Professional Recommendations for Use of Pharmacologic Interventions to Reduce Breast Cancer Risk
CLINICAL ACTIONS:
Both USPSTF and ASCO have released guidance on the use of medications to reduce breast cancer risk in women who meet a certain risk threshold. The USPSTF guidance is in alignment with ASCO in the recommendation of aromatase inhibitors, along with tamoxifen and raloxifene, as drugs suitable for use as risk-reducing medications for women at increased risk for breast cancer and at low risk for adverse medication effect (USPSTF Grade B – offer or provide this service). Based on data review, the USPSTF and ASCO determined that certain medications have the potential to reduce the risk of estrogen receptor positive breast cancer by almost 50% in women. An individualized approach which integrates personal and family medical history is used to determine the best risk reduction approach.
USPSTF Recommendations
Risk Assessment
All patients should initially be assessed to determine if they are at high risk for breast cancer and if so, appropriate referral should be considered in the following circumstances
Personal history of breast cancer, LCIS or DCIS
Personal history of mantle radiation for Hodgkin’s lymphoma
Personal or family history suggestive of high risk for pathogenic variants in BRCA1, BRCA2 and other high or intermediate risk genes that may cause heritable cancer syndromes
If patients do not meet the above high-risk criteria, an absolute 5-year risk score can be calculated using a validated assessment tool (see ‘Learn More – Primary Sources’ below; both publicly available)
Offer pharmacologic interventions if at least 3% (1/33) risk of breast cancer in next 5 years
Gail or Breast Cancer Surveillance Consortium (BCSC) Risk Calculator for women who are ≥ 35 years of age are validated 5-year risk assessment tools
BCSC Risk Calculator includes field for breast density
Alternatives to the above as per the USPSTF, clinicians may consider a combination of risk factors including (but not limited to)
Age 65 years or older with 1 first-degree relative with breast cancer
45 years or older with more than 1 first-degree relative with breast cancer or 1 first-degree relative who developed breast cancer before age 50 years
40 years or older with a first-degree relative with bilateral breast cancer
Presence of atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a prior biopsy.
Medication Options
Tamoxifen, raloxifene, and aromatase inhibitors all reduce primary breast cancer risk in postmenopausal women
Use of raloxifene and aromatase inhibitors is indicated only in postmenopausal women
Only tamoxifen is indicated for risk-reduction of primary breast cancer in premenopausal women
ASCO Recommendations
Risk Assessment
Women with 1 or more factors are most likely to benefit from endocrine therapy risk reduction
Prior diagnosis of atypical hyperplasia or lobular carcinoma in situ
5-year risk by the NCI Breast Cancer Risk Assessment Tool of at least 3%
10-year risk by the IBIS/Tyrer Cuzick Risk Calculator of 5% or higher
Relative risk of 2X or greater than the average for age group if age 45-69
Relative risk of 4X or greater than the average for age group if age 40-44
Medication Options
Postmenopausal women at elevated risk: Prescribe daily for 5 years
Anastrozole 1 mg
Tamoxifen 20 mg
Raloxifene 60 mg
Exemestane 25 mg
Premenopausal
Tamoxifen 20 mg/day for 5 years in women who are at least 35 years old and have completed childbearing
KEY POINTS:
5-year risk assessment is not appropriate as an initial assessment in high risk families
Referral to genetic counseling should be made if there is a significant family history of cancers including non-breast malignancies, such as colon, ovarian and uterine
Paternal family history of breast and other cancers is critical in this setting and requires a multiple generation pedigree analysis
See “USPSTF Guidelines for Primary Care Clinicians: BRCA-Related Cancer Risk Assessment” in Related ObG Topics below
USPSTF recommends against the use of medications to reduce breast cancer risk in women ≥ 35 who are not at increased risk (Grade D – discourage the use of this service)
Harms Associated with Risk Reduction Medications
Tamoxifen and raloxifene are associated with small to moderate harms
Increased risk for VTE
Tamoxifen > raloxifene | Greater risk in older women
Tamoxifen increases risk for endometrial cancer (not raloxifene)
Hot flashes common with both
Aromatase inhibitors are associated with small to moderate harms including
Hot flashes | GI symptoms | MSK pain | Possible cardiovascular events (e.g., stroke)
USPSTF Guidelines for Primary Care Clinicians: BRCA-Related Cancer Risk Assessment
Summary:
USPSTF released updated guidelines (2019) to help primary care professionals identify women who would benefit from further genetic counseling and testing for BRCA1 and BRCA2. Two major changes from previous USPSTF recommendations address the inclusion of two additional patient groups: (1) women with previous breast cancer or ovarian cancer who are considered cancer-free; (2) the explicit inclusion of ancestry.
