Genetic Risk Assessments in Individuals at High Risk for Inherited Breast Cancer in the Breast Oncology Care Setting

Abstract

Background

It has become increasingly common to consider BRCA mutation status when determining optimal cancer risk management and treatment options in order to improve patient outcomes. Knowledge about the risk for hereditary cancer at or as close as possible to the time of diagnosis allows patients access to the most risk reduction options available.

Methods

This paper illustrates the role of genetic risk assessment for hereditary breast cancer, using hereditary breast and ovarian cancer (HBOC) syndrome as a model due to germline mutations in the BRCA1 and BRCA2. Specifically, the value of genetic counseling and testing for HBOC across the cancer prevention and control continuum is outlined as it pertains to breast cancer.

Results

In recognition of the importance of risk assessment for hereditary breast cancer, leading health professional organizations have developed specific guidelines and recommendations to providers for identification of women at increased risk for carrying a BRCA mutation.

Conclusions

Institutional efforts specific to genetic counseling and testing have resulted in the implementation of a model driven by physician recommendation as a referral system for high-risk breast cancer patients. Establishing an infrastructure to support research, education, and outreach initiatives focused on BRCA genetic counseling and testing will provide information that can improve the delivery of cancer genetics services.

Overview of Genetic Counseling and Testing Using BRCA as a Model

The majority of inherited breast cancers are attributed to hereditary breast and ovarian cancer (HBOC) syndrome due to mutations in the BRCA1 and BRCA2 (BRCA) genes. Although there are several other genes that also lead to hereditary breast cancer predisposition (eg, PTEN, P53, STK11), they are much rarer. Furthermore, for the purposes of this review, we will not specifically consider individuals at high risk by virtue of a striking family history, in whom a germline BRCA mutation is not identified (recognizing that in the clinical setting, it may be appropriate to offer these individuals many of the risk management options recommended for BRCA mutation carriers). Consequently, we use HBOC as a model for outlining the importance of genetic counseling and testing services across the cancer prevention and control continuum (Figure).

Figure.

Management of inherited breast cancer across the cancer prevention and control continuum.

The BRCA genes were discovered approximately 15 years ago,^1,2 representing a tremendous opportunity to identify individuals at greatly elevated risk for HBOC.^1–3 Mutations in these genes account for approximately 5% of all breast cancers⁴ and 10% to 15% of all ovarian cancers.^2,5,6 Lifetime cancer risks to age 70 in BRCA mutation carriers are approximately 60% to 70% for breast cancer^7–11 and 40% or lower for ovarian cancer.^7,9 Moreover, the risk of a second primary breast cancer in BRCA mutation carriers, particularly those diagnosed with breast cancer at a younger age, is much higher (upwards of 50%) than in non-carriers.^12,13 It is becoming exceedingly important to identify women who carry BRCA mutations so that they may utilize the latest medical advances in prevention, early detection, and treatment.^3,14–19 To facilitate identification and referral of patients most likely to benefit from these advances, the National Comprehensive Cancer Network (NCCN) publishes annual guidelines that outline referral criteria for genetic counseling and testing in the oncology care setting.²⁰ NCCN criteria for appropriate referrals in those with a personal and family history of breast cancer include, but are not limited to, early age of diagnosis of breast cancer (ie, ≤ age 50), number of relatives with breast cancer, two breast cancer primaries, triple-negative disease, male breast cancer, and previously identified BRCA mutation in the family (Table 1). Other considerations for referral include ethnic background, limited family size/structure, and presence of other BRCA-associated cancers in the family.

Table 1.

NCCN Referral Criteria for Further Genetic Risk Evaluation for HBOC

An affected individual with one or more of the following: Early-age-onset breast cancer Triple negative (ER−, PR−, HER2−) breast cancer Two breast cancer primaries in a single individual Breast cancer at any age, and ≥ 1 close blood relative with breast cancer ≤ 50 y old, or ≥ 1 close blood relative with epithelial ovarian/fallopian tube/primary peritoneal cancer at any age, or ≥ 2 close blood relatives with breast cancer and/or pancreatic cancer at any age From a population at increased risk A combination of breast cancer with one or more of the following: thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, pancreatic cancer, brain tumors, diffuse gastric cancer, dermatologic manifestations or leukemia/lymphoma on the same side of the family (especially if early onset) Ovarian/fallopian tube/primary peritoneal cancer Male breast cancer

