Hereditary breast cancer risk assessment in primary care

Clinicians should be proficient at assessing hereditary breast cancer risk in their patients and be aware of the indications for referral to genetic counseling.

Because of early detection and more efiective treatment regimens, the number of women living with breast cancer in the United States has increased to approximately 2.8 million.1 Although it does occur in men, breast cancer is the most common cancer in women, irrespective of a woman's race or ethnicity. Based on current rates of breast cancer incidence, approximately one in every eight women born today will be diagnosed with breast cancer during her lifetime.

Treatment of breast cancer has steadily improved in the 21st century. These improvements have been accomplished through advances in breast imaging, recognition and identification of germline mutations, and evidence-based interventions, including risk-reducing medications and lifestyle changes.

Primary care clinicians should complete a hereditary cancer risk assessment at each patient visit. Although cancer risk assessment may be unfamiliar to many primary care clinicians, it is incumbent on them to be proficient and thorough in this type of evaluation. These practices should include recognition of familial disease patterns suggestive of inherited susceptibility to breast cancer, risk assessment, referral to genetic counseling and testing, and interpretation of these results into practice.

Evaluating family history

Evaluation of family history is one of the most efiective and least expensive tools to identify individuals at increased risk for breast cancer, and yet many providers do not adequately assess their patients' familial and genetic risk of developing breast cancer. All breast cancers are genetic, but not all breast cancers are hereditary; breast cancer can be attributed to sporadic, familial, or genetic causes.

Approximately 5% to 10% of breast cancers can be linked to genetic mutations from the maternal or paternal side; a woman's risk of breast cancer approximately doubles if she has a first-degree relative who has been diagnosed with the disease.2 Sporadic breast cancer can be partly explained by known risk factors such as age at menarche, age at first live birth, age at menopause, history of proliferative breast disease, and lifestyle factors.

Hereditary breast and ovarian cancer (HBOC) syndrome, which is caused by a germline mutation in the high-penetrance breast cancer genes BRCA1 or BRCA2, is characterized by an increased risk for breast cancer.3 An increased likelihood of a BRCA1 or BRCA2 mutation can be suspected on the basis of certain personal and family history characteristics and clinical criteria. The lifetime risk for breast cancer in individuals with a mutation in BRCA1 or BRCA2 is estimated to be 40% to 80%.4

The prognosis for patients with BRCA1- or BRCA2-related breast cancer depends on the stage at which the cancer is diagnosed, and early diagnosis may depend on a patient's awareness of increased familial or genetic risk. Similarly, patients with mutations in other high-penetrance genes such as tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), serine/threonine kinase 11 (STK11), and cadherin 1, type 1 (CDH1) may develop cancer predisposition syndromes associated with the development of several types of cancer, and they have a higher likelihood of developing breast cancer in their lifetimes. Moderate-penetrance breast cancer susceptibility genes that can increase breast cancer risk during a woman's lifetime include checkpoint kinase 2 (CHEK2), ataxia telangiectasia mutated serine/threonine kinase (ATM), nibrin (NBN), RAD50 homolog, double strand break repair protein (RAD50), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and partner and localizer of BRCA2 (PALB2).5 In men, 3 classes of genetic susceptibility to breast cancer (high-, moderate-, and low-penetrance) are recognized, but the genes that are involved and their impact do not exactly overlap in female and male breast cancer.6

An increased likelihood of a genetic mutation in moderate- and high-penetrance genes can be suspected on the basis of certain personal and family history characteristics and clinical criteria. Clinicians may then be able to advise patients who carry a genetic mutation or know of their increased risk of management strategies that might mitigate their breast cancer risk.