The USPSTF recommends that primary care clinicians, using an “appropriate brief familial risk assessment tool” should screen women with
Personal or family history of breast, ovarian,
tubal, or peritoneal cancer or
Ancestry associated with BRCA1/2 gene mutation
The USPSTF document further states that
Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing. (Grade B – The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial)
Note: A patient
with a family member with known BRCA1/2 pathogenic variant should also be
referred to genetic counseling
For women whose personal or family history or ancestry is not associated with potential harmful BRCA1/2 gene mutations
The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing (Grade D – The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits)
Appropriate Familial Risk Assessment Tools
USPSTF evaluated the following validated tools that can help estimate the likelihood of BRCA1/2 pathogenic variants and guide genetic referral
Note: NCCN and ACMG/ NSGC also have guidelines regarding when to refer women for genetic counseling (see ‘Learn More – Primary Sources’ below for links to these sites) | ACOG recommends that “Genetic counseling is recommended before initiation of genetic testing and can be performed by an obstetrician–gynecologist (or other gynecologic care provider) who has expertise in cancer genetics or by a genetic counselor”
KEY POINTS:
BRCA1/2 pathogenic variants
Occur in an estimated 1/300 to 1/500 women and account for the following percent of cancer cases
Breast cancer: 5% to 10%
Ovarian cancer: 15%
Significantly increase cancer risk breast cancer: 45% to 65% (cumulative age 70)
Significantly increase ovarian, fallopian tube, or peritoneal cancer risk (cumulative age 70)
BRCA1: 39%
BRCA2: 10% to 17%
Note: See ‘BRCA1
& BRCA2 Mutations: What Are the Risks for Developing Breast and Ovarian
Cancer?’ in ‘Related ObG Topics’ below
NCCN and other professional bodies recommend offering BRCA testing to any women with ovarian cancer
15% of women with epithelial ovarian cancer will have a pathogenic variant in BRCA1/2
NCCN also recommends that all individuals with pancreatic cancer be offered BRCA1/2 testing along with other related genes associated with this malignancy
2.5% (1/40) individuals of Ashkenazi Jewish heritage (unselected – i.e. do not need high risk family history) will have one of the 3 founder BRCA1/2 variants vs 0.1% in the general population
90% of pathogenic BRCA1/2 pathogenic variants belong to one of the 3 founder mutations
NCCN updated its guidance (December 2019) and now states that testing for the 3 founder mutations can be ‘considered’ in an AJ individual without personal cancer history | Ideally testing should be offered within a longitudinal study, but if such a study is not readily available, the test may be provided if there is pre-test and education and post-test counseling available
Multigene Panel Testing: USPSTF does not endorse the use of multigene panel testing beyond BRCA1/2, due to limited data regarding clinical utility
Benefit of multigene panels: Will detect variants associated with other cancers that are seen in conjunction with breast cancer, for example
Pancreatic cancer | Prostate cancer | Melanoma
Risks associated with multigene panels: While multigene panel testing offers more comprehensive coverage of other important genes there is additional risk for
Identifying variants of uncertain significance (VUS)
Clinical follow-up may not be well defined
Pre and post genetic counseling may be especially beneficial for those offered multigene panel testing
Note: ACOG does address multigene panels and finds that “Genetic testing may be performed using a panel of multiple genes through next-generation sequencing technology” | Heritable cancer syndromes may overlap such that a strong family history for ovarian cancer may be the result of a pathogenic variant in BRCA1/2 or genes associated with Lynch Syndrome
This USPSTF guidance specifically addresses women and not men
Metastatic prostate cancer
BRCA1/2 found in 6% of metastatic prostate | NCCN therefore considers this pathology an indication for genetic counseling and BRCA1/2 testing
Population addressed in this current USPSTF guideline: Higher risk only and, therefore, may benefit from genetic counseling regarding BRCA1/2
USPSTF has another guideline specific to average risk population
All women at average risk (i.e., not at higher risk for BRCA1/2) should have a 5-year breast cancer risk assessment to determine if they may benefit from chemoprophylaxis (e.g., tamoxifen, raloxifene or aromatase inhibitor)
These risk assessment tools are different than those described above and focus on breast density, prior history of breast atypia etc. (See ‘Related ObG Topics below)
New treatments (not addressed in this guidance)
Knowledge of BRCA status has implications for treatment
Poly (ADP-ribose) polymerase (PARP) inhibitors block an enzyme involved in DNA damage repair
FDA has approved PARP inhibitors for treatment of BRCA-associated metastatic breast and ovarian cancers, and other cancers in various pharmaceutical pipelines
Professional organizations continue to release evidence based guidance on mammography, with ACP the latest to provide updated recommendations. While required frequency and starting age may differ, they all emphasize shared decision making with patients, which entails counseling about uncertainty, risk/benefit and related patient values.
