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Risk Assessment, Genetic Counseling, and Clinical Care for Hereditary Breast Cancer Jacquelyn Powers and Jill Elise Stopfer

Correspondence Jill E. Stopfer, MS, CGC, Abramson Cancer Center University of Pennsylvania, 3 Perelman West, 3400 Civic Center Blvd, Philadelphia, PA 19104. [email protected]

ABSTRACT During the last 30 years, key advances in the field of cancer genetics have improved identification of high-risk families in which cancer risk can be linked to mutations in cancer susceptible genes. Identification of individuals with heritable cancer risk may influence short- and long-term medical management issues. Heightened screening and risk reducing options can offer lifesaving interventions for the woman and family members who are at risk.

JOGNN, 43, 361-373; 2014. DOI: 10.1111/1552-6909.12304 Accepted December 2013

Keywords Hereditary breast cancer risk cancer genetic counseling breast cancer risk assessment

Jacquelyn Powers, MS, CGC, is a genetic counselor in the Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA. Jill Elise Stopfer, MS, CGC, is a genetic counselor in the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

pproximately one of every eight women (13%) in the United States will develop breast cancer in her lifetime; of these 80% are diagnosed when they are older than age 50 (Howlader et al., 2013). Compared to women without a family history, the risk of breast cancer is twofold for women with one affected first-degree relative, threefold for women with two affected first-degree relatives, and nearly fourfold for women with three or more affected first-degree relatives. Risk to relatives is also affected by the age of breast cancer diagnosis with earlier ages of onset being more suggestive of inherited or genetic risk (Collaborative Group on Hormonal Factors in Breast Cancer, 2001; Pharaoh, Day, Duffy, Easton, & Ponder, 1997).

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in families can be attributed to mutations in these high-risk genes. Other genes increase risk more moderately, and in some cases multiple genes inherited together may create a genetic profile of risk. Genetic testing opportunities have largely focused on testing for rare genes with very significant impact on risk, and testing for these genes will continue to be critically important. This review provides clinicians with guidance about hereditary conditions including breast cancer, obtaining and interpreting relevant personal and family histories, performing risk assessments, identifying genetic testing candidates, and helping patients understand how these assessments may influence their long-term medical management, as well as provide their families with critical and potentially lifesaving information.

Disclosure: Jacquelyn Powers is supported by the Mariann and Robert MacDonald Cancer Risk Evaluation Center and the Basser Center for BRCA. Jill Stopfer is supported by the Marjorie Cohen Foundation, the Mariann and Robert MacDonald Cancer Risk Evaluation Center, and the Basser Center for BRCA.

Family history of breast cancer is one of the most well recognized risk factors for the disease, although only 5% to 10% of all breast cancer is considered hereditary (Claus, Schildkraut, Thompson, & Risch, 1996; Pharaoh et al., 2002; Whittemore, Gong, & Itnyre, 1997). Generally hereditary breast cancer is indicative of the presence of a mutation in a highly penetrant gene such as BRCA1, BRCA2, or TP53, which have profound effects on breast cancer risk. However, genetic risk for breast cancer is heterogeneous, and not all risk that runs

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Major Inherited Cancer Syndromes Including Breast Cancer Most of the major inherited cancer susceptibility syndromes involving breast cancer are inherited by an autosomal dominant mechanism and are due to germline (inherited) mutations in tumor suppressor genes. Such genes are important in maintaining genomic stability by promoting precise DNA repair as cells replicate and divide.

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Accurate and thorough collection of family history remains the cornerstone of cancer risk assessment and identification of high-risk families.

This concept was first studied in patients with retinoblastoma and Wilm’s tumor, demonstrating that deficiencies in this process may lead to a diagnosis of cancer (Cavenee et al., 1983; Pritchard-Jones, 1997). Genetic conditions inherited in an autosomal dominant fashion require only one gene in the gene pair be nonfunctional to manifest increased cancer risk. Those who carry a disruptive gene mutation have a 50% chance to pass it along to each child, regardless of gender – males and females are equally at risk for inheriting a gene mutation although cancer risks for men and women may vary. Autosomal dominant genes do not skip a generation – a person who did not inherit a mutated copy of a dominant cancer susceptibility gene from a parent cannot then pass it along to the next generation. Penetrance, or the chance that an inherited gene mutation will lead to a cancer diagnosis, may vary in families due to the existence of other risk modifying genes that interact with a high-risk cancer susceptibility gene like BRCA1 or 2. In addition penetrance may be affected by the coexistence of other endogenous or lifestyle risk factors. Further research into modifiers of major cancer risk genes will allow individuals who carry these mutations to be offered more tailored risk estimates on which to base their decisions. Personalized risk estimates that incorporate the impact of risk modifier genes are not yet available, so counseling about cancer risks are based on the best estimates available from large collaborative studies.

