Early-onset breast cancer is breast cancer occurring in women aged 18–45 years. From 2012 to 2016, early-onset breast cancer accounted for 10.3% of all new female breast cancer cases. Furthermore, 5.6% of breast cancer deaths in the United States occur in women younger than 45 years.1 Approximately 15% of breast cancer deaths result from breast cancers initially diagnosed before age 45 years.2 Because of the young age of onset, women with early-onset breast cancer have special survivorship issues, including contraception, management of menopausal symptoms, fertility conservation, and pregnancy. The Centers for Disease Control and Prevention (CDC) sponsored development of educational material on early-onset breast cancer. The educational material geared towards patients, Bring Your Brave, is available on the CDC website (https://www.cdc.gov/cancer/breast/young_women/bringyourbrave/index.htm). The CDC awarded the American College of Obstetricians and Gynecologists (ACOG) a grant to develop accompanying health care provider material, available on line at www.acog.org/eobc.
The American College of Obstetricians and Gynecologists convened an expert panel to identify the best evidence and practices from the literature, existing relevant society guidelines, and available validated specific or generalizable clinical tools. The panel was recruited from the Society for Academic Specialists in General Obstetrics and Gynecology to review and summarize the evidence. Panel members were required to have expertise in evidence review and synthesis. Subspecialty expertise in breast disease was also sought. Several of the panel members had completed subspecialty fellowship training in breast disease. The panel developed 10 separate research questions and used the PICO criteria (P=patient, problem, or population; I=intervention; C=comparison, control, or comparator; O=outcome[s]) to frame the literature review. These questions form the organizing basis for this executive summary.
Experts in literature searches from the ACOG Resource Center searched the Cochrane Library, MEDLINE through Ovid, and PubMed for references not indexed through MEDLINE from January 2010 to January 2019. Literature was organized by level of evidence. Published guidelines were categorized separately from references. A primary reviewer was assigned to each topic to review titles and abstracts, then the entire manuscript when appropriate. Panel members expanded the search criteria when necessary, either increasing the timeframe or broadening the search to other populations, particularly when inadequate evidence was found on the 18–45 years age group. Reference lists from papers found in the search were also reviewed. Internet searches with standard search engines were performed to seek guidelines, recommendations, and tools that might not have been published in peer-reviewed publications. Relevant information was compiled into an evidence summary template. Completed templates were then reviewed by a secondary reviewer and the primary and secondary reviewer worked together on revisions in response to the secondary reviewer's comments.
The American College of Obstetricians and Gynecologists convened the Early-Onset Breast Cancer Evidence Review Conference in Washington, DC, April 1–2, 2019, including the panel members and representatives from stakeholder professional and patient advocacy organizations (Table 1). Panel members presented their reviews to the convened group, which discussed each section. Comments from the discussion were integrated into the review summary by the primary reviewer. The revised summaries were sent to a tertiary reviewer for final review, and final revisions were made by the primary reviewer. The final reviews (see Appendices 1–10) were used to develop the educational material.
EPIDEMIOLOGY, DEMOGRAPHICS, AND SURVIVAL
Breast cancer is the most common form of cancer in women and represents the second leading cause of cancer death in women.3 National Cancer Institute data from 2012 to 2016 indicated that 1.9% of new breast cancer cases and 0.9% of cancer deaths occurred among women aged 20–34 years, and 8.4% of new breast cancer cases and 4.7% of breast cancer deaths occurred among women aged 35–44 years. Black women had the highest death rate at 28.1 per 100,000 persons. Although 5-year relative survival rates were largely similar across age groups, women younger than age 45 years had among the lowest rates, second only to women aged 75 years and older.1,4 See Table 1 in Appendix 1, available online at http://links.lww.com/AOG/B864, for breast cancer incidence rates by age and race. See Table 2 in Appendix 1 (http://links.lww.com/AOG/B864) for breast cancer mortality rates by age and race.
Younger women tend to have more aggressive and biologically unfavorable tumor subtypes than older women and poorer survival in early stage disease (stages I and II) when compared with women older than 40 years. In advanced stages, younger women have lower mortality, likely because of overall general health.5 Although mortality trends have improved in all women, young black women continue to have higher mortality rates than other young women with breast cancer, irrespective of stage or hormone receptors. Annual hazard rates of death of young black women are improving more slowly than other races and ethnicities, suggesting less benefit from advances in treatment. Poorer prognosis in black women is thought to result from multiple factors, including more aggressive tumors, access barriers, and social determinants of health6 (see Appendix 1 [http://links.lww.com/AOG/B864] for complete evidence summary).
GENETIC RISK FACTORS
Cancer genes such as autosomal dominant single gene pathogenic variants account for approximately 5–10% of all cases of breast cancer. The BRCA1 and BRCA2 genes are the most common, representing more than 50% of all genes associated with early-onset breast cancer. Women who carry pathogenic variants have an increased lifetime risk of breast and other cancers and are at higher risk of developing early-onset breast cancer. BRCA pathogenic variants occur more frequently in certain populations (Table 2), most notably in persons of Ashkenazi Jewish descent. The prevalence of BRCA1 and BRCA2 pathogenic variants is 1 in 40 (2.5%) in Ashkenazi Jews, compared with the general population prevalence of 1 in 400–600.7,8 In Ashkenazi Jews, three site-specific founder mutations have been identified (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2), representing more than 90% of the BRCA mutations.
In the United States, African American women have a lower incidence of breast cancer than Caucasian women, but higher breast cancer mortality rates.9 The higher mortality rate seems to be associated with two patterns: proportionally more African American women are diagnosed before 50 years of age (30–40% of all breast cancers in African American women) compared with Caucasian women (approximately 20% of all breast cancer in Caucasian women), and African American women have a twofold higher rate of breast cancers that lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, known as triple-negative cancer.10 Triple-negative tumors are biologically more active, with higher recurrence and mortality rates compared with most other breast cancer phenotypes.10,11 These differences do not appear to be due to higher carriage rates of single gene mutations such as BRCA1 and BRCA2 alone.