An unaffected individual with a family history of one or more of the following: ≥ 2 breast primaries, either in 1 individual or 2 different individuals from the same side of the family (maternal or paternal) ≥ 1 ovarian primary from the same side of the family (maternal or paternal) First- or second-degree relative with breast cancer ≤45 y A combination of breast cancer with one or more of the following: thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, pancreatic cancer, brain tumors, diffuse gastric cancer, dermatologic manifestations or leukemia/lymphoma on the same side of the family (especially if early onset) A known mutation in a breast cancer susceptibility gene within the family Male breast cancer

Reproduced/adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian. V.1.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines^® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to www.NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, NCCN GUIDELINES^™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Several models have been developed that predict the probability of a BRCA mutation in individuals or families, including those based on Bayesian approaches and statistical models²¹ or empiric observations (such as those based on Myriad prevalence tables).²² Overall, the use of prediction models has been shown to improve the ability of clinicians as to which patients are most likely to harbor a BRCA mutation.²³ Studies that compared the different models suggest that no single model is consistently superior to others.^24,25 Additional means shown to better improve the performance of prediction models and discriminate between BRCA1 and BRCA2 are inclusion of breast tumor markers such the estrogen receptor, progesterone receptor, and Her-2/neu status.^26–28

Prevention

A number of studies have evaluated medical and surgical options for breast cancer prevention in BRCA mutation carriers. Tamoxifen has been the primary agent evaluated in the medical context. However, its role for primary prevention in BRCA carriers remains unclear. Specifically, a single small study of 8 BRCA1 carriers and 11 BRCA2 carriers showed a 62% reduction in breast cancer incidence in BRCA2 carriers who used tamoxifen, but no similar risk reduction was observed in BRCA1 carriers. To date, no larger studies have been conducted to examine the efficacy of tamoxifen for primary prevention of breast cancer. Additionally, there has been speculation that poly ADP-ribose polymerase (PARP) inhibitors may someday be considered as targeted chemoprevention agents for primary prevention of breast cancers in BRCA mutation carriers,²⁹ and future efficacy studies are expected. For women with a prior breast cancer diagnosis, several studies have demonstrated a 50% to 70% reduction in risk for contralateral disease with use of tamoxifen.^30–32 While promising, each of these studies have limitations such as retrospective design and lack of histopathological data (especially estrogen and progesterone receptor status) of the primary tumor.

In terms of surgical options, bilateral prophylactic mastectomy represents the highest level of risk reduction in BRCA mutation carriers. Multiple studies demonstrate a greater than 90% reduction in breast cancer risk.^33–39 (For an overview of bilateral mastectomy in the context of a breast cancer diagnosis, refer to the Treatment section.) Another surgical option for breast cancer prevention is prophylactic bilateral salpingo-oophorectomy, which reduces ovarian cancer risk by approximately 80%^40,41 and also confers a 50% reduction in breast cancer risk when performed premenopausally in BRCA carriers.^41–43 It is unclear whether the magnitude of breast cancer risk reduction depends on time since oophorectomy, particularly when it is performed premenopausally, although available data suggest prophylactic oophorectomy performed after the age of 50 likely does not lower breast cancer risk.⁴⁴ In terms of survival, prophylactic bilateral salpingo-oophorectomy has been reported to lead to a reduction in breast and ovarian cancer-specific mortality as well as overall mortality.³⁹ Finally, there are data to suggest that prophylactic oophorectomy may also reduce contralateral breast cancer risk.⁴⁵ A recent computer-simulated survival analysis examined the impact of screening and prophylactic surgeries in BRCA mutation carriers⁴⁶ and developed an online tool for guiding management in patients.⁴⁷ Recognizing the numerous assumptions on which modeling studies are based, these studies may nevertheless provide additional information for both patients and providers when making challenging management decisions.

Early Detection and Diagnosis

Several studies in BRCA mutation carriers have evaluated the impact of various breast cancer screening modalities on early cancer detection. For women with a BRCA mutation, the NCCN has issued recommendations for breast cancer surveillance,⁴⁸ including monthly breast self-examination, semiannual clinical breast examination, annual mammogram, and annual breast magnetic resonance imaging (MRI), as illustrated in Table 2. Although yearly mammograms starting as early as 25 years of age are recommended as part of the screening strategy in BRCA mutation carriers, one potential concern is that BRCA carriers may be more prone to radiation-induced breast cancers than nonmutation carriers due to the role of the BRCA genes in DNA repair.⁴⁹ However, there is currently insufficient evidence to indicate that radiation exposure from mammograms increases breast cancer risk.^50–52

Table 2.