Breast cancer is a major component of LiFraumeni syndrome (LFS), a condition associated inherited mutations in the gene TP53 that predisposes individuals to a strikingly high lifetime risk for a wide variety of cancers. Although the TP53 gene is one of most commonly somatically mutated genes in human cancer, inherited germline mutations in TP53 are rare. This condition was initially characterized by Li and Fraumeni in families with pediatric soft-tissue sarcomas, earlyonset breast cancer, adrenocortical carcinoma, and brain tumors. These tumors remain highly characteristic of LFS. The classic clinical criteria for the diagnosis of LFS are an individual diagnosed with sarcoma younger than age 45, and a first-degree relative with any cancer younger than age 45, and a first- or second-degree relative with any cancer younger than age 45 or sarcoma at any age (Li et al., 1988). Families meeting the classic familial criteria for LFS have the highest chance of having a detectable germline mutation found in TP53, but the clinical presentation has been recognized more recently to be quite variable. Additional clinical diagnostic and testing criteria have been developed to broaden chances of identifying this syndrome (Birch et al., 1994; Chompret et al., 2001; Tinat et al., 2009) and are summarized in Table 2 along with criteria for genetic testing.

Mutations in the BRCA1/2 genes are found in every ethnic and racial group. About one in 500 individuals carry an inherited mutation in either gene, but those who are of Ashkenazi or Eastern European Jewish ancestry have a significantly higher

Breast cancers associated with LFS can manifest extraordinarily early, occasionally presenting in teenagers and adults in their early twenties, although the median age of onset is age 33. Breast cancer accounts for 50% of all female cancers in those with LFS, and women have an overall lifetime cancer risk approaching 90% (Olivier et al., 2003). Individuals with LFS commonly develop multiple primary malignancies, with the risk of a second cancer approaching 57% at 30 years beyond the initial diagnosis, and the risk of a third primary cancer of 38% at 10 years beyond the second diagnosis (Cohen, Curtis, Inskip, & Fraumeni, 2005; Malkin et al., 1992). A significant number of individuals (7%–20%) are the first ones in their family to have LFS as a result of a de novo, or new mutation arising in the formation of the egg or sperm that participated in fertilization (Gonzalez et al., 2009). Therefore, the typical autosomal dominant pattern may not be present.

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Due to inherited mutations in the BRCA1 and BRCA2 genes, hereditary breast ovarian cancer syndrome (HBOC) is perhaps the best characterized of the hereditary cancer syndromes. Inherited mutations in BRCA1/2 dramatically increase risk for a variety of cancers as outlined in Table 1. Since 1996 clinical genetic testing for mutations in BRCA1/2 has been exclusively commercially available in the United States through Myriad Genetics, and in 2013 reinterpretation of patent law allowed other commercial labs to offer this testing.

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or one in 40 chance of carrying a mutation in either gene (Tonin et al., 1996). Knowledge about Jewish ancestry can have a profound effect on the prior probability of a BRCA1/2 mutation and is therefore an important component of breast cancer risk assessment.

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Table 1: Cancer Risk Ranges for BRCA1 and BRCA2 Carriers Lifetime BRCA1 and BRCA2 Cancer Risks for Women

Type of

Women with

Women with

Average woman in United

Cancer

BRCA1 Mutation

BRCA2 mutation

States without mutation

Breast

46–63%

38–53%

13%

Ovarian

34–44%

12–20%

1–2%

Pancreatic

2–3%

3–5%

1%

Melanoma

–

3–5%

1–2%

Lifetime BRCA1 and BRCA2 Cancer Risks for Men

Type of Cancer

Men with BRCA1 Mutation

Men with BRCA2 mutation

Average man in United States without mutation

1–5%

5–10%

0.1%

∗

15–25%∗

16%

Pancreatic

2–3%

3–5%

1%

Melanoma

–

3–5%

1–2%

Breast Prostate

Note. For more information please refer to Chen et al. (2006) and Chen & Parmigiani (2007).

Cowden syndrome is one of the phosphatase and tensin homolog (PTEN) multiple harmartoma syndromes (Weary, Gorlin, Gentry, Comer, & Greer, 1972) associated with germline mutations of the PTEN tumor suppressor gene. Women with Cowden syndrome have an approximately 35% lifetime risk for developing breast cancer, with a mean age at diagnosis at 42 (Eng, 1997). Thyroid cancer risk approaches 20% and is usually follicular, rarely papillary, and typically not medullary (Harach, Soubeyran, Brown, Bonneau, & Longy, 1999).