Currently, population-based screening for BRCA genes in the absence of other risk factors is not broadly recommended, given their rarity and the uncertain benefit of large-scale testing.12 Because Ashkenazi Jews have a 10-fold increased risk of carrying a founder mutation in BRCA1 or BRCA2, consensus guidelines recommend offering routine testing for the three specific mutations.12,13
The National Comprehensive Cancer Network, ACOG, the U.S. Preventive Services Task Force, the American Society of Breast Surgeons, and the American College of Medical Genetics provide recommendations for risk assessment, referral to genetic counseling or offering of genetic testing based on risk identification, and management of men and women identified with a genetic predisposition for early-onset breast cancer (see Table 2 in Appendix 2, available online at http://links.lww.com/AOG/B865). Common factors considered in risk assessment include the following:
- Personal history of breast, ovarian, tubal, pancreatic, prostate, and other cancers and either early age of onset of these cancers or other cancer-specific factors that increase the likelihood of carrying a pathogenic variant in a breast cancer gene (eg, triple-negative tumors).
- Family history of breast, ovarian, tubal, pancreatic, prostate, and other cancers suggesting an autosomal dominant pattern of inheritance.
In addition to BRCA1 and BRCA2, other important but less common autosomal dominant genes are associated with early-onset breast cancer risk. Panel testing has emerged in the past few years to assess for possible gene alterations that have been implicated in early-onset breast cancer. The specific panels are usually defined by the laboratory offering the testing. A woman identified with a pathogenic variant placing her at increased risk for early-onset breast cancer can undergo increased surveillance to detect breast cancer at earlier stages, risk-reduction surgery, or chemoprophylaxis.13 Depending on the gene, surveillance may start at an earlier age and include mammography, magnetic resonance imaging (MRI), or both. The natural history of early-onset breast cancer is fairly well understood for some genes (eg, BRCA), but there is less complete understanding of the penetrance and age of onset for those with non-BRCA genes associated with breast cancer. Table 3 provides an overview of common genes included in panel testing, along with recommendations for surveillance and risk reduction (see Appendix 2 [http://links.lww.com/AOG/B865] for complete evidence summary).
FAMILY HISTORY OF EARLY-ONSET BREAST CANCER
Assessment of family history is essential when evaluating young women accessing primary care. Understanding a woman's family history of breast cancer can identify individuals at elevated risk for hereditary breast cancer or women who would benefit from increased breast cancer surveillance. The American College of Obstetricians and Gynecologists, the Society of Gynecologic Oncologists, the U.S. Preventive Services Task Force, the National Institute of Health Care Excellence, and the National Comprehensive Cancer Network have published guidelines recommending assessment of family history and screening for patients at increased risk of breast cancer. The American College of Obstetricians and Gynecologists states that screening should include at minimum a personal cancer history and first- and second-degree relatives' cancer history that includes a description of the type of primary cancer, the age of onset, and the lineage of the family member.14 The National Comprehensive Cancer Network clinical guidelines recommend genetic assessment for all patients with first- and second-degree relatives diagnosed with breast cancer younger than age 50 years.13 The U.S. Preventive Services Task Force recommends screening of women who have family members with breast, ovarian, tubal, or peritoneal cancer using one of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing.12 Genetic counselors can help determine which of the many available panels of genetic testing are most appropriate and cost-effective.
Women with deleterious genetic mutations tend to present with breast cancer at an earlier age. However, some studies suggest that women with a positive family history and no known genetic mutation are at increased risk of developing breast cancer and these cancers occur at an earlier age compared with those in the general population who did not have a known mutation.15–17 The Nurses' Health Study and a systematic review and meta-analysis by Pharoah et al identified consistent findings.18,19 In the Nurses' Health Study, women with a family member diagnosed with breast cancer before age 50 years had an increased risk for breast cancer compared with women of the same age who had family members diagnosed at older ages. Compared with women with no family history, those whose mother was diagnosed before age 50 years had an adjusted relative risk (RR) of 1.69 (95% CI 1.39–2.05), and those whose mother was diagnosed at 50 or older had an RR of 1.37 (95% CI 1.22–1.53).18 Pharaoh et al found that a history of breast cancer in at least one first-degree relative resulted in RR estimates ranging from 1.2 to 8.8, with most studies showing RRs between 2 and 3.19 The pooled risk estimate for having two affected first-degree relatives was 3.6 (95% CI 2.5–5.0).19 Genetic mutations were not factored out in many of the older studies.
There are limited data on outcomes for women with an elevated risk of breast cancer by family history without an established familial genetic mutation. National guidelines consistently emphasize the importance of gathering a thorough family history of breast cancer. However, these guidelines are based on limited data estimating lifetime and age-based breast cancer risk for women in families that do not have identified genetic mutation carriers. Many of the current guidelines are based on expert opinion and studies of family history that were published before the availability of genetic testing for mutations such as BRCA1 and BRCA2.
