Breast cancer is the most diagnosed invasive cancer in the United States, with 1 in 8 people assigned female at birth (AFAB) being affected.1 It is imperative that health care practitioners remain current and well-versed in identifying individuals at high risk for developing breast cancer. This article outlines an approach for obstetrics/gynecology practitioners to identify high-risk patients and to counsel on appropriate breast cancer screening, prevention, and risk-reduction options.
Takeaways
- Breast cancer is the most diagnosed cancer among people assigned female at birth in the United States, with a national prevalence of 13%.
- Lifetime risk assessment for breast cancer should be universally performed by age 25. However, individual cancer risk assessment is an ongoing process that could change over time with evolving family history and other personal risk factors.
- Risk assessment begins with gathering a thorough family history that explores first-, second-, and third-degree family members with cancer, along with personal risk factors for breast cancer.
- Patients with pathogenic gene mutations, elevated lifetime risk 20% or greater based on family history, high-risk breast lesions (such as atypical hyperplasia and lobular carcinoma in situ), or a history of chest wall radiation between 10 and 30 years old are at increased lifetime risk of breast cancer.
- Options such as intensive breast surveillance with mammography and supplemental breast MRI, chemoprevention, and risk-reducing mastectomy (when appropriate) should be discussed with high-risk patients.
Risk assessment
According to the National Comprehensive Cancer Network (NCCN) and the American College of Radiology, all AFAB people should undergo lifetime risk assessment for breast cancer by the age of 25.2,3 In many practices, however, lifetime risk assessment for breast cancer is not routinely performed. While there is no established or universal clinical scenario in which risk assessment should be performed, routine health maintenance visits and visits for which patients present specifically with breast complaints represent opportune times. It should also be understood that risk assessment is an ongoing process that can be repeated, as risk can change over time.
Risk factors for breast cancer include dense breasts, early menses (<12 years old), late menopause (>55 years old), nulliparity or first live birth older than 30 years, current use of postmenopausal hormone therapy, increasing age (>65 years), history of a high-risk breast lesion (such as atypical hyperplasia or lobular carcinoma in situ [LCIS]) and history of high-dose thoracic ionizing radiation.4 One of the most important risk factors is a family history of breast cancer, which can increase risk as high as 3.6-fold.5
Breast cancer risk assessment begins with gathering a 3-generation family cancer history. All cancers from both maternal and paternal lineages should be included for all people regardless of gender assignment at birth. Family cancer history should document the relationship of the individual to the patient (clarifying maternal or paternal lineage), age of cancer diagnosis, if the person underwent genetic testing, cancer subtype (if known, such as triple-negative breast cancer), and age at death (or noting if the family member is still living and at what age). General red flags include (but are not limited to) personal history or family history of multiple breast cancers (particularly on the same side of the family), early-onset breast cancer (breast cancer ≤50 years old), ovarian cancer, pancreatic cancer, male breast cancer (in people assigned male at birth), and those with triple-negative breast cancer at any age. Additionally, practitioners should inquire about Ashkenazi Jewish ancestry, as BRCA pathogenic variants among this population are 1/406 (compared with 1/300-800 in the general population).7 For patients who are adopted and/or have limited information about family cancer history, genetic testing can be considered.
The criteria for genetic counseling and testing relating to breast, ovarian, pancreatic, and prostate cancer have been set forth by the NCCN and are currently employed nationwide.6 Practitioners should refer to these criteria to guide decision-making regarding who should be referred to see a genetic counselor unless they have specific expertise in genetics. A certified genetic counselor should be consulted if there are any questions or discrepancies in testing criteria. Patients who do not meet NCCN criteria for genetic testing but wish to explore their genetics can still elect to undergo testing but should be cautioned about potential variability in insurance coverage and out-of-pocket costs.
It is preferable for practitioners to refer patients to a certified genetic counselor for genetic counseling and testing in lieu of ordering testing directly. Genetic counseling and testing require specific expertise, can be time intensive, and require a thorough explanation of risks and benefits as a component of informed consent. It is also important for the practitioner to ensure comprehensive testing based on the presenting family history, for which multi-gene panel testing has largely replaced single-site testing for BRCA1/2, which was historically the standard practice. In the setting of equivocal genetic testing results (called variants of uncertain or unknown significance [VUS]), it remains the ordering provider’s responsibility to follow up and provide subsequent counseling if the VUS later reclassifies.