Structural thyroid disease such as goiter or benign thyroid nodules are also common as well as uterine fibroids, fibrocystic breast disease, and benign (hamartomatous) polyps of the gastrointestional tract. Other associated malignancies include endometrial cancer, melanoma in women and in men, and kidney (renal cell) cancer. The overall cumulative risk for any cancer by age 70 was reported to be as high as 85% (Tan et al., 2012). Skin manifestations for Cowden syndrome include the pathognomonic finding of trichilemmomas

Table 2: Criteria for Referral for Genetic Counseling and Testing for Li-Fraumeni Syndrome (LFS) 1. Classic criteria for Li Fraumeni Syndrome met (in-text) 2. Chompret criteria met: • Patient with a tumor in the LFS spectrum ≤ age 46 AND • At least one first- or second-degree relative with an LFS associated tumor (except breast cancer if initial patient has breast cancer) diagnosed ≤ age 56 or with multiple primary cancers at any age OR • Patient with multiple primary cancers (except two breast cancers), two of which belong in the LFS spectrum with the first primary cancer ≤ age 46 OR • Patient with a diagnosis of adrenocortical carcinoma or choroid plexus carcinoma at any age 3. Early-onset breast cancer diagnosed ≤ age 35 with negative BRCA1/2 genetic testing 4. Known TP53 gene mutation in the family. Note. For more information please refer to National Comprehensive Cancer Network (2014).

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(benign wart-like skin lesions) as well as lipomas and papillomatous papules. Macrocephaly, developmental delay, and behavioral manifestations along with autism spectrum are also found in a significant number of families with Cowden syndrome (Pilarski et al., 2013). More than 50% of individuals with Cowden syndrome appear to be the first ones in the family to be affected (Marsh et al., 1997). This rate is hypothesized to be due to the presence of a de novo mutation, estimated to occur in 10% to 47% of cases or due to the variability in presentation with no recognizable features identified in the prior generation (Mester & Eng, 2012). As many as 80% of individuals meeting the most stringent diagnostic criteria for Cowden syndrome (initially developed by the International Cowden Consortium) will have a detectable mutation in the PTEN gene (Marsh et al., 1997). Based on clinical and demographic features of the patient, a risk calculator can provide the prior probability of finding a PTEN mutation in children and adults (Genomic Medicine Institute, 2014). Peutz Jeghers syndrome (PJS) is a rare gastrointestinal harmartomatous polyp condition caused by germline mutations in the STK11 gene that includes a significantly elevated breast cancer risk for women among the many component malignancies (Boardman et al., 1998; Giardiello et al., 2000; Hearle et al., 2006). Women with PJS have as much as a 57% chance of developing breast cancer by age 70 (Hearle et al., 2006). Other tumor types include gastric, colon, small bowel, pancreatic, lung, and ovarian cancer. A rare sex cord ovarian tumor with annular tubules (SCTAT) is also highly correlated with this condition in girls, and Sertoli cell tumors of the testis can develop in prepubescent boys. Individuals affected by PJS typically have characteristic mucocutaneous freckling, most commonly around the vermillion border of the lips, which is often the first sign to appear in young children. The pigmented macules may fade after puberty but tend to persist in the buccal mucosa. The colon polyps tend to have a characteristic frond-like branching appearance with cystic gland dilatation and may display pseudoinvasion that can be mistaken for an invasive carcinoma. Peutz Jegher polyps are most commonly found in the small bowel leading to pain and intussusceptions. Polyps frequently become symptomatic in children and are seen in 33% of affected individuals by age 10 and in 50% of affected individuals by age 20. Approximately 45% of individuals with PJS have no known

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family history of this condition (Giardiello et al., 2000).

Identification of Hereditary Breast Cancer Risk Accurate and thorough collection of family history remains the cornerstone of cancer risk assessment to identify the presence of hereditary cancer syndromes (Bennett, 1999). Primary care and obstetric/gynecologic clinicians, including nursing professionals, are uniquely positioned to identify individuals at increased hereditary or familial risk of cancer (American College of Obstetricians and Gynecologists, 2009). Family history information should be kept updated since a nonsuggestive family history could change over time to one that is highly suggestive of inherited cancer risk. The family history should include a minimum of three generations on the maternal and paternal sides. An example of a cancer family history represented as a family tree (also known as a pedigree) may be seen in Figure 1. Because patients may commonly think that the paternal side is not relevant when discussing risk assessment for female cancers, providers need to explicitly elicit details about both sides of the family. Key pieces of information to record about affected and unaffected relatives to capture an informative pedigree are summarized in Table 3. Time constraint has been documented as one of the leading barriers for the collection of an adequate pedigree (Flynn et al., 2010). Online tools such as the web-based My Family Health Portrait (U.S. Department of Health and Human Services, 2014) can help facilitate this process. Clinicians may also wish to use family health questionnaires. Providing patients with these questionnaires ahead of an appointment can allow them to contact their relatives and obtain more information to significantly increase the accuracy and utility of the family history (Armel et al., 2009). When interpreting cancer family histories it is important to identify hallmarks of genetic risk for breast and other cancers including the following: (a) age at diagnosis may be significantly younger than when that cancer typically occurs, (b) multiple family members in > one generation with the same or related types of cancer, (c) individuals with multiple primary cancers, and (d) presence of rare cancers (e.g., male breast cancer). In some families, a pattern of cancer is obvious, whereas in others it may be difficult to detect a pattern due to small family size, adoption, if family is male