NCCN Management Recommendations for HBOC Syndrome Management

Women Breast self-examination training and education starting at age 18 y Clinical breast examination, every 6–12 months, starting at age 25 y Annual mammogram and breast MRI screening starting at age 25 y, or individualized based on earliest age of onset in family Discuss option of risk-reducing mastectomy on case-by-case basis and counsel regarding degree of protection, reconstruction options, and risks Recommend risk-reducing salpingo-oophorectomy, ideally between 35 and 40 y, and upon completion of child bearing, or individualized based on earliest age of onset of ovarian cancer in the family. Counseling includes a discussion of reproductive desires, extent of cancer risk, degree of protection for breast and ovarian cancer, management of menopausal symptoms, possible short-term hormone replacement therapy (HRT) to a recommended maximum age of natural menopause, and related medical issues For those patients who have not elected risk-reducing salpingo-oophorectomy, consider concurrent transvaginal ultrasound (preferably day 1–10 of menstrual cycle in premenopausal women) + CA-125 (preferably after day 5 of menstrual cycle in premenopausal women), every 6 months starting at age 30 y or 5–10 y before the earliest age of first diagnosis of ovarian cancer in the family Consider chemoprevention options for breast and ovarian cancer, including discussing risks and benefits Consider investigational imaging and screening studies, when available (eg, novel imaging technologies and more frequent screening intervals) in the context of a clinical trial

Risk to Relatives Advise about possible inherited cancer risk to relatives, options for risk assessment, and management Recommend genetic counseling and consideration of genetic testing for atrisk relatives

Reproductive Options For couples expressing the desire that their offspring not carry a familial BRCA mutation, advise about options for prenatal diagnosis and assisted reproduction, including pre-implementation genetic diagnosis. Discussion should include known risks, limitations, and benefits of these technologies For BRCA2 mutations carriers, risk of a rare (recessive) Fanconi anemia/brain tumor phenotype in offspring if both partners carry a BRCA2 mutation should be discussed.

Reproduced/adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian. V.1.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines^® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to www.NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, NCCN GUIDELINES^™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Studies have consistently shown that MRI is more sensitive than mammography and/or breast ultrasound in detection of early-stage breast cancers in BRCA mutation carriers.^53–58 Furthermore, a prospective study of BRCA mutation carriers annually screened by MRI reported a significant reduction in the incidence of advanced breast cancer compared with those not screened by MRI.⁵⁹ The optimal benefit of MRI appears to be achieved through annual screening between the ages of 25 to 65 years. The benefits of screening in this age group likely do not persist much beyond 2 years after the date of the last MRI; moreover, the long-term health implications of 40 doses of gadolinium in BRCA carriers have not been evaluated.⁴⁴ Although trials indicate that MRI is superior to mammography in the detection of breast cancer, mammography identifies some cancers not detected by MRI, particularly ductal carcinoma in situ with microcalcifications.^60,61 As a consequence, current evidence supports the benefits of both mammography and breast MRI annually in BRCA mutation carriers.^3,46,62–64 Despite the proven benefits of MRI for breast cancer detection^53–58 and recent data which suggest that it reduces the risk of advanced breast cancer,⁵⁹ it is currently unknown if MRI results in a survival benefit.

Treatment

Several treatment considerations should be addressed for women with breast cancer who carry a BRCA mutation, including the high risks for contralateral disease and ovarian cancer, as well as the emergence of targeted treatment approaches currently offered in the context of clinical trials. Contralateral breast cancer rates in BRCA carriers are higher than that of non-carriers, with 10-year rates reported as 25% to 27% for carriers and 1% to 9% for non-carriers.⁶⁵ Furthermore, recent studies indicate that contralateral breast cancer risk depends of age at first breast cancer diagnosis (with substantially elevated risks in those diagnosed at an early age) as well as affected BRCA gene (with higher risks for those with BRCA1 mutations).^12,13 In fact, the lifetime contralateral breast cancer risk was reported to be over 60% in those with BRCA1 mutations diagnosed below the age of 40 after 25 years of follow-up.¹² Because the presence of a germline BRCA mutation diagnosed at the time of a breast cancer diagnosis raises an individual’s risk of a synchronous and metachronous tumor, surgical treatment decision is often influenced by this knowledge. Due to this increased risk of a second primary breast cancer, approximately half of North American women with a BRCA mutation who are diagnosed with unilateral breast cancer select bilateral mastectomy for surgical treatment.⁶⁶ This finding is supported by two US-based studies of newly diagnosed high-risk breast cancer patients who underwent BRCA testing at or near the time of diagnosis. In both studies, women who tested positive for a BRCA mutation chose bilateral mastectomy more often than women who received negative or uninformative results.^67,68