BENEFITS OF MAMMOGRAPHY
Appears to decrease breast cancer mortality by 15 to 20%
Studies demonstrate varying magnitude
ACS (RCT data): Relative risk 0.80-0.82
Recent data from the Canadian National Breast Screening Study did not show decrease when comparing mammography to controls, perhaps due to more recent improvements in treatments but does not take in to account advances in imaging
May increase life expectancy (ACS systematic review) but could not quantitate
HARMS OF MAMMOGRAPHY
False Positives (additional images and benign biopsies)
USPSTF review
Collaborative modeling data: Screening biennially from ages 40 to 74 years would result in 1376 false-positive results per 1000 women screened over a lifetime of screening
ACS review
Increased risk of false positive with dense breasts among women 40-49
Callbacks minimized if prior films available
Anxiety and Distress
May persist even if follow-up is normal
Financial concerns as patient may be responsible for paying for additional tests
Overdiagnosis and Overtreatment
Overdiagnosis is defined as detecting a cancer that would have remained indolent and not become apparent without screening
Overtreatment is defined as treatment for an overdiagnosed cancer
Difficult to discern actual number of overdiagnosed cancers
Collaborative modeling data (USPSTF): Screening biennially from ages 40 to 74 years would lead to 14 overdiagnosed cases of breast cancer per 1000 persons screened over the lifetime of screening with a very wide range of estimates (4 to 37 cases) across models
Other organizations such as ACS make the point that certain assumptions may not be verifiable in addition to bias in methodology and design
PROFESSIONAL GUIDELINES:
ACOG
Start Age
Recommend at age 50
Offer from age 40 (shared decision making)
Screening Interval
Every 1 or 2 years (shared decision making)
Stop Age
Age 75
> 75 shared decision making including overall health and longevity
USPSTF
Start Age
Recommend at 40 years
Screening Interval: Every 2 years until 74 years
Stop Age
≥ 75 years: Insufficient evidence to recommend for/against
ACS
Start Age
Recommend at age 45 years | Consider 40 years if patient desires
Screening Interval
45 – 50 years: annual
≥55 years: Every 2 years or can choose annual
Stop Age
Continue if good health and life expectancy >10 years
ACR
Start Age
Recommend at 40 years
Screening Interval: Annual
Stop Age
“Screening should continue past age 74 without an upper age limit, unless severe comorbidities limit life expectancy or ability to accept treatment.“
Note: ACR updated guidelines to include transgender patients stating “Annual screening at age 40 is recommended for transfeminine (male-to-female) patients who have used hormones for ≥5 years, as well as for transmasculine (female-to-male) patients who have not had mastectomy”
ACP
Start Age
Recommended at 50 years
40-49 years: Discuss risks vs benefits and patient preference (“potential harms outweigh the benefits for most women” in this age bracket )
Screening Interval: Every 2 years
Stop Age
Screening not recommended for women ≥75
Life expectancy ≤10 years
NCCN
Start Age
Recommend at 40 years
Screening Interval: Annual
Stop Age
Upper age limit not yet established
Consider comorbidities that may impact life expectancy (≤10 years)
Canadian Task Force on Preventative Healthcare
Start Age
Recommend not to screen women 40 to 49 years (conditional recommendation; low-certainty evidence)
Screening Interval
Every 2 to 3 years
50 to 69 years: “Conditional on the relative value that a woman places on possible benefits and harms from screening (conditional recommendation; very low-certainty evidence)”
50 to 59 years: 1333 women is the number needed to screen (NNS) to prevent one death from breast cancer (95% CI, 909 to 2857)
60-69 years: NNS is 1087 (95% CI, 741 to 2325)
70-74 years: NNS is 645 (95% CI, 441 to 1389)
Stop Age
No evidence found regarding harms vs benefits of screening ≥75 years
Note: The Canadian Task Force did not make any significant change from the previous guideline, however certainty of evidence – now ‘very low- to low-certainty’ was downgraded based on serious concerns of previous study bias
American Society of Breast Surgeons
Start Age
Non-dense breasts (A and B density): 3D preferred modality | Age 40 | No need for supplemental imaging
Dense breasts (C and D density): 3D preferred modality | Age 40 | Consider supplemental imaging
Screening Interval
Annual
Stop Age
When life expectancy is <10 years
ADDITIONAL KEY POINTS:
Clinical Breast Examination (CBE)
ACOG & NCCN: Offer every 1 to 3 years for women 25 to 39 years and annually for ≥ 40 years
USPSTF & AAFP: Insufficient evidence to recommend for or against
ACS, ACP & Canadian Task Force on Preventative Healthcare: Not recommended
WHO: CBE may be of benefit for women age 50 to 69 years with poor access to healthcare resources
Most professional organizations find insufficient evidence to recommend adjunctive screening using breast ultrasonography, MRI, Digital Breast Tomosynthesis, or other method in the setting of a normal mammogram and no other risk factors
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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
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presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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