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Table 3: Information to Collect on Affected and Unaffected Relatives for Cancer Family Tree • Record all siblings, children, parents, grandparents, maternal aunts and uncles, cousins, and nieces and nephews whether or not affected with cancer • The ratio of affected to unaffected relatives helps establish the possible mode of inheritance. When cancer history extends into more distant relatives (such as siblings of grandparents, cousins, etc.) through an unbroken line of descent, this additional information can add to the interpretation • Record all incidences of cancer, including ages at diagnosis and death o Distinguish primary from metastatic sites o Record whether cancer was unilateral, bilateral, or multifocal • Record current ages and causes of death • Record risk-reducing surgeries or treatments such as chemoprevention that might have affect cancer risk on relevant individuals • Record ethnicity including the presence of Jewish ancestry in each branch of the family

dominated, or if family history is incompletely reported or elicited from the patient (Qureshi et al., 2007; Weitzel et al., 2007).

Breast Cancer Risk Assessment Models The goal of cancer risk assessment is to identify women who could benefit from consideration of genetic counseling and testing or changes to cancer risk management (Domchek et al., 2003). Two types of models are frequently used for breast cancer risk assessment. The first is used to estimate the risk of developing breast cancer over time; examples are the Gail and Claus models. The second is used to estimate the likelihood of detecting a mutation in a cancer susceptibility gene and helps determine appropriate candidates for genetic testing. This type of model is often referred to as a prior probability model. The Claus model is based on empiric data from the Cancer and Steroid Hormone Study and consists of a series of precalculated tables that provide lifetime breast cancer risk estimates for women based on the history of breast cancer in their first- and second-degree relatives. Strengths of this model include incorporation of paternal and maternal family history, stratification of risk based on the relative’s age at diagnosis, and ease of use. The Claus model does not include well-known epidemiologic risk factors such as age at menarche, age at first birth, or biopsy information, nor does it capture third-degree relatives or male breast cancer (Claus, Risch, & Thompson, 1994).

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The Breast Cancer Risk Assessment Tool (National Cancer Institute, 2014), also known as the Gail model, is a web-based tool developed by scientists at the National Cancer Institute to estimate a woman’s risk in the next 5 years and her lifetime risk to age 70. This model combines nongenetic risk factors such as breast biopsy history, presence of atypical hyperplasia, reproductive history (age at menarche, age at first live birth), with limited family history. Family history is captured by entering whether the woman has 0, 1 or >1 first-degree relatives. A major limitation of the Gail model is that is does not capture any paternal history and does not stratify by age at diagnosis of the affected relative (Gail et al., 1989). The Penn II model (University of Pennsylvania, 2014) is a web-based, easy-to-use, logistic regression model to predict the chance of finding a BRCA1 or 2 mutation based on the presence or absence of characteristic features of HBOC. The model was developed using a set of 966 families presenting to breast cancer risk evaluation clinics in the United States and United Kingdom who underwent both BRCA1 and BRCA2 genetic testing (Lindor et al., 2010). Myriad Genetic Laboratories currently houses the majority of BRCA1 and BRCA2 testing data in the United States. This database has enabled the laboratory to calculate prior probabilities based on a sampling of over 10,000 tested individuals. This information has been adapted into tables that may be downloaded and printed. Also, the BRCA Risk Calculator (Myriad Genetic Laboratories, 2014) is a fast and easy checklist that will calculate

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Irish/Scoƫsh

German/German

Breast dx 44 y a. 87

69 Breast dx 39 y a. 62

Breast dx 29 y d. 44

d. 92

67

67

d. 79

59

d. 69

33

27

Legend

30

Female

No known Ashkenazi Jewish ancestry on either side of the family.

Male

3

1 Breast cancer

Figure 1. Example of a cancer history family tree. The arrow points to the patient seeking consultation or the proband. This family tree includes the proband’s children (two sons), her parents (directly above her), aunts/uncle, grandparents, and children of those who have been diagnosed with breast cancer. It is also important to document ancestry for maternal and paternal sides of the family and whether there is known Ashkenazi Jewish ancestry. This allows the clinician to more easily visualize patterns and assists with the identification of familial risk.

When there is evidence of a hereditary cancer condition, properly trained clinicians may decide to provide genetic counseling and testing on their own. If a syndrome is identified, or if a clinician does not feel they have the time or expertise to appropriately offer these services, then referral to a cancer genetics provider is suggested. Can-

cer genetic services, typically provided by clinicians with expertise in oncology and genetics, include risk assessment and education, facilitation of genetic testing, pre- and posttest counseling, provision of personally tailored cancer risk management options and recommendations, and psychosocial counseling and support services (Stopfer, 2000). Table 5 provides resources for identifying multidisciplinary clinicians with this expertise. Counseling regarding genetic risk is a communication process that can but does not always lead to genetic testing. Genetic counseling, however, is a critical part of any genetic testing and should be provided by a professional with the appropriate training and time to ensure that the testing leads to informed decision-making in an appropriately supportive environment (Peters & Stopfer, 1996; Stopfer, 2000).