Germline gene mutations
The primary goal of genetic testing is to identify germline gene mutations that increase cancer risk (also called pathogenic or likely pathogenic variants). The NCCN has identified actionable breast cancer susceptibility genes, some of which are classified as high-penetrant (such as BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53) and moderate- or low-penetrant (such as ATM, BARD1, CHEK2, NF1, RAD51C, and RAD51D).6Table 1 summarizes these genes. Practitioners should recognize that most of these pathogenic/likely pathogenic variants confer increased risk of not only breast cancer but other cancers as well. Complete cancer risk for each of these pathogenic variants is outside of the scope of this article. NCCN guidelines should be reviewed by the practitioner and other cancer risks addressed with the patient by a specialist as needed.
Genetic testing results should be interpreted with the assistance of a genetic counselor or clinical genetics specialist. Pathogenic and likely pathogenic variants are considered clinically actionable, whereas benign or likely benign variants do not demonstrate increased risk of cancer. As previously mentioned, VUS are equivocal, nonactionable results that are monitored over time for changes in classification.
Elevated risk due to family history
In some settings of benign, equivocal, or negative genetic testing results, a lifetime risk calculation based on family history alone may be the next appropriate step. Numerous breast cancer risk assessment models are software tools or research-based models that estimate lifetime breast cancer risk. These models include:
- Tyrer-Cuzick model (also known as the International Breast Cancer Intervention Study)
- Claus model
- Breast Cancer Risk Assessment Tool, also known as the Gail model
- Rosner-Colditz model
- BRCAPRO model
- Breast Cancer Surveillance Consortium model
- Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm.
Multiple models can be used simultaneously to calculate and compare the upper limit of lifetime risk. Any risk that is 20% or greater is considered to be an increased lifetime risk of breast cancer.
There are several points to consider when calculating lifetime risk. Each tool has its strengths and limitations; practitioners should be mindful of this when counseling patients. While some tools may include other significant risk factors (such as breast density or genetic testing results), others may not. Some calculators may be more inclusive of extended family members, whereas others may calculate risk based on first- and/or second-degree relatives only. Risk calculations may also be limited in their interpretation in the setting of key family members deciding not to undergo testing or being unable to undergo testing (ie, if they are deceased). Risk calculators are also not intended to be used for those with a personal history of breast cancer. Finally, it should be noted that these calculators were largely developed with data from predominantly European populations and may potentially underestimate risk among Black communities.8 Other models such as the Black Women’s Health Study Breast Cancer Risk Calculator9,10 and a model by Gail et al using data extrapolated from the Women’s Contraceptive and Reproductive Experiences study11 were designed to address these disparities in breast cancer risk calculations among Black people.
Other high-risk groups
Figure 1 outlines categories for those that are considered at increased risk and who meet criteria for medical intervention. This includes those with high-risk breast lesions (atypical ductal hyperplasia [ADH], atypical lobular hyperplasia [ALH], and LCIS), which are markers of future increased risk of breast cancer. ADH and ALH are estimated to increase breast cancer risk 3- to 5-fold, whereas LCIS is estimated to increase risk 6- to 10-fold.12,13 These lesions tend to be incidentally discovered at the time of screening mammography and often do not present with a palpable mass. Patients with these lesions should meet with a breast surgical oncologist to discuss indications for surgical excision based on specific pathology. However, even following excision of the lesion, patients are still deemed to be at increased lifetime risk and meet criteria for intensive surveillance options and chemoprevention to begin at the time of diagnosis.
Additionally, those with radiation exposure to breast tissue (such as ionizing chest wall radiation between the ages of 10 and 30 years for conditions such as Hodgkin lymphoma) are considered to carry an increased lifetime risk of breast cancer. While data are variable, 1 systematic review evaluating breast cancer after chest wall radiation noted incidence ratios ranging from 13.3 to 55.5.14
Options for patients at increased risk for breast cancer
Any patient who is determined to be at increased risk for breast cancer should be offered the following options for early detection and risk reduction, as summarized in Figure 2.