There is general consensus that women with a lifetime risk of breast cancer greater than 20%, as determined by any model, are at high risk. Multiple validated models can be used to determine the probability of a genetic mutation, which increases the risk of breast cancer. There is no consensus and there are no data to support the recommendation of one model over another.20 Currently, the National Comprehensive Cancer Network recommends that women with an estimated lifetime risk of breast cancer of 20% or higher, determined by models largely based on family history (eg, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, Claus, BRCAPRO, or Tyrer-Cuzick) should be offered annual mammography screening starting at age 30 years and annual breast screening by MRI starting at age 25 years13,21 (see Appendix 3, available online at http://links.lww.com/AOG/B866, for complete evidence summary). This is in contrast to screening recommendations for average risk women, which all recommend screening with mammography alone, starting at age 40–50 years, depending on the source.14
UNDERSTANDING GENETIC COUNSELING AND TESTING
There are at least moderate-quality data that risk assessment, referral for genetic counseling, and genetic testing provide net benefit in women at high risk for early-onset breast cancer. These steps can form the basis for intensive surveillance for early detection or use of risk-reduction methods that have proven effective in detecting breast cancer at an earlier stage and decreasing mortality rates.12
The National Institutes of Health maintains a periodically updated list of online resources designed to educate and assist health care providers on various topics ranging from basic genetics, understanding risk assessment, criteria for referral to genetic counseling, and interpretation of genetic test results.22 Other national societies have created genetics “toolkits” or published guidance to educate health care providers on basic cancer genetics, risk assessment, and referral recommendations23,24 (see Table 1 in Appendix 4, available online at http://links.lww.com/AOG/B867, for a list of useful websites).
Providers can also learn about these topics through other mechanisms, such as continuing medical education and online learning. The depth and detail of the material covered range from superficial (eg, short “expert” videos) to online courses that take place over several months. Very few online courses provide a validated assessment of competency or certification. The content of specific training and assessment of competency for physicians who counsel patients about genetic testing have not been standardized.
The U.S. Preventive Services Task Force concluded that health care providers should assess risk based on personal or family history and refer women who screen positive to cancer genetic counselors.12 A number of validated tools exist to determine who should be referred for genetic testing,25–29 and several professional specialty societies have developed lists of indications for referral and testing.13,14,30 These tools are specifically designed to evaluate who should be referred for BRCA testing; however, because BRCA carriers represent the greatest proportion of women at genetic risk for early-onset breast cancer, these tools are reasonable proxies for genetic screening for early-onset breast cancer. These tools have been validated in some populations (non-Hispanic white women), and it is not known how the tools perform in nonwhite populations. It remains unclear how frequently these tools are used in practice by physicians. Evaluation suggests that the tools miss a substantial proportion of carriers.31,32 Interpretation of genetic test results can be complex and usually requires a qualified individual who has specific training in cancer genetics.12,33,34
A number of tools and calculators are used to estimate lifetime invasive breast cancer risk, but not necessarily the predicted age of onset (See Table 2 in Appendix 4, http://links.lww.com/AOG/B867, for a comparison of four commonly used risk-assessment models: Tyrer-Cuzick, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, Claus, and the modified Gail model, also called the Breast Cancer Risk Assessment Tool).
Numerous national consensus guidelines and recommendations have been developed to assist health care providers in communicating with patients about referral to genetic counseling or testing for early-onset breast cancer genes or both.13,14,30 Some specialty societies have produced separate guidance specifically addressing both the interpretation of genetic test results and how to communicate these results to patients.33 Some guidelines are frequently updated,13 whereas others are periodically revised (ie, every few years),12,14,30 resulting in guidance that may differ, causing confusion among health care providers and patients. All current guidelines recommend that women should be screened for personal and family history of breast and other related cancers and referred for genetic counseling or testing or both as appropriate. In addition, all guidelines recommend that determination for testing and pretest and posttest counseling should be performed by individuals with appropriate training. However, there is a shortage of genetic counselors in the United States, which has been identified as a barrier to effective counseling35,36 (see Appendix 4 [http://links.lww.com/AOG/B867] for complete evidence summary).
DENSE BREASTS AND THE RISK OF EARLY-ONSET BREAST CANCER
Breast tissue is comprised of fibroglandular tissue and fat. The fibroglandular tissue is a mixture of fibrous stroma and ductal epithelium and appears denser or brighter on mammography because the X-rays are not able to penetrate at the same rate as fatty tissue. The Breast Imaging-Reporting and Data System for mammography developed by the American College of Radiology includes a subjective assessment of how much fibroglandular tissue is present (see Table 1 in Appendix 5, available online at http://links.lww.com/AOG/B868). As women age, breast tissue typically becomes less dense. Most of the data about breast density and cancer risk come from women older than age 50 years. Dense breasts are present in the majority of younger women.
A systematic review of risk for breast cancer in women aged 40–49 years reported that extremely dense breasts were associated with an increased risk of breast cancer when compared with breasts with scattered fibroglandular densities (RR 2.04, 95% CI 1.84–2.26).37 In a more recent case-control study of 213 Korean women with breast cancer, women who had the highest breast density, described as 50% density or higher, after adjusting for multiple variable, had an adjusted odds ratio of 2.98 (95% CI 0.99–9.03) for breast cancer. The wide CIs in this nonsignificant finding is likely related to the small numbers of included women and future studies should be monitored. Median age in the study was 51.5 years, with 45% of cancers diagnosed before age 50 years.38 Older studies are harder to interpret because they used many different ways of characterizing breast density, but in general, when comparing the most dense with the least dense group, there appears to be an increased risk of breast cancer, with RRs as high as 4.64 (95% CI 3.64–5.91) reported.39 As the majority of premenopausal women have dense breasts, it is not clear that RRs estimated from comparisons of extremes of breast density categories are appropriate measures of risk in this age group.