A number of organizations provide guidelines to identify, refer, and counsel newly diagnosed high-risk breast cancer patients for genetic counseling, including those from the American Society of Clinical Oncology (originally published in 2003)^69–71 and the American Society of Breast Surgeons (issued in 2009).⁷² However, a 2011 study of administrative data from a sample of 14.4 million commercially insured patients over a 3-year period found that of approximately 1,500 women with early-onset breast cancer ≤ age 40, only 30% had genetic testing, with even lower rates among black and Hispanic patients.⁷³ Importantly, this study found that even among those who had testing (and presumably pretest genetic counseling), less than 20% did so within a month of diagnosis, suggesting that testing (and presumably pretest genetic counseling) generally occurred after definitive surgical treatment.

When considering ipsilateral breast cancer risk, a number of studies support breast conservation therapy (ie, lumpectomy and radiation) for treatment of the primary tumor, based on similar ipsilateral recurrence rates in carriers and non-carriers at 10 years of follow-up.^12,74–76 However, at 15 years of follow-up, the risk of ipsilateral events (including second primary cancer and recurrence of initial cancer) has been reported to be as high as 24%.^74,76 Ultimately, there is no documented difference in overall survival of BRCA carriers choosing breast conservation therapy vs mastectomy at 15 years following treatment.⁷⁴ However, some data suggest it may take 20 years or more of follow-up to definitively determine whether bilateral mastectomy results in a mortality reduction.^44,77 Another consideration for BRCA mutation carriers who select lumpectomy and radiation therapy but who may consider bilateral mastectomy in the future is the potential impact of radiation on breast reconstruction options. Changes to the skin caused by radiation have been well documented,⁷⁸ and several reports have substantiated that implant reconstructions subsequent to radiation therapy have a significantly higher complication rate.⁷⁹ Given the possibility of fewer options, BRCA mutation carriers should be fully informed about the impact of radiation therapy on future breast reconstruction.

While the influence of BRCA mutation carrier status on surgical decisions has become more widely considered in treatment planning,⁸⁰ options to inform medical treatment strategies based on BRCA mutation carrier status are imminent in the era of personalized medicine. For example, preclinical models suggest BRCA1-associated breast cancers are resistant to taxanes and sensitive to DNA damaging agents such as mitomycin C and cisplatin.⁴⁴ Subsequently, data have emerged to suggest that taxanes may not be useful in neoadjuvant treatment of BRCA1-associated breast cancers,^81–84 whereas these cancers may be particularly sensitive to platinum agents.^85,86 Currently, it remains unclear whether responsiveness to platinum-based agents in BRCA1-related breast cancers relates to the triple-negative phenotype or specifically to the BRCA mutation status itself. Interestingly, in a study of 28 women with stage II/III triple-negative breast cancer treated with cisplatin, 6 patients achieved complete clinical response, which included 2 women with BRCA1 mutations in the entire sample.⁸⁷ However, more data are needed regarding the use of cisplatin in the clinical setting before clinical recommendations can be made.

Among the many tailored treatments currently under investigation,⁸⁸ much interest has focused on the PARP inhibitors, which may be particularly effective in BRCA-associated cancers.^89–92 This is the first treatment regimen to be based on a synthetic lethality approach, as inhibiting PARP-mediated pathways selectively affects only those cells that have lost BRCA-associated homologous recombination function (ie, tumor cells), whereas normal cells are unaffected. Consequently, this approach is associated with minimal systemic toxicity.¹⁸ Several international trials are underway to test the effectiveness of PARP inhibitors in BRCA mutation carriers,^{17–19,91,93–95} and many have reported promising preliminary results.^17–19 Notably, single-agent PARP (olaparib) has shown effectiveness in treating metastatic breast cancer.^18,96

In individuals with a new diagnosis of breast cancer and determined to have a BRCA mutation, another concern is the high risk of metachronous ovarian cancer, which is a common cause of mortality in those BRCA mutation carriers who were successfully treated for early-stage breast cancers.⁹⁷ Specifically, patients with a BRCA mutation also have a 7% to 13% chance of developing ovarian cancer within 10 years after diagnosis.⁹⁷ As surveillance has not been shown to be effective in detecting early-stage ovarian cancers, the benefits of bilateral salpingo-oophorectomy (in addition to lowering the risk of breast cancer) are related to their effect on survival from ovarian cancer.⁹⁷ Further discussion of bilateral salpingo-oophorectomy is included below (related to the management of symptoms associated with menopause) and in the Prevention section (related to breast cancer risk reduction).