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BRCA1/2 prior probabilities without having to reference the tables directly. The tables were most recently updated in 2010 and are subject to change as more individuals (and ethnicities) are tested. General referral criteria for patients appropriate for BRCA1/2 testing who are affected or cancer free are provided in Table 4.

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Table 4: Indications for Genetic Counseling and Testing for BRCA1 and BRCA2 Affected individuals based on personal history: • Breast cancer diagnosed at or before age 45 • Triple negative breast cancer (ER-, PR-, her-2-) diagnosed at or before age 60 • Two breast primaries when first breast cancer diagnosis at or before age 50 • Epithelial ovarian cancer diagnosed at any age • Male breast cancer diagnosed at any age • Ashkenazi (Eastern European) Jewish ancestry and breast or ovarian cancer at any age • A known gene mutation in BRCA1 or BRCA2 in a close blood relativea Affected in individuals based on personal and family history: • Breast cancer diagnosed at any age and ≥1 close relativeb diagnosed with breast ≤ age 50 • Breast cancer diagnosed at any age and ≥1 close relative diagnosed with epithelial ovarian cancer at any age • Breast cancer diagnosed at any age and ≥2 close relatives diagnosed with breast cancer at any age • Breast cancer diagnosed at any age and ≥2 close relatives diagnosed with pancreatic cancer or aggressive prostate cancer (Gleason score ≥7) • Personal history of pancreatic cancer or aggressive prostate cancer (Gleason score ≥7) at any age with ≥2 close relatives with breast and/or ovarian cancer and/or pancreatic or aggressive prostate cancer (in the same lineage) Unaffected (cancer-free) individuals based on family history: • Has a first-degree relative meeting any of the above criteria • Testing of unaffected individuals should only be considered when an appropriate affected family member is unavailable for testing. Note. a close blood relative is defined as a first-, second-, or third-degree relative related by blood. b Although there is no convincing evidence of overall increased risk of prostate cancer, men with BRCA1 mutations may develop prostate cancer at a younger age than men in the general population. BRCA2 mutations are associated with an increased risk of prostate cancer, which also can be of earlier onset. For more information please refer to National Comprehensive Cancer Network (2014).

Careful assessment of the cancer pedigree enables providers to establish whether the history supports genetic testing and if so which gene(s) to evaluate. A key principle in genetic testing for hereditary cancer is to initiate testing in a family member who has been diagnosed with a representative cancer for the heritable condition in question (Stopfer, Venne, & Schneider, 2008). Testing the individual who is affected whenever possible can help determine whether the pattern of cancer risk is due to a detectable mutation in the family or whether the pattern of cancer is suspicious but without a gene mutation that can be

Nursing professionals are ideally situated to identify individuals who could benefit from cancer genetics services by obtaining and assessing family history.

tracked. Sometimes a pattern of cancer may be due to shared common environmental factors, or the pattern of cancer in the family may represent a series of sporadic events. In addition, not all mutations in cancer susceptibility genes are detectable due to laboratory methodology limitations.

Table 5: Resources to Assist in Locating Cancer Genetics Professionals 1. American College of Medical Genetics (ACMG): www.ACMG.net 2. National Society of Genetic Counselors (NSGC): www.NSGC.org 3. National Cancer Institute (NCI): http://www.cancer.gov/cancertopics/genetics/directory 4. NCI-Designated Cancer Centers: www.cancercenters.cancer.gov Increasingly genetic counseling services are available through telephone and telemedicine such as Informed DNA when a local cancer genetics specialty clinic is not available. See www.informedDNA.com

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Some individuals are reluctant to pursue genetic predisposition testing due to fear of discrimination. The Genetic Information Nondiscrimination Act (GINA) is a federal law passed in 2008 that prohibits using genetic information in underwriting decisions for health insurance coverage or for employment decisions, including hiring and promotions (Equal Employment Opportunity Commission, 2010). GINA, together with already existing nondiscrimination provisions of the Health Insurance Portability and Accountability Act (HIPAA), generally prohibit health insurers or health plan administrators from requesting or requiring genetic information from an individual or the individual’s family members or using such information for decisions regarding coverage, setting rates, or determining preexisting conditions. The law also prohibits most employers from using genetic information for hiring, firing, or promotion decisions. Although many people fear genetic discrimination, little evidence supports that this type of discrimination has been a significant problem. Providers should be prepared to discuss the realistic threats of genetic discrimination to patients so they can make informed decisions about whether the benefits outweigh their concerns.