Dense breasts decrease the sensitivity of mammography because dense breast tissue appears radiopaque, similar to breast cancers, decreasing visual contrast (“masking”). In women with extremely dense breasts, mammography has 62% sensitivity for detection of breast cancer, compared with 88% sensitivity for women with fatty breasts.40 One way to assess delay in diagnosis is to determine the rate of interval cancers, those cancers found between recommended screening intervals after a normal mammogram. No studies evaluating masking due to breast density have exclusively evaluated women with early-onset breast cancer. Most studies included large proportions of women older than age 50 years, though women aged 40–49 years were included. More recent evidence suggests that dense breasts appear to be associated with at least a twofold increased risk of interval cancers as well as a worse prognosis, including larger tumor size and more node-positive disease.41–43
Studies of adjunctive screening of women with dense breasts with ultrasonography and MRI generally noted higher cancer detection rates and earlier diagnoses, but also showed increase in biopsy for benign lesions and increased healthcare costs, and no study showed improvement in mortality (see Appendix 5 [http://links.lww.com/AOG/B868] for complete evidence summary). The majority of women under age 46 years have dense breasts, so any recommendations for additional screening in this age group would require additional testing in a large number of women whose baseline risk is low.
Most organizations, including ACOG and the U.S. Preventive Services Task Force, do not recommend additional screening in women younger than age 46 years with a normal mammogram and dense breasts. The Society of Breast Imaging expresses concern for a delay in diagnosis and later stage at diagnosis of noncalcified breast cancers because of dense breast tissue and suggests that ultrasonography may be of benefit, provided the woman is willing to accept an increased risk of false-positive results.44 The National Comprehensive Cancer Network recommends that women with mammographically dense breast tissue (heterogeneously or extremely dense tissue) be counseled about the risks and benefits of supplemental screening.45 Neither of these organizations specifically address dense breasts in younger women.
Mandatory breast density reporting has been enacted as legislation in an increasing number of states. Many patients receive letters notifying them of their breast density, and interpretation of these letters can be challenging for patients and health care providers. In early 2019, Congress authorized the U.S. Food and Drug Administration to amend the Mammography Quality Standards Act of 1992 to include mandatory breast density reporting at the federal level. The public comment period for the proposed changes to the legislation ended in June 2019, and final regulations should be forthcoming. The American College of Obstetricians and Gynecologists recommends that health care providers comply with state laws that require disclosure of breast density in mammogram reports.46
Younger women with dense breasts and no other risk factors can be counseled that dense breasts are very common in this age group, and supplemental screening methods are available. However, they are not specifically recommended, have significant risk of false positives, and have not been shown to change outcome. When mammographic density in combination with other risk factors places the woman at above-average risk, additional screening with ultrasonography may be warranted and a shared decision-making model can be applied. Some breast cancer risk calculators integrate breast density and can be used to assess overall risk in these women (see Appendix 5 [http://links.lww.com/AOG/B868] for complete evidence summary).
EFFECT OF HEALTH HISTORY ON EARLY-ONSET BREAST CANCER
History of Proliferative Breast Disease
Many proliferative breast diseases increase the risk of breast cancer, but the effect on early-onset breast cancer risk is unknown. Atypical ductal hyperplasia carries a more than 20% risk of ductal carcinoma in situ (DCIS) or invasive malignancy at the time of diagnosis, so it is typically excised.47 Both atypical ductal hyperplasia and atypical lobular hyperplasia are associated with a fourfold increased lifetime risk of breast cancer.47–49 When atypical lobular hyperplasia is an incidental finding and there is concordance between radiologic and pathologic findings regarding the targeted biopsied lesion, it is less likely to be associated with a concurrent malignancy, so close monitoring is usually appropriate.48 Lobular carcinoma in situ is not considered a preinvasive malignancy like DCIS, but does significantly increase the lifetime risk of breast cancer (RR 6.9–11, absolute risk 7.1% over 10 years).50,51 Pleomorphic lobular carcinoma in situ may increase that risk even further.52 Radial scars are characterized microscopically by a fibroelastic core with radiating ducts and lobules. Radial scars and complex sclerosing lesions carry an 8–15% risk of DCIS or invasive malignancy at the time of excision.47,53–57 Radial scars are usually managed by excisional biopsy.45
There are limited data with which to determine the optimal screening strategy after atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ. Breast MRI may improve breast cancer detection over mammography alone, but it is associated with more biopsies in this population.58 The National Comprehensive Cancer Network is the only professional society with screening recommendations for those who have had atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ45:
- Annual mammography (not before age 30 years). Consider tomosynthesis.
- Consider annual breast MRI (not before age 25 years).
- Clinical breast examinations every 6–12 months.
- Engage in breast self-awareness (women should be familiar with their breasts and report changes to their health care provider promptly).
Past or Present Use of Hormonal Contraception
There have been conflicting data regarding the effect of hormonal contraception on breast cancer risk. A large meta-analysis in 1996 revealed a small increased risk of breast cancer among women with current or recent oral contraceptive use (RR 1.07, SD 0.02, P<.001).59 Similar findings were noted in a large cohort study in 2017 (RR 1.20, 95% CI 1.14–1.26).60 The absolute risk was quite small (one additional breast cancer diagnosis for every 7,690 women using hormonal contraception each year).60 In both studies, breast cancer risk returned to baseline 5–10 years after discontinuing hormonal contraception.59,60 Most studies do not suggest an increased risk of breast cancer among women using a levonorgestrel intrauterine system (IUS) or depo-medroxyprogesterone injections.60–64 There are limited data regarding the etonogestrel implant, but no study to date has demonstrated an increased breast cancer risk.63
The risks of hormonal contraception must be weighed against the health, social, and economic consequences of unplanned pregnancy, as well as the many noncontraceptive benefits of hormonal contraception.65 The maternal mortality rate in the United States in 2015 was 26.4 deaths per 100,000 pregnancies, which is comparable with the rate of excess breast cancer diagnoses (13 [95% CI 10–16]/100,000 person years) related to hormonal contraception suggested by the 2017 cohort study.60,66 Hormonal contraception, particularly oral contraceptives, significantly decreases the risk of ovarian and endometrial cancers.67,68 There are no screening guidelines that specifically address exposure to hormonal contraception, so routine breast cancer screening is recommended in the absence of other risk factors for early-onset breast cancer.