Quality of Life and Survivorship

Several important considerations regarding quality of life and survivorship are unique to women who carry a BRCA mutation, including the impact of risk-reducing surgery, fertility and reproductive health concerns, communication of genetic test results, and concerns about insurability and discrimination. Overall, the published literature indicates high levels of satisfaction (80% to 100%) with prophylactic mastectomy over time.^98–102 One of the first studies of psychosocial outcomes of prophylactic mastectomy to include only women who were genetically susceptible to breast cancer was published in 2006.¹⁰³ Among the 114 Dutch women who underwent prophylactic mastectomy and breast reconstruction, after a median follow-up of 3 years, 60% of participants were satisfied with the results of the surgery. The sample included 63 women with BRCA mutations and 14 at high risk for breast cancer by virtue of their strong family history. Those who perceived a lack of information, experienced complications, had ongoing feelings that the reconstructed breasts did not feel like their own, and stated they would not choose this type of reconstruction again were least likely to be satisfied and to report adverse effects on their sexual relationship. Additionally, negative impacts on the patient’s sexual relationship were also associated with altered feelings of femininity, discrepant expectations, and perceptions that the partner had a negative perception of femininity and sexuality. The level of satisfaction reported in this study is lower than what has previously been reported in women who were not specifically identified as BRCA mutation carriers. Since this study was conducted in the Netherlands, there may be some variation specific to the healthcare system; however, it is also possible that there are psychosocial issues specific to BRCA mutation-positive women undergoing prophylactic mastectomy that warrant further exploration.

For women who undergo bilateral prophylactic oophorectomy, evidence suggests an improvement in psychosocial functioning after surgery. Among 846 Dutch women at high risk for HBOC, 44% selected prophylactic bilateral salpingo oophorectomy and 56% selected surveillance.¹⁰⁴ Women who selected oophorectomy had fewer breast and ovarian cancer worries compared with those selecting surveillance. However, those who selected surgery were also significantly more likely to report menopausal symptoms and worse sexual functioning (eg, less pleasure during sexual activities). The use of hormone replacement therapy (HRT) to mitigate the symptoms associated with surgical menopause in young women who undergo bilateral prophylactic oophorectomy has been an issue of debate. A concern about HRT in BRCA carriers is its potential to raise the risk of breast cancer, as seen in the general population.^105–107 However, two studies in BRCA mutation carriers reported that HRT did not increase the subsequent risk of breast cancer, nor did it appear to reduce the protective effect of oophorectomy on breast cancer risk.^108,109 Recent results from the Women’s Health Initiative in the general population also provide reassurance as to estrogen use for about 5 years in terms of breast cancer risk and mortality.¹¹⁰ Ultimately, HRT mitigates many of the symptoms associated with menopause. However, studies have suggested that quality of life does not return to presurgical levels.^104,111

Fertility has been identified as a leading quality of life concern among breast cancer patients diagnosed during their reproductive years.¹¹² Estimated infertility risks for women treated with adjuvant breast cancer therapy for 6 weeks with the most commonly used chemotherapy regimens are > 80% for premenopausal women aged 40 and above, 20% to 80% for women aged 30 to 39, and < 20% for women under age 30.¹¹³ In recognition of the immediacy of fertility concerns, professional guidelines have been released by both the American Society for Reproductive Medicine (ASRM) in 2005 and the American Society of Clinical Oncology (ASCO) in 2006 that highlight the role of oncologists to initiate discussion of fertility so their patients can make family-building decisions that are right for them.^113,114 Despite these guidelines, research suggests a lack of patient knowledge and a need for improved communication about fertility between cancer patients and their providers. A survey of cancer survivors found that only 57% of patients report receiving information about fertility from healthcare providers.¹¹⁵ Another study of young female cancer survivors reported a higher discussion rate of 72%.¹¹⁶ However, only 51% of these women felt their concerns were addressed adequately, suggesting that even if this communication is occurring, patients may not receive sufficient information regarding fertility risk and fertility preservation options. Finally, a national study of US oncologists found that 47% of respondents reported routinely referring cancer patients of childbearing age to a reproductive endocrinologist.¹¹⁷