Arranging Genetic Testing Traditionally genetic testing has been used to look for gene mutations for a specific hereditary condition. However, new multigene panels using next generation sequencing technology have increased the feasibility of comprehensive evaluation of multiple genes simultaneously and at lower costs (Pennington & Swisher, 2010). Instead of sequential single gene testing, a gene panel may reduce patient burden by facilitating broader scale testing for 25 genes or more after a single evaluation and specimen collection and may increase the chance to detect a deleterious mutation as family histories can be suggestive of more than one condition. The advent of gene panels and larger scale clinical DNA evaluation does bring controversy and debate. Many of the gene panels currently offered include highly penetrant genes that confer significantly elevated cancer risks and moderately penetrant genes that may increase risk more marginally. The clinical utility of evaluating moderately penetrant genes remains unknown, and presymptomatic testing for moderate-penetrance genes does not provide the same clarity or guidance as testing for high-penetrance genes, even when a mutation is known to be present in a fam-

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ily (Domchek, Bradbury, Garber, Offit, & Robson, 2013). Furthermore, panel testing may include genes that are less well characterized, so there is a higher likelihood testing will identify variants of uncertain significance (VUS). The VUS represents an alteration in the genetic code, but the functional significance of this alteration is not well understood. The VUS may in fact represent normal sequence variability, or the VUS may disrupt normal gene function; the final determination is uncertain. Given the complexities of panel testing, clinicians who order these tests need to consider their ability to help guide their patients through the process and to provide detailed pre- and posttest counseling (Domchek et al., 2013). Identification of a mutation in a cancer susceptibility gene can be an extremely helpful outcome of genetic testing. Generally, once a mutation has been identified, testing for relatives will be for this specific mutation rather than sequencing of a gene or genes. Targeted mutation testing is also far less expensive. When testing a patient for a targeted known mutation, obtaining the relative’s genetic testing lab report demonstrating the exact mutation is critical. Relying on patient report or seeing a description of the mutation in a medical record could lead to erroneous results if the mutation was incorrectly specified. Generally it is best to send a copy of the relative’s lab report with the sample when ordering site specific mutation testing. One common exception to the general rule of testing only for a known family mutation if known occurs in Ashkenazi Jewish families with one of the common founder mutations in BRCA1 or BRCA2. There are three specific mutations, 187delAG, 5382insC in BRCA1 and 6174delT in BRCA2, that account for 90% of detectable mutations in this population. Even in the presence of a specific founder mutation, it is recommended that other family members continue to be tested for all three common mutations. The frequency of BRCA1/2 mutations in the Ashkenazi Jewish population is sufficiently high that testing for all three common mutations is necessary to not to miss a different mutation being inherited through another branch of the family. If a known mutation in the family exists, and another relative tests negative for this known mutation, then this result is considered a true negative and the patient can be counseled that he or she is at average risk for cancer, as long as a significant family history of cancer is not present on the

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other side of the family. However, if an affected individual is tested and no mutation is found, context is critical. No test is currently available that can capture every source of genetic or inherited cancer risk, so if the family history is suggestive, medical management guidelines will need to continue to take into account personal medical history and family history information. Variants of uncertain significance cannot be used in interpreting source of cancer susceptibility.

Cancer Risk Management Protocols for cancer risk management for the main hereditary cancer syndromes including breast cancer are summarized in Table 6. It is important to note that all individuals, especially those with high genetic risk, are encouraged to minimize alcohol intake to fewer than —two to three drinks per week, maintain healthy body weight especially after menopause, and partake in regular aerobic exercise. Some women are also eligible to consider chemoprevention or taking a selective estrogen receptor modulator (SERM) such as tamoxifen or raloxifene to lower breast cancer risk. The Breast Cancer Prevention Trial demonstrated that Tamoxifen given for 5 years reduced breast cancer incidence in high-risk women by 49% (Fisher et al., 1998). More recent data from additional studies demonstrated a 30% to 40% reduction in estrogen-receptor positive invasive breast cancers specifically with the use of Tamoxifen (Cuzick et al., 2007; Powles, Ashley, Tidy, Smith, & Dowsett, 2007). The U.S. Preventive Services Task Force (USPSTF) recently recommended that clinicians engage in shared, informed, decision making with women who are at increased risk for breast cancer and at low risk for adverse medication effects about medications to reduce their risk (Moyer, 2013). To address the markedly elevated lifetime risks of developing breast and ovarian cancer associated with inherited BRCA1/2 mutations, risk-reducing salpingo-oophorectomy (RRSO) is an important intervention that decreases the risk of ovarian cancer by approximately 80%. When RRSO is performed in a premenopausal woman, breast cancer risk is also reduced by about 50% (Rebbeck, Kauff, & Domchek, 2009). This procedure has also been shown to reduce short-term overall mortality in BRCA1/2 mutation carriers. As a result, RRSO is recommended by age 40, or once childbearing is complete, though generally not before age 35. BRCA1 carriers have earlier reported onset of ovarian cancer than carriers of BRCA2 mutations.