Past or Present Use of Fertility Treatments
Many fertility treatments cause an increase in circulating estrogen and progesterone levels, which theoretically could increase future breast cancer risk.69 Most studies have demonstrated no change or a decreased risk of breast cancer after fertility treatments.59 Few studies specifically evaluated the risk of early-onset breast cancer. Very limited data suggest an increased risk of breast cancer among specific populations, including women exposed to many high-dose cycles of clomiphene citrate and women undergoing in vitro fertilization before age 24 years.70,71 The American Society for Reproductive Medicine states that there is “fair evidence that fertility drugs are not associated with an increased risk of breast cancer (Grade B).”69 No screening guidelines specifically address fertility treatment exposure, so routine breast cancer screening is recommended in the absence of other risk factors for early-onset breast cancer.
History of Radiation Exposure
Chest radiation therapy before age 30 years is a well-established risk factor for early-onset breast cancer.45,72 Treatments of concern include mantle radiation for Hodgkin's lymphoma and moderate-dose chest radiation therapy for non-Hodgkin's lymphoma, leukemia, bone malignancies, or pediatric solid tumors (eg, Wilms tumor, neuroblastoma, and soft-tissue sarcoma). The cumulative incidence of invasive breast cancer in these patients is 13–20% by age 40–45 years, similar to that seen among BRCA1 or BRCA2 mutation carriers.73–75 Risk is greatest among women treated with 40 Gy or more, but all women treated with 20 Gy or more are at increased risk for early-onset breast cancer.73,74,76 This increased risk is evident 8–10 years after completion of radiation therapy and does not plateau at any point after treatment.73–75,77
Early initiation of breast cancer screening is effective for reducing stage at diagnosis in this population.73 Both mammography and breast MRI are effective screening studies after chest radiation therapy, but mammography has higher specificity.74,77–80 Multiple professional organizations have published screening guidelines for women with a history of chest radiation therapy (Table 4). There are limited data to suggest superiority of one screening protocol over others. Shared decision making, including the discussion of risks of false positives and negatives, is recommended when deciding on a screening strategy.
Prior Breast or Ovarian Cancer
Breast cancer survivors remain at risk for a second breast cancer, but the risk for a second early-onset breast cancer among young breast cancer survivors is unknown. Among survivors of any age without a known cancer gene mutation, the risk of a second breast cancer is approximately 3% and 7% at 10 and 15 years after diagnosis, respectively.81 There are no data regarding risk of early-onset breast cancer in women with ovarian cancer in childhood, adolescence, or early adulthood.
After breast cancer treatment, survivors require clinical and imaging follow-up to assess for recurrence and second malignancies. Both the National Comprehensive Cancer Network and the European Society of Breast Cancer Specialists recommend annual mammograms starting 6–12 months after completion of treatment.52,82 Breast MRI should be considered in patients at high risk for a second cancer (eg, BRCA1 or BRCA2 mutation carriers)52,82 (see Appendix 6 [http://links.lww.com/AOG/B869] for complete evidence summary).
EFFECT OF HEALTH DISPARITIES ON EARLY-ONSET BREAST CANCER
Objective measures of health disparities are well established, and health disparity populations83 exhibit differences in rates of mammography screening, age at breast cancer diagnosis, stage at time of diagnosis, and rates of cancer treatment. African American women are significantly more likely to experience higher mortality from breast cancer compared with white women (Fig. 1).84 Other health disparity groups, such as American Indians and Alaska Natives, Asians, Hispanics, and Native Hawaiians and other Pacific Islanders, are affected but often inadequately studied, as are sexual and gender minority persons.
The increased incidence of more-aggressive tumor types only partly explains the survival gap for black women.6,85 Social determinants of health, such as systemic racism, poverty, and the environment, greatly affect cancer screening rates and outcomes.86 Health literacy, childcare concerns, financial difficulties, and transportation affect the likelihood of receiving preventive health services such as mammography.87,88
Geography is a particularly important factor. Rural women are more likely to live in poor counties, with greater barriers to accessing primary care.89 Poverty or lack of a regular primary care provider who recommends mammography is highly predictive of not being screened.90,91 In general, poverty status correlates with more advanced stage at diagnosis, receiving less aggressive treatment, and higher risk of all-cause mortality.92
Physical proximity to urban centers is not a panacea. In 2014, African American women with breast cancer in Georgia living in isolated rural areas were 45% more likely to die than white women, whereas African American women living in urban areas were 24% more likely to die than white women.92
Provider-level bias and discrimination in breast cancer care treatment exist. For example, when genetic testing is indicated, African American women are less likely to be referred for genetic testing for pathogenic variants than white women.93,94 African American women are also less likely to receive any type of lymph node surgery for axillary staging overall.95
Women of lower socioeconomic status are adversely affected by lack of health insurance coverage.89 Cost affects primary care utilization and is a factor in patient decision making regarding mammography.96 By one estimate, up to 37% of the mortality difference in breast cancer among black compared with white women can be attributed to disparities in health insurance.97
Intensive focus on modifiable system factors would be beneficial, such as expanding insurance coverage, addressing transportation barriers to appointments, and increasing access to primary care. The use of patient navigators and advocates, translator services, and tracking systems across different health systems could reduce the effect of limited health literacy, mistrust, and negative prior experiences with health care.98 General practitioners who provide counseling and recommendations on health care preventive services can improve the rates of mammography for underscreened groups, such as recent immigrants.99
Bias by health care providers and health systems leading to disparate rates of services offered to patients should be corrected, and to further decrease differences in mortality, emphasis should be placed on ensuring equal treatment after diagnosis.100 Groups such as the Black Women's Health Imperative are at the forefront of working to reduce these disparities, and can serve as a resource for both patients and health care providers. Efforts to promote quality improvement and adherence to national guidelines are important.