The possibility of transmitting a mutation to a child may also pose a concern to families with a BRCA mutation,¹¹⁸ perhaps to the extent that some carriers may avoid childbearing.^119,120 These concerns may prompt women to consider using a preimplantation genetic diagnosis (PGD), a newer technique used to test fertilized embryos for genetic disorders prior to uterine implantation.^121–124 PGD involves the use of in vitro fertilization, in which an egg is fertilized and develops for 3 days until it reaches the 8-cell stage, at which time 1 cell is removed and examined using polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH).¹²² Using the information obtained from the genetic testing, potential parents can decide whether or not to implant embryos. A review by Offit et al¹²⁵ indicated that PGD has been used in the context of several hereditary cancer syndromes, including HBOC. Given the immediate and long-term issues related to reproductive health based on medical and surgical treatment and risk reduction options for BRCA mutation carriers, the optimal time for oncology care providers to discuss fertility-related concerns is prior to the initiation of chemotherapy.¹²⁶

A primary motivation for many breast cancer patients to undergo BRCA testing is to provide information to their at-risk relatives.^127–130 In clinical practice, healthcare providers give test results directly to patients and encourage them to share the results with at-risk family members.¹³¹ Several studies to date have documented that women generally share BRCA test results with their at-risk relatives.¹³² However, some studies indicate that females who have been tested may choose less frequently to share results with their relatives who are male, with those they do not feel emotionally close to, or with those whose emotional or psychological well being is a concern.^133–137 Although likely uncommon, a recent case report documented deliberate disclosure of incorrect test results by a patient to her at-risk family member.¹³⁸ There is also recent literature suggesting that parents are disclosing test results to minor children.^139–141 While there is no specific clinical guidelines about the appropriate age to disclose a parent’s test results to children, there are clear guidelines against testing minor children for BRCA mutations. Consensus guidelines from experts consistently emphasize that genetic testing for adult onset conditions should be deferred until legal adulthood (age 18), when individuals can decide for themselves whether they would like to pursue testing.^70,142–144 This guideline reflects concerns regarding autonomy, potential discrimination, and possible psychological effects.^142,144,145 Therefore, in HBOC, where there is no risk of malignancy in childhood and no risk reduction strategies are recommended in minors, testing should not be offered. Even after 18 years of age, testing is generally not strongly recommended due to potential implications to future insurability in the absence of any medical interventions implemented at this age. The age at which screening strategies are initiated is in the mid 20s (Table 2), which is typically the time at which many clinicians recommend testing for at risk women.

Other concerns expressed by women considering BRCA testing are those related to genetic discrimination and insurability. Specifically, when embarking on genetic testing for inherited cancer susceptibility, particularly in the context of a family member who does not have a cancer diagnosis, potential implications regarding future insurability are an important aspect of discussion during the genetic counseling session. At the federal level, the Genetic Information Non-Discrimination Act (GINA) was passed in 2008, which imparts protections for individual and group health insurance policies as well as in the workplace.¹⁴⁶ Note that GINA does not cover life insurance, disability insurance, or other supplemental insurances. In addition, those in the military are not covered under GINA. However, other protections against discrimination are in place.¹⁴⁷

As patients move from treatment to survivorship, it is important to consider their transition back to primary care providers. Given the strict laws in some states with regard to confidentiality of genetic test results, some centers limit documentation of BRCA mutation results in the medical record and/or implement additional safety guards to house and release this information within the medical record. Consequently, patients may share some responsibility to inform their healthcare providers of their mutation results, particularly as they are transitioning back to primary care settings. This information will be useful for providers to not only make cancer screening recommendations based on mutation status, but also ensure that patients follow recommended screening and behavioral guidelines for prevention and early detection of non–BRCA-related cancers.¹⁴⁸

These quality of life and survivorship issues in conjunction with the difficulty some patients may have to accurately recall their test results^149–151 underscore the importance of pre- and posttest genetic counseling that is provided by a knowledgeable genetics professional. In addition to expertise in cancer risk assessment and medical management of individuals with hereditary cancer predisposition, these individuals are also trained to identify potential psychosocial and educational needs of patients.¹⁵² They are critical members of the healthcare team and can help ensure that patients understand the medical and psychosocial implications of results for themselves and at-risk family members and serve as a resource for patients to develop strategies for effective communication.