Intensive surveillance
Intensive surveillance generally represents the mainstay for patients at increased lifetime risk of breast cancer. The goal of intensive surveillance is to detect breast cancer at earlier, treatable stages. Mammography represents the standard of care for breast imaging and decreases the risk of breast cancer by 40% for those at average risk with annual use beginning at age 40.15 Breast MRI carries higher sensitivity, with 1 randomized controlled trial of those at high risk for breast cancer due to family history demonstrating that more breast cancers were identified with MRI compared with mammography, were smaller in size, and were less likely to have positive lymph nodes.16 Therefore, annual mammography plus annual supplemental breast MRI with and without contrast is recommended for high-risk patients. It is often clinically recommended that mammogram and MRI be staggered by 6 months, although there are no data suggesting improved cancer detection with this method. This screening is coupled with clinical breast exams every 6 to 12 months at the time of initiation of intensive surveillance, along with ongoing self-breast awareness.
While mammograms represent a rapid and largely accessible study, breast MRI may pose barriers for some patients. Breast MRI may be cost prohibitive for some and may not be available at all radiology centers. For patients with claustrophobia, breast MRI may induce anxiety and cause early termination of the study. Treatment with a one-time dose of a benzodiazepine taken 30 minutes before the MRI may help some patients. Allergies to gadolinium contrast could pose challenges, although some facilities may provide the option of a steroid prep (± diphenhydramine) for gadolinium intolerance. Due to comorbidities (such as morbid obesity, congestive heart failure, or severe pulmonary disease), patients may not be able to tolerate lying prone for extended periods of time. Patients should also be counseled on the higher risk of false positives that could lead to more breast biopsies. For patients who are unable to tolerate or undergo breast MRI, other options such as contrast-enhanced mammography or molecular breast imaging can be explored. Whereas breast ultrasound may also be considered, it does not have comparable sensitivity.
Age of initiation varies based on the reason for increased lifetime breast cancer risk. The recommendations based on high-risk category are outlined in Table 1 and Table 2. There are certain general age considerations regarding imaging. Breast MRI is generally not performed before age 25 (although with some exceptions) and mammogram is generally not performed before age 30. The question of when to discontinue breast screening often arises. While there are no clearly defined guidelines, age 75 is a time at which to consider a risk-benefit discussion. If a patient is overall healthy with a life expectancy of 10 or more years, it is reasonable to continue intensive screening. However, if a patient has medical comorbidities in which life expectancy is not projected to exceed 10 years, shared decision-making should be employed to determine if the patient is capable of continuing screening, and whether they would accept intervention if there were a suspicious finding.
There are certain considerations for high-risk screening during pregnancy and lactation. Breast MRI should be deferred during pregnancy or if the patient is actively trying to conceive. The gadolinium-based contrast used in breast MRI crosses the placenta and can result in fetal exposure and gadolinium retention. Although some small retrospective studies show no adverse effects, animal studies have demonstrated some fetal malformations and demise after supra-clinical doses.17,18 Despite the data being limited and inconclusive, MRI should be avoided due to the potential teratogenicity. Mammography, however, is considered safe in pregnancy and delivers fetal doses of 0.03 mGy, for which the fetal dose is negligible.19 During lactation, both mammogram and breast MRI can be used, although the breast tissue is denser during this time which may limit sensitivity of breast imaging. Pumping or breast/chest feeding prior to imaging is recommended for both modalities to improve sensitivity, specificity, and patient comfort.
Chemoprevention
Tamoxifen is a selective estrogen receptor modulator (SERM) that is shown to reduce breast cancer risk by 49%.20 Whereas the standard dose is 20 mg daily for 5 years, low-dose tamoxifen (5 mg for 3-5 years) can be considered for patients unable to tolerate the higher dose.20,21 (Of note, because 5-mg dosage is not available in the United States, 10 mg every other day could be considered.) Although the benefit of tamoxifen in BRCA1/2 carriers is less well studied, limited data still suggest a possible benefit.22 Tamoxifen can be taken by both pre- and postmenopausal patients starting at age 35, although it should be avoided in those who wish to conceive or are pregnant due to the potential teratogenic effects. Despite the risk-reduction benefits, tamoxifen is associated with vasomotor symptoms, venous thromboembolism (VTE), stroke, cataracts, ovarian cysts, and vaginal discharge. Due to its partial estrogen agonist/antagonist effect on the endometrium, other adverse effects could include amenorrhea, abnormal bleeding patterns, endometrial proliferation including the spectrum of polyps, hyperplasia, invasive carcinoma, and uterine sarcoma (in postmenopausal patients).23
Raloxifene is a SERM that is approved for the treatment and prevention of osteoporosis in postmenopausal AFAB people. It is also used for breast cancer risk reduction after demonstrating effectiveness in the Study of Tamoxifen and Raloxifene (STAR) trial, for which the standard dosage was 60 mg daily for 5 years. Whereas results of the trial showed similar efficacy in decreased invasive breast cancer risk in both tamoxifen and raloxifene groups, raloxifene was not as effective in decreasing the risk of noninvasive breast cancer (ductal carcinoma in situ [DCIS]) or LCIS.24 Long-term data from the STAR trial demonstrates that raloxifene retains 76% of tamoxifen’s effectiveness in reducing the risk of invasive breast cancer in a median follow-up of 81 months.25 Raloxifene also carries a lower risk of VTE and cataracts, as well as a nonsignificant reduction in endometrial cancer. Therefore, while less efficacious regarding breast cancer risk reduction compared with tamoxifen, raloxifene has a more favorable adverse effect profile.