Breast cancer incidence is higher in younger African American women and other ethnic groups. In contrast, among postmenopausal women, breast cancer incidence is highest in white women. The proportion of breast cancer diagnoses by age for nonwhite patients with breast cancer peaks in the late 40s, whereas diagnosis for white patients peaks in their 60s; this phenomenon is known as the crossover effect (Fig. 2).101
Most breast cancer research has been conducted on white women. Major professional society screening guidelines developed using this body of evidence might not be adequate for nonwhite populations. No national guidelines address this concern, but in 2018, the American College of Radiology commented that women at high risk, particularly black women and those of Ashkenazi Jewish descent, should be evaluated early in life to discuss potential benefit from supplemental screening.102 Consideration should be given to encouraging screening before age 50 years, especially for African American women (see Appendix 7, available online at http://links.lww.com/AOG/B870, for complete evidence summary).
Although there are no validated tools or best practices specific to identifying risk factors or estimating the risk of early-onset breast cancer, there are multiple tools that may be helpful to identify short-term risk in younger women. Current best practices aim to identify women at risk of familial cancer syndromes on the basis of family history to determine who may benefit from genetic testing.
The three most widely used tools for predicting BRCA gene carrier probability are BRCAPRO, BOADICEA (the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), and Penn II.103 BRCAPRO and BOADICEA also provide cancer risk estimates in addition to estimates of likelihood of genetic mutations. These models might be useful to direct women to genetic testing and counseling who are at increased risk of genetic mutations that pose a high risk of early-onset disease. BRCAPRO is a validated statistical program to estimate individual carrier probabilities on the basis of family history. It is not specific to any age range and does not directly estimate the risk of early-onset cancer, but rather the risk of carrying a BRCA1 or BRCA2 mutation. BOADICEA likewise was developed using population data from families in the United Kingdom to create a model based on family history and requires detailed family pedigree. The Penn II model uses clinical questions based on family history to reach a carrier probability, but does not calculate cancer risks. Once a BRCA1 or BRCA2 mutation is identified the Stanford risk-assessment tool for BRCA carriers may aid in decision making for preventive measures based as it provides age-related risk of cancer and compares multiple intervention strategies.104
Additional widely validated models to assess cancer risk include the Tyrer-Cuzick, modified Gail, and Breast Cancer Surveillance Consortium models. None specifically assess risk of early-onset or premenopausal breast cancer, although most provide estimated 5- or 10-year cancer risk as well as lifetime risk of breast cancer. No models used validation cohorts with patients younger than 20 years. The modified Gail model has been validated in women 35 years and older to assess 5-year invasive cancer risk.105 The Tyrer-Cuzick model has been studied in women older than age 20 years to assess 10-year cancer risk and has been shown to perform better in women with a family history of breast cancer.106 The Breast Cancer Surveillance Consortium risk calculator is validated for women older than age 35 years to provide 5- and 10-year risks and includes family history factors as well as breast density in the calculation.107 There are limited data on the use of these models to specifically address cancer risk reduction in young women.
Family history should be collected and updated periodically to identify patients who may be at increased risk of predisposing genetic mutations. Tools that may aid in collecting family history are the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, and FHS-7.12,13 There is no evidence to recommend one method over another. Those who screen positive or who meet published guidelines for qualifying family histories should be referred for genetic counseling and testing.13
There are no guidelines or best practices for identifying risk factors or for the use of tools to estimate risk specific to early-onset breast cancer. However, multiple organizations provide guidance for assessing risk of breast cancer in general.
The U.S. Preventive Services Task Force advocates use of brief familial assessment tools to assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1 or BRCA2 gene mutations. The U.S. Preventive Services Task Force reviewed six tools that were adequately validated, but found insufficient evidence to recommend one tool over another.12 Other organizations likewise do not advocate for use of any specific tool.14,108–111
National Comprehensive Cancer Network guidelines on breast cancer risk reduction recommend assessing family history and referring to genetic counseling when appropriate as well as use of the modified Gail or Tyrer-Cuzick model to assess risk among women older than age 34 years.112 The National Comprehensive Cancer Network has also established criteria for genetic testing for high-risk mutations.13 These guidelines recommend assessment no earlier than age 18 years based on family history. No specific tool is recommended, and the recommendations are not specific to reducing the risk of early-onset cancer (see Appendix 8, available online at http://links.lww.com/AOG/B871, for complete evidence summary).
Shared decision making is a key component of patient-centered health care, particularly because there is often more than one option for screening. Although patient decision aids and risk calculators help enumerate risk and are adjuncts to shared decision making, the process is more involved.113 Using narrative risk communication strategies,114 communicating absolute rather than RR,115 and managing framing bias116 are important considerations in communicating risk of early-onset breast cancer.
Many decision aids and calculators are directed to specific populations (eg, subtypes or age ranges), but none are specific for communicating risk of early-onset breast cancer. Several tools may be useful:
- Families Sharing Health Assessment and Risk Evaluation (Families SHARE, a product of the National Institutes of Health's National Human Genome Research Institute) is a decision aid that is useful for shared decision making for individuals of varied age groups and can be used within and outside of an office setting.117
- Breast Screening Decisions (developed collaboratively by the Weill Cornell Medical College and Sloan Kettering Cancer Center) is directed to women aged 40–49 years.118
- Breast Cancer Screening (PDQ) has both a patient and health care provider tool, which can be used as companion documents.119
- The University of Wisconsin School of Public Health's Health Decision tool was originally created and tested at the University of California, San Francisco.120–122 It includes a breast cancer screening module that can be integrated into some electronic health record systems.