Even if no hereditary susceptibility is suggested by the family history, individuals having one or more close relatives with breast cancer may benefit from beginning cancer surveillance at a younger age and/or with more intensive screening than those in the general population. National guidelines recommend that individuals with hereditary breast cancer susceptibility be screened earlier and consider more sensitive screening tests, risk-reducing medications, and/or risk-reducing surgery.7

Risk of sporadic, familial, and hereditary breast cancer may be modified by lifestyle and environmental factors, breast imaging, chemoprevention, and/or prophylactic surgery,8 but awareness and knowledge about techniques to reduce breast cancer risk varies tremendously among individuals, providers, and populations nationwide. It has been hypothesized that when individuals are made aware of the level of their breast cancer risk and are given appropriate tools, support, and screenings, they would take proactive steps to mitigate their risk of developing cancer and increase their odds of survival if breast cancer does occur.9 It is also thought that if patients are informed of their elevated risk for breast cancer, their compliance with breast cancer prevention measures is greater.9 Of note, tools to identify women at elevated risk of developing breast cancer have been validated.10

The National Comprehensive Cancer Network (NCCN),11 a not-for-profit alliance of 26 of the world's leading cancer centers that is devoted to patient care, research, and education, has developed breast cancer risk-reduction guidelines that can be used in clinical practice. Individuals at elevated risk of developing breast cancer can be identified and encouraged to follow these clinical guidelines to reduce their risk.

Indications for referral to genetic counseling

It is important for clinicians in primary care to recognize when referral to a genetic counselor is recommended. A cancer risk assessment should be conducted at every primary care visit, and the patient's family cancer history should be updated as appropriate at every visit.

NCCN guidelines7 recommend referral to a cancer genetics professional when there is a history involving either side of the family-maternal or paternal-of any of the following:

* A known mutation in a cancer susceptibility gene in the family

* A first- or second-degree relative with breast cancer at age 45 or younger (includes ductal carcinoma in situ). First-degree relatives include siblings, parents, and children; second-degree relatives include grandparents, aunts, uncles, half-siblings, nieces, and nephews; third-degree relatives include cousins, half-aunts and uncles, great aunts and uncles, great grandparents, and great grandchildren.

* A close family member with at least two primary breast cancers. Close blood relatives include first-, second-, and third-degree relatives.

* At least two closely related individuals on the same side of the family with breast cancer

* At least one woman in the family with invasive ovarian cancer (including fallopian tube and primary peritoneal cancer)

* Breast cancer in a male family member

* Three or more individuals on the same side of the family with pancreatic or prostate cancer (Gleason score ≥ 7)

* Ashkenazi (Eastern European) Jewish ancestry and breast, ovarian, or pancreatic cancer at any age

There are less common hereditary cancer syndromes that confer an increased risk of developing breast cancer. These syndromes may seem a bit more elusive but it is imperative that clinicians assess their patients for their presence because an increased incidence of breast cancer is seen within families that carry these syndromes. Clinicians should be suspicious of these less common hereditary syndromes when three or more findings occur in any of the four following groups:

* Sarcoma, adrenocortical carcinoma, brain tumor

* Endometrial cancer, thyroid cancer, kidney cancer, macrocephaly, skin findings of trichilemmoma, multiple palmoplantar keratosis, multifocal or extensive oral mucosal papillomatosis, multiple cutaneous facial papules

* Diffuse gastric cancer

* Hamartomatous polyps of the gastrointestinal tract

Patients whose family histories suggest a less common hereditary breast cancer syndrome should also be referred to a genetics professional for genetic counseling. Less common hereditary breast syndromes include Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer.

Genetic counseling and testing

Many individuals with typical family histories greatly overestimate their risk for breast cancer and may unnecessarily live with a disproportionate fear of developing the disease. Genetic counselors specializing in hereditary and familial cancer are trained in hereditary cancer risk assessment in individuals at high risk and can provide expert guidance.

Genetic counselors are health professionals with specialized graduate degrees and experience in the areas of medical genetics and counseling. Genetic cancer counseling integrates the following components:

* Collection and documentation of a detailed family history of cancer

* Review of appropriate medical records

* Pedigree assessment and recognition of cancer susceptibility syndromes (includes all cancer types)

* Calculation of hereditary cancer risk using risk assessment models

* Explanation of inheritance pattern and implications for family members

* Assistance in exploring the medical and psychologic implications of genetic testing

* Review of costs, benefits, and limitations of genetic testing

* Provision of informed consent, including issues of privacy, confidentiality, and legal protections against genetic discrimination

* Assistance in obtaining insurance coverage for testing

* Selection of appropriate genetic