested – but that they be evaluated and then considered for testing based on likelihood of having a deleterious (harmful) mutation. They recommend against risk assessment, genetic counseling and genetic testing in those with a personal or family history of cancer or ancestry not associated with a high likelihood of deleterious BRCA mutations. 

Identification of patients who carry mutations in these genes is important for several reasons. In those who do not have cancer, identification of a mutation carrier may lead to recommendations for more intensive screening (most commonly annual MRI in addition to annual mammography for breast cancer surveillance) or prophylactic surgery. Family members can also be appropriately counseled and tested. Tamoxifen may be considered for breast cancer risk reduction. However, in an accompanying editorial, Dr. Lisa Newman noted that breast cancers that develop in women with BRCA 1 mutations are more likely to be “triple negative”, which are not responsive to tamoxifen or other therapies that target the estrogen receptor. BRCA 2 related breast cancers are more often estrogen receptor positive, and tamoxifen may be an option in these patients for risk reduction.

In patients that have a history of a BRCA-associated cancer, knowledge of genetic status can inform surveillance recommendations for other associated cancers as well as counseling and testing of family members. 

The USPSTF specified that patients with a prior history of BRCA-associated cancers, who “have completed treatment are considered cancer-free but have not been previously tested” are included in this guideline. I believe it is unfortunate that they did not include newly diagnosed patients in this guideline as knowledge of mutation status can influence surgical recommendations and may influence systemic therapy (chemotherapy) recommendations, a point made in the editorial by Drs. Sharon Domchek and Mark Robson. There may also be value in testing patients who have metastatic disease as their family members can then make informed decisions regarding their own health. The most recent American Society of Breast Surgeons genetic testing guideline recommends that all breast cancer patients be considered for genetic testing.

The USPSTF recommendations did not touch on this, but It is important to note that if BRCA testing was performed prior to 2012-2014, consideration should be given to repeat testing. A large number of mutations have been identified since that time, and some who have previously testing negative may actually carry a deleterious mutation.

Genetic testing in men was not addressed in the current USPSTF statement. Drs. Rachel Yung and Larissa Korde, in an accompanying editorial, stated that lack of inclusion of men in the guideline was a “missed opportunity”. They noted that that metastatic prostate cancer is the most common BRCA-associated cancer in men and that the National Comprehensive Cancer Network (NCCN) guidelines list family history of metastatic prostate cancer is an indication for genetic counseling and BRCA testing. Many patients (and some physicians) are unaware that BRCA mutations can be inherited from male relatives and may lead to cancer development in men. For that reason, some have called for the renaming of “Hereditary Breast and Ovarian Cancer Syndrome” to “King Syndrome”, after Dr. Mary-Claire King, the scientist who discovered the location of the BRCA 1 gene and its relationship to hereditary breast and ovarian cancer.

In addition, not specifically covered in this statement, but discussed in editorials by Dr. Lisa Newman, Drs. Susan Domchek and Mark Robson, and Dr. Padma Sheila Rajagopal et al was racial and socioeconomic disparities in genetic testing and the importance of ongoing work in this area.

While (in my opinion) the current recommendations are incomplete, they are a step forward in helping to ensure patients with deleterious mutations, and their family members, are properly identified and counseled regarding their risk and their options. 

Men and women should be aware of their family history of all cancers (going back 3 generations), not just breast and ovarian cancer. Those who feel they fit the new guidelines based on family history, personal history, or ethnic background, even if previously tested (before 2012-2014) should speak with their physician about referral to a provider who specializes in cancer genetics for consideration of testing. 

If access to any of the references articles is desired, please email me: contact at drattai dot com and I will be happy to provide a copy.

References and Resources:

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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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