Studies of decision aids for breast cancer prevention in BRCA1 and BRCA2 mutation carriers demonstrated that cancer-related distress was reduced among those who used a decision aid compared with those who did not. Decisional conflict did not change with use of the aid.123,124 The following tools may be useful for women at high risk of hereditary breast and ovarian cancer:
- The Cancer Risk Education Intervention Tool is a web-based (noninteractive) adjunctive tool for use in low socioeconomic settings and among ethnically diverse women.125
- The Stanford Shared Decision Making Tool for women with BRCA1 or BRCA2 was developed to guide decision making about screening and treatment based on calculated risk.104
For minority groups, the Health Belief Model was used as a construct for developing a school-based classroom and online tool that increased knowledge about breast cancer risk among African American women aged 20–39 years.126
Because we anticipated that a literature search would find limited information specific to communicating risk of early-onset breast cancer, we deliberately conducted a broad search encompassing other aspects of breast cancer and other cancers and health conditions. Patient decision aids for colorectal cancer screening have been shown to improve knowledge and interest in screening compared with no information, but are no better than general colorectal cancer screening information.127 Healthwise Knowledge Base is an evidence-based interactive platform to inform patients about mammogram initiation that includes a shared decision making breast cancer screening tool for women aged 40–50 years (see Appendix 9, available online at http://links.lww.com/AOG/B872), as well as a tool for assisting in decisions about BRCA testing. The user's concerns, desires, and fears are weighed in response to evidence provided about the risks and benefits of screening, and a score indicating preferences and readiness for screening is calculated.128 A decision analytic model was used to improve estimation of benefits and risks for patients undergoing thrombolysis, with the added benefit that this computerized decision aid can be embedded in an electronic health record.129 This approach could be translated to support integration of the Gail or Families SHARE model, for example, into a primary care or a woman's personal electronic health record.
There are no current major professional society or health services guidelines about communicating the risk for early-onset breast cancer. Shared decision making has been endorsed by ACOG for deciding the age at which to initiate breast cancer screening.109 The American College of Obstetricians and Gynecologists acknowledges the importance of screening for social determinants of health in all patients, as these factors may influence decision making and communication.86
U.S. Preventive Services Task Force guidelines do not address early-onset breast cancer risk, except to state that the recommended screening guidelines do not apply to women with prior chest radiation or known underlying genetic mutations such as BRCA1 or BRCA2. National Institute of Health Care Excellence guidelines recommend providing information and support for decision making, but do not recommend any specific tool or decision aid. National Institute of Health Care Excellence guidelines regarding familial breast cancer also recommend the use of shared decision making, materials, and decision aids as well as standardizing the discussion involved in counseling patients and families at risk for familial breast cancers108 (see Appendix 9 [http://links.lww.com/AOG/B872] for complete evidence summary).
There is limited evidence for risk modification specific to the outcome of early-onset breast cancer. The evidence for risk reduction among younger women is most robust for BRCA mutation carriers.
Risk-reducing bilateral mastectomy should be considered in women with a genetic mutation conferring a high risk of breast cancer.112 There are no guidelines or studies addressing the age at which risk-reducing mastectomies should be undertaken. Age-related risk estimation tables may be useful to counsel women with BRCA mutations on the timing of prophylactic procedures.130 There is no evidence supporting risk-reducing mastectomies for women with low-risk genes or whose risk is based on nonhereditary factors alone.
We found no evidence to support oophorectomy for the purposes of preventing early-onset breast cancer. The use of bilateral salpingo-oophorectomy to prevent lifetime risk of breast and ovarian cancer has been estimated to be as high as 50% for BRCA1 and BRCA2 carriers, although more recent publications question these results.131
There are no guidelines or studies about the use of risk-reducing agents expressly for the purpose of reducing the risk of early-onset breast cancer. Tamoxifen is the only agent indicated for use in premenopausal women at increased risk of breast cancer, and is recommended for women with 5-year risk of 1.7% or higher. The risks and benefits in women younger than 35 years is not known.112 Most large trials of chemoprevention were performed in older women who had completed menopause. The National Surgical Adjuvant Breast and Bowel Project P-1 trial found a 44% decrease in cancer among women younger than 50 years treated with tamoxifen for chemoprevention.132
There are limited data regarding the magnitude of risk reduction with the use of tamoxifen for BRCA1 and BRCA2 mutation carriers or women with prior thoracic radiation. However, cohort data suggest there might be a benefit for BRCA2 carriers; the National Surgical Adjuvant Breast and Bowel Project P-1 study showed a nonsignificant 62% decrease relative to placebo (RR 0.38, 95% CI 0.06–1.56).112,132 Although other European studies have shown mixed effects, this overall reduction is supported by a systemic review of randomized controlled prevention trials across all studied populations showing a 44% decrease in the risk of breast cancer for women younger than 50 (hazard ratio 0.66, 95% CI 0.52–0.85).133
There is limited evidence for the modification of health behaviors to reduce the risk of early-onset breast cancer. A recent meta-analysis assessed numerous risk factors for BRCA carriers.134 Later age at the time of first live birth was associated with a decreased lifetime risk of breast cancer for BRCA1 carriers (effect size for women aged 30 years or older=0.65 vs women aged younger than 30 years, 95% CI 0.42–0.99). There was no effect of age at first birth for BRCA2 carriers.