Considerations for Delivery of BRCA Counseling and Testing in the Breast Oncology Care Setting

Several health and professional organizations strongly encourage referral to a certified/credentialed cancer genetics professional for pretest counseling, prior to genetic testing.^{20,70,143,152–156} There are three main groups of healthcare professionals with advanced degrees and experience in genetics. (1) A Certified Genetic Counselor (CGC) has at least a Master’s degree in genetic counseling and has passed a national board examination, (2) a Diplomate, American Board of Medical Genetics (DABMG), or Fellow, American College of Medical Genetics (FACMG) is a physician who has completed residency or fellowship training in medical genetics and passed the board examination, and (3) an Advanced Practice Nurse in Genetics (APNG) has completed both a graduate nursing program and professional portfolio review process.¹⁵⁷ As outlined in a recent publication,¹⁵⁸ the traditional model of delivering genetic counseling and testing services involve five steps: patient identification, genetic consultation, genetic testing if appropriate, posttest counseling, and cancer risk management.

Patients are referred by healthcare providers or family members, or they are self-referred. The model for providing comprehensive BRCA testing begins with an in-person pretest genetic counseling session during which time informed consent for genetic testing is obtained followed by a results disclosure session.¹⁶ During this session, the patient typically meets with a genetics professional with the training described above. The professional obtains personal and family cancer history and provides the patient with a risk assessment, including which, if any, genetic tests may be appropriate to perform. Given the complexities of delivering high-quality genetics services, ASCO provides key points that should be discussed with any patient during a pretest genetic counseling session (Table 3).^70,143 This initial appointment typically lasts 60 to 90 minutes. One of the primary goals of the initial session is to determine whether genetic testing is appropriate for a given patient and then proceed accordingly.¹⁵² For those who proceed with testing, the patient returns for in-person disclosure of test results and discussion of medical management options. However, over the last decade, the delivery of genetics services (including who provides these services) has evolved, resulting in new models to optimize development of and access to these services.^158–160 Increasingly, comprehensive services for hereditary breast cancer are delivered by a multidisciplinary team that includes genetic counselors working in conjunction with oncologists, medical geneticists, other medical specialists, and often a mental health professional.¹⁶¹ This interdisciplinary approach can help avoid problems such as inappropriate or incomplete testing, misinterpretation of test results by both patients and clinicians, inappropriate cancer screening and prevention recommendations, and psychological issues.^71,162,163

Table 3.

Basic Elements of Informed Consent for Cancer Susceptibility Testing

Information on the specific test being performed Implications of a positive and negative result Possibility that the test will not be informative Options for risk estimation without genetic testing Risk of passing a mutation to children Technical accuracy of the test Fees involved in testing and counseling Psychological implications of tests results (benefits and risks) Risks and protections against genetic discrimination by employers or insurers Confidentiality issues Options and limitations of medical surveillance and strategies for prevention following testing Importance of sharing genetic test results with at-risk relatives so that they may benefit from this information

From American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):2397–2406. Reprinted with permission. © 2003 American Society of Clinical Oncology. All rights reserved.

Compared with most other clinical services, provision of genetic counseling involves significant amounts of provider time.^{160,164–167} However, low reimbursement rates relative to the time required to provide adequate services impedes the provision of adequate risk counseling, particularly for providers outside of an academic setting.¹⁶⁸ One study found that only one-third of the time needed to deliver genetic counseling services involves face-to-face patient care that can be billed.¹⁶⁹ Specifically, most genetic counseling programs cost more than the direct revenue they generate.⁷⁷ However, another crucial consideration to illustrate institutional value of genetic counseling programs must incorporate “downstream revenue analysis,” which includes reimbursement from surveillance, prophylactic surgeries, or cancer treatments for individuals with BRCA mutations.¹⁷⁰ Thus, the inclusion of this income is essential in any cost-benefit calculation of genetic counseling services, and additional research regarding this revenue is needed. Ultimately, public and private healthcare policy reform is needed to address the gap in insurance coverage for adequate risk counseling and genetic analyses as a component of preventive care.