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Because RRSO in premenopausal woman leads to abrupt premature menopause, women who have never had breast cancer can consider using short term hormone replacement therapy (HRT) to mitigate symptoms. One of the arguments for not using HRT following RRSO is a theoretical increased risk of breast cancer in this population. However, researchers have demonstrated that shortterm HRT after RRSO in premenopausal women does not negate the protective benefit of RRSO on breast cancer risk reduction (Domchek et al., 2010). Personal medical history may favor complete hysterectomy if a woman has had a history of symptomatic fibroids or dysfunctional bleeding. A potential advantage for women who are taking tamoxifen and having a complete hysterectomy is the slightly decreased risk for endometrial cancer associated with this medication. In addition, HRT for premenopausal women can be simplified posthysterectomy sinbecausece a woman is then a candidate to take unopposed estrogen. There may be a benefit to this approach in that progesterone supplementation appears to raise subsequent breast cancer risk more than estrogen monotherapy when provided to postmenopausal women (de Villiers et al., 2013). Finally, theoretical risk exists for the development of cancer in the remaining stump of fallopian tube imbedded within the wall of the uterus (Collins, Domchek, Huntsman, & Mitchell, 2011). Although each of these issues in isolation may not be enough to guide a woman’s decision about oophorectomy or hysterectomy, the additive effect of these potential benefits may influence a woman’s choice. Because the recovery time for complete hysterectomy is longer that RRSO, the choice remains a personal decision for each women in consultation with her gynecologic provider to determine the individual optimal approach. Several researchers have examined the safety of birth control pills in women who have mutations in a BRCA gene, and some suggested that the risk reduction for ovarian cancer can be as much as 50%. However, some conflicting findings about the association between birth control pills and breast cancer risk have been identified. Some researchers have shown a small increased risk of breast cancer associated with these medications (Mooreman et al., 2013) However, many researchers included women who were on higher dosages of hormones prior to the 1970s, and current formulations of birth control pills have lower hormone levels and may therefore be associated with lower risks. Ultimately, it is important to balance the risk of breast cancer for which effective

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Consider risk reducing mastectomy

Consider chemoprevention options

done q 12 mos starting at age 18

Capsule endoscopy or MR enterography of small intestine starting between ages 4–8. Repeat q 3 years if polyps found or again at age 18 Colonoscopy and EUS starting at age 8. Repeat q 3 years if polyps found or again at age 18 Pelvic exam and pap smear q12 mos starting at age 18 MRI-MRCP or endoscopic ultrasound

Comprehensive physical exam with attention to the thyroid starting at age 18 or five years earlier than earliest cancer case in family Thyroid ultrasound q 12 mos starting at age 18 Colonoscopy at age 35, then q 5–10 years or more frequently based on symptoms or polyps Consider dermatology exam q12 mos

index of suspicion for rare cancers, careful skin and neurological exam Colonoscopy q 2–3 years starting no later than age 25 Can offer novel approaches including rapid whole body MRI, abdominal ultrasound and brain MRI Additional surveillance based on family history

Pelvic/pap smear q 12 mos starting at age

18 Can consider pancreatic cancer

screening by age 50 if BRCA2 positive

and positive family history of pancreatic

cancer in first or second degree relative

Dermatology exam q 12 mos

Males Only: Clinical breast exams q 6–12

age 25 Males only: testicular exam q year from infancy. Ultrasound if

mammograms starting at 40 if

gynecomastia present. Annual PSA and

prostate exam starting at 40

symptomatic or abnormality on exam

of the pancreas q 1–2 years starting at

mos starting at 35. Consider

Colonoscopy q 5 years starting age 50. Can

be more frequent if polyps found

then removal of ovaries (BSO)

earliest onset until childbearing complete,

at age 30, or 5–10 years prior to the

Ovarian ultrasound Both tests can be

Both tests can be done q 6 mos starting

CA-125 blood test

Ovarian ultrasound

CA-125 blood test

Comprehensive physical exam with high

Breast MRI q 12 mos starting at age

Consider risk reducing mastectomy

Breast MRI q 12 mos starting at age 20–25

Breast self exam q 1mos

Consider risk reducing hysterectomy

25

Breast MRI q 12 mos starting at age 25

20–25

Breast MRI q 12 mos starting at 25

25 Consider risk reducing mastectomy

Mammogram q 12 mos starting at age

Mammogram q 12 mos starting at age 25

Mammogram q 12 mos starting at age

Mammograms q 12 mos starting at 25

Consider risk reducing mastectomy

5–10 years prior to earliest onset

prior to earliest onset

CBE q 6 mos starting age 25 or

(STK11)

Peutz Jegher

5–10 years prior to earliest onset

CBE q 6 mos starting age 25 or 5–10 years

(PTEN)