Breastfeeding also appeared protective for lifetime risk of cancer for BRCA1 carriers, although meta-analysis could not be performed because of study heterogeneity. Reported effects based on case–control studies showed a 32–50% decreased risk if breastfeeding continued for more than 1 year compared with never breastfeeding. Additionally, three or more live births also appeared to have a protective effect for BRCA1 carriers (effect size=0.57, 95% CI 0.39–0.85) as well as BRCA2 carriers (effect size=0.52, 95% CI 0.30–0.86), compared with nulliparity. For BRCA1 or BRCA2 carriers, there were no significant or reliably duplicated results of effects of alcohol consumption, oral contraceptive use, or smoking.134,135 In review articles on risk factors for women at average risk, there was no reliable effect seen for alcohol consumption or modification of other dietary factors for premenopausal breast cancer.136,137
There are no guidelines specific to the prevention of early-onset breast cancer. Those that may be considered relevant address lifetime breast cancer risk reduction, largely among women older than age 35 years. The National Comprehensive Cancer Network recommends tamoxifen, 20 mg/d, for up to 5 years for women aged 35 years and older with a high 5-year risk of breast cancer, defined as a 5-year risk of 1.7% or higher using the Gail model, or prior lobular carcinoma in situ.112 U.S. Preventive Services Task Force guidelines for reducing the risk of primary cancer state that women at increased risk should engage in shared decision making regarding chemoprevention.
The National Comprehensive Cancer Network advises a healthy lifestyle for reduction of risk for breast cancer for all women, though the magnitude of this reduction and whether it reduces the risk of early-onset breast cancer or premenopausal breast cancer is unknown.97 Elements of healthy lifestyle advised by the National Comprehensive Cancer Network include limited alcohol consumption, vigorous physical activity, maintaining a healthy weight, and breastfeeding (see Appendix 10, available online at http://links.lww.com/AOG/B873, for complete evidence summary).
Breast self-examination is no longer part of major society guidelines for average risk women given the high number of false positives and absence of supportive evidence for benefit.2,12,109 Our literature review found no evidence for its use in women at risk for early-onset breast cancer, but women should be counseled to be familiar with their breasts and promptly report changes to their breasts to their health care provider.
SPECIAL CONSIDERATIONS FOR EARLY-ONSET BREAST CANCER
Survivorship in women with early-onset breast cancer is a critical component to initial evaluation and treatment as well as ongoing care. Chemotherapy is often and variably responsible for chemotherapy-induced amenorrhea, menopause, or true ovarian failure, resulting in consequences such as infertility or subfertility, bone loss, and increased cardiac risk as well as menopausal symptoms, which can have a significant effect on quality of life. Age at diagnosis, receptor status, and treatment regimen are important considerations in managing ongoing care for women affected by early-onset breast cancer.
The National Comprehensive Cancer Network and the American Society of Clinical Oncology have produced comprehensive guidelines for survivorship.138,139 The American Cancer Society and the American Society of Clinical Oncology jointly created survivorship guidelines after systematic review in 2015.140 Although not specific for early-onset breast cancer, ACOG provides resources about managing gynecologic issues in women with breast cancer, many of which are applicable for women with early-onset breast cancer.141 The American College of Obstetricians and Gynecologists recommendations include use of nonhormonal interventions for symptomatic patients, because data are conflicting about the deleterious effects of hormone therapy on recurrence and overall survival rates.141 Although not specific to women with early-onset breast cancer, the North American Menopause Society and the International Society on Women's Sexual Health have co-authored recommendations regarding the treatment of genitourinary syndrome of menopause in women with breast cancer.142
Management of women who have or have had early-onset breast cancer should include attention to the issues of contraception, fertility, and pregnancy:
- Effective contraception is often overlooked as part of the treatment regimen for patients with early-onset breast cancer, and family planning consultation should be considered.143 The copper IUS is the preferred contraceptive method for women with breast cancer, although the levonorgestrel IUS can safely be used in combination with tamoxifen.144,145 The preferred method of emergency contraception is the copper-containing IUS, although progestin regimens can also be used.146
- All women with early-onset breast cancer should have fertility preservation counseling.147 Oocyte and embryo cryopreservation is considered first-line treatment.147 Treatment with gonadotropin-releasing hormone agonist during chemotherapy should be considered when ovarian oocyte and embryo cryopreservation is not possible; it affords some protection to the ovary and is associated with increased fertility rates when compared with no treatment.148 Aromatase inhibitors and gonadotropin-releasing hormone agonist triggers should be used when employing controlled ovarian stimulation for women undergoing fertility treatments with a history of early-onset breast cancer to lower estrogen levels.149 Prenatal genetic diagnosis should be considered in women with BRCA mutations or other documented germ line mutations undergoing in vitro fertilization procedures. Ovarian tissue harvesting offers a promising alternative to cryopreservation therapies.149
- Pregnancy after a diagnosis of early-onset breast cancer has not been shown to increase the risk of recurrence.150 When considering timing, pregnancy occurring at least 10 months after breast cancer diagnosis was not found to be harmful and may even contribute to survivorship.151 When breast cancer is diagnosed in pregnancy, chemotherapy can be safely instituted in the second and third trimesters.150
See Appendix 1 (http://links.lww.com/AOG/B864) for complete evidence summary.
RESEARCH GAPS AND OPPORTUNITIES
The evidence review and subsequent stakeholder discussion revealed the following research gaps and opportunities for early-onset breast cancer (see Appendix 11, available online at http://links.lww.com/AOG/B874, for a more in-depth assessment):
- Develop risk-assessment tools specific to early-onset breast cancer
- Optimize integration of risk assessment into primary care visits and electronic health records
- Obtain data on and determine optimal screening for nonwhite populations
- Determine risks associated with dense breasts in young women
- Determine appropriate adjunctive screening for young women with dense breasts
- Validate epidemiologic data largely based on European populations in U.S. women, including underrepresented subgroups
- Develop strategies to eliminate implicit bias among health care providers and medical systems
- Expand screening, genetic counseling, and testing among high-risk women
- Develop and validate tools for communicating early-onset breast cancer risk to patients
- Develop and validate training techniques for health care providers to screen, test, and initiate risk-reducing strategies in women at risk for early-onset breast cancer
- Determine safety and optimal timing of pregnancy after treatment for early-onset breast cancer
- Optimize fertility preservation in women undergoing treatment for early-onset breast cancer
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