Institutional Efforts Specific to Genetic Counseling and Testing

At our institute, a model driven by physician recommendation has been implemented as a referral system for recently diagnosed high-risk breast cancer patients. The available personal and family history records for newly diagnosed breast cancer patient are reviewed by a genetic counselor during the weekly Breast Program tumor board meetings to assess if the patient meets NCCN guidelines for referral to the Cancer Genetic Counseling and Testing Service, as illustrated in Table 1.²⁰ Each patient who is discussed and meets these criteria is noted by the genetic counselor. A letter is generated by the Cancer Genetic Counseling and Testing Service and sent to the surgeon for his or her signature. In addition to a surgeon discussing genetic counseling and testing during the initial consultation, a referral letter signed by the patient’s physician (often a surgeon) is sent to a breast cancer patient who has been identified as meeting NCCN criteria. This brief letter is addressed directly to the patient, signed by his or her surgeon, and recommends that the patient make an appointment for genetic counseling.¹⁷¹ In an effort to continually improve our delivery of clinical services, our team evaluates important outcomes such as patient uptake of and satisfaction with genetics services.^172,173 These data are in turn used to generate additional research opportunities. For example, we were recently awarded peer-reviewed funding to develop and test an educational intervention specific to postsurgical breast cancer patients at risk for HBOC who are transitioning to survivorship care.

While the physician referral model works well in settings with access to trained genetics professionals, there are many rural areas or certain states where such professionals are not readily available.^174,175 This shortage is compounded by the paucity of education and training opportunities in clinical cancer genetics,¹⁷⁶ despite priorities set forth by key stakeholders emphasizing the need for cancer genetics education.^177–185 Thus, integrating genetic counseling and testing for HBOC into clinical care remains an ongoing challenge. However, several innovative approaches to delivering quality genetics services to an increasing number of patients in community settings have been developed. For example, successful strategies for delivering comprehensive genetic counseling and testing services include academic-community partnerships that focus on collaboration with nongenetics providers to offer genetic testing for hereditary cancers.^158,159 This approach can leverage the expertise of an academic center for challenging cases as well as allow patients to remain in their community and provide better access to resources for long-term follow-up care. Other innovative approaches to successfully identify high-risk patients, particularly in the primary care and community setting, include automated family collection tools through which risk assessment is performed at a hospital or practice-wide level and appropriate patients are identified and referred for genetic counseling and testing.^186–188 These software tools are particularly of interest as many hospitals and practices transition to electronic health records, and they have the potential to enhance the identification of patients at risk for inherited cancers at a system-wide level.

At our institute, we secured peer-reviewed funding to develop an infrastructure (called the Inherited Cancer Research [ICARE] Initiative) to support research, education, and outreach initiatives focused on BRCA genetic counseling and testing. The ICARE Initiative leverages a state mandate to reach the citizens of Florida and provide access to high-quality cancer care. Moffitt works with its partners (referred to as “affiliates”) to offer clinical expertise and research trials found at an NCI-designated Comprehensive Cancer Center. The Moffitt Affiliate Network (MAN) Program represents strategic affiliations with 15 Florida hospitals, 1 Georgia hospital, and more than 400 community oncologists, through which Moffitt reaches approximately 20% of Florida cancer patients. Through networking with our MAN sites, providing access to a genetic counselor for general questions, and utilizing other directed learning opportunities and educational resources/materials over the last year, 12 of the 15 sites have actively participated in our bimonthly case conferences. Furthermore, an additional 2 sites have requested and received in-person presentations from the ICARE team on the topic of inherited cancer susceptibility. In addition to our educational and outreach efforts, MAN practitioners refer high-risk patients to our research registry to provide the research link, which has in turn contributed to the tremendous growth of our registry since initiation of the grant in the summer of 2010. This provides unprecedented opportunities to understand cancer risk management practices and recommendations in BRCA mutation carriers at the patient and practitioner level. These efforts will provide information that can improve the delivery of cancer genetics services in the state of Florida and serve as a model for other states.

Conclusions

Over the last several years, it has become increasingly common to consider BRCA mutation status when determining optimal cancer risk management and treatment options in order to improve patient outcomes. Knowledge about the risk for hereditary cancer at or as close as possible to the time of diagnosis allows patients access to options that may improve their outcome and reduce treatment-associated risks. Thus it has become important for providers in the breast oncology care setting to identify at-risk patients and offer testing, either by themselves or through referral to a cancer genetic counseling and testing service. As such, leading health professional organizations such as the National Comprehensive Cancer Network,²⁰ the American Society of Breast Surgeons,⁷² and the American Society of Clinical Oncology¹⁸⁹ provide specific guidelines and recommendations to providers for identification of women at increased risk for carrying a BRCA mutation. For those providers without in-house clinical cancer genetics providers, several promising collaborative models across the United States are successfully bringing the expertise of these providers to breast oncology care for patients in community settings.^158,159