Cowden

months (mos) starting at 25

CBE q 6 mos starting age 20–25 or

Fraumeni (TP53)

Note. BSO = bilateral saplingo-oophorectomy; EUS = endoscopic ultrasound; MR = magnetic resonance; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging. For more information please refer to National Comprehensive Cancer Network (2014).

cers

Other can-

Ovarian

Breast

Clinical breast exams (CBE) every (q) 6

Cancer

Female

Hereditary Breast Ovarian

Syndrome (BRCA1, BRCA2)

Type of

Table 6: Heritable Breast Cancer Syndromes Management Recommendations

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Powers, J., and Stopfer, J. E.

screening is available against the reduced risk of ovarian cancer while considering individual decisions regarding the need for effective birth control. Discussion of the benefits and risks on an individual basis is strongly encouraged. Genetic testing at the time of initial diagnosis can affect surgical decision making since the risk of developing a second primary breast cancer approaches 50% in BRCA1/2 carriers. Some women will elect to have bilateral mastectomies at the time of their initial breast cancer diagnoses, even if they are candidates for breast conservation because of their desire to maximally lower the chance of developing a second primary. Sometimes RRSO can be arranged at the same time as bilateral mastectomy with reconstruction, which can minimize the number of surgeries. Treatment decisions can sometimes be influenced since advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly (ADP-ribose) polymerase (PARP) inhibitors (Maxwell & Domchek, 2012).

Family history assessment enables clinicians to determine whether genetic testing is indicated and how to arrange and offer appropriate guidelines for cancer risk management.

ity, it is likely that uptake will increase. However, the broad and high risk for cancer combined with significant risk for pediatric cancers and lack of proven modalities to significantly lower these risks is overwhelming for some individuals contemplating this testing. Because TP53 is included in most breast cancer susceptibility testing panels, it is important that pretest counseling include some mention of this condition and the potential clinical consequences. Screening guidelines for PJS are provisional, largely based on expert opinion, and may vary from center to center. Goals in screening for PJS include the reduction of polyp burden to prevent bleeding and obstruction and close monitoring to maximize chances for early cancer diagnoses while still amenable to cure. Because the risk for breast cancer associated with PJS is similar to that for women affected with BRCA1/2, close breast surveillance including mammography, breast MRI, clinical breast exams, and consideration of risk reducing surgery are all appropriate considerations. A summary of consensus guidelines for management of PJS are presented in Table 6.

Clinical surveillance protocols are available for those with LFS, but challenges remain in screening for such a large variety of cancers. International LFS screening regimens vary per country, and in the United States, the National Comprehensive Cancer Network has published consensus recommendations shown in Table 6. Individuals with LFS are particularly sensitive to ionizing radiation and have been reported to be at increased risk to develop new cancers such as sarcomas in the radiation field at treated sites. Avoiding radiation in young women being treated for breast cancer can lead to the need for rapid testing around the time of diagnosis to help inform treatment decisions. Even young women with small tumors otherwise amenable to breast conservation and radiation may be better candidates for mastectomy or bilateral mastectomy to avoid the need for radiotherapy (Heymann et al., 2010). Mammography is not contraindicated in women with LFS since the benefits of early breast cancer detection likely outweigh the risk from such minimal radiation exposure (Villani et al., 2011). Further studies are needed to determine the effectiveness of these interventions for those with LFS.

Conclusion

Historically, uptake of genetic testing in families with known TP53 mutations has been lower than in families with other hereditary cancer conditions (Patenaude et al., 1996). As further data become available about the clinical utility of screening and the ability to reduce cancer burden and mortal-

Major advances in the understanding of inherited risk for breast cancer have provided individuals and families with critical opportunities to prevent or lower cancer risks and optimize chances for early detection and cure. When a specific gene mutation associated with inherited cancer risk can be found, multiple family members can be tested and

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Preimplantation genetic diagnosis (PGD) can be an option for individuals who carry a known genetic syndrome and wish to dramatically reduce the chances of passing this on to a child. This procedure is used in combination with in vitro fertilization to screen embryos for a specific genetic mutation allowing for embryos without the known mutation to be transferred into the woman. The genetic mutation must first be identified in a parent, whether male or female, to perform PGD, and PGD does not guarantee that the transferred embryos will lead to a full-term pregnancy. However, PGD remains an option in addition to prenatal diagnosis to changing the odds of having a child who will also carry inherited susceptibility to cancer.

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learn whether they are at high risk. Even when specific genetic risk cannot be identified with current genetic testing methodologies, clinicians can still provide risk assessments that help guide screening and cancer risk management recommendations. Nursing professionals are ideally situated to play a critical role in this process by obtaining and assessing family history information, facilitating the process of genetic counseling and testing, and deciding if a patient referral to a cancer genetic specialist is appropriate. Opportunities for identification of genetic risk for breast cancer and interventions to ameliorate risks based on this information will continue to expand as new genes and technologies are developed.

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