Both aromatase inhibitors (AIs)—exemestane (25 mg daily for 3 years) and anastrozole (1 mg daily for 5 years)—have been shown to reduce risk of breast cancer in large randomized trials by at least 53%.26 While both drugs are approved by the FDA for breast cancer treatment, neither are specifically labeled for preventive use by the FDA. Furthermore, there is little evidence demonstrating the effectiveness of AIs as chemoprevention for those with BRCA1/2 pathogenic variants.6 Adverse effects include vasomotor symptoms, diarrhea, and arthralgias, with no increased risk of VTE or endometrial cancer. Raloxifene and AIs should not be administered to premenopausal patients in this clinical context unless as part of a clinical trial.20
Risk-reducing mastectomy
Risk-reducing mastectomy decreases the risk of breast cancer by at least 90%.27 This option can generally be explored in patients who have a pathogenic/likely pathogenic high-penetrant breast cancer susceptibility gene (as outlined in Table 1), compelling family history, or those with a history of radiation therapy to the breast tissue prior to 30 years of age. There is no established risk benefit in those with pathogenic/likely pathogenic moderate- or low-penetrant genes, or those without a compelling family breast cancer history.20 One prior study suggests a potential mortality benefit to risk-reducing mastectomy in BRCA1/2 pathogenic/likely pathogenic mutation carriers.28 Another prospective analysis shows significant risk reduction in BRCA1/2 patients but that longer follow-up is required to determine true survival benefit.29 Results of one prospective study demonstrated a significantly reduced risk of breast cancer among BRCA1/2 gene mutation carriers (HR, 0.02) and reduced breast cancer-specific mortality (HR, 0.26), with a less than 1% probability of dying from breast cancer 15 years after mastectomy.30 However, much of the historical data on mastectomy in breast cancer survivors do not demonstrate a significant mortality benefit.31,32
Choice of risk-reducing mastectomy is a highly personal decision. For many patients, both the decreased risk of future breast cancer and the discontinuation of intensive surveillance can be primary motivating reasons. For many, the high sensitivity of breast MRI can lead to repeated biopsies (many representing false positives), which can be anxiety provoking and physically painful. For others, witnessing loved ones experience breast cancer could be another motivator to proceed with surgery.
However, there are other considerations. Surgical risk and the possible need for multiple surgeries to achieve aesthetic outcome should be acknowledged. The inability to subsequently breast/chestfeed may lead patients to delay risk-reducing mastectomy until after childbirth. For some, no longer undergoing intensive screening with mammogram and MRI can be stressful due to the very small but not impossible risk of breast cancer following risk-reducing mastectomy (for which the recommended surveillance post mastectomy is continued breast/chest wall awareness and annual clinical exam only). While some may be satisfied with their decision to proceed with mastectomy, others may experience regret.33 There are also multiple studies showing the possible physical and psychological impact of mastectomy on self-esteem, sexuality, and body appearance.34-36
It is important that practitioners share this information with patients during decision-making. Management should be individualized, and patients who wish to explore mastectomy should be referred to a breast surgical oncologist and plastic surgeon for a more in-depth discussion of surgical considerations and reconstruction options.
Conclusion
With the high prevalence of breast cancer nationwide, it is common for ob-gyn practitioners to encounter patients who have a family history of breast cancer or who have been diagnosed with breast cancer themselves. It is important to identify those who may be at increased lifetime risk of breast cancer with interventions that can facilitate early detection or decreased future risk of breast cancer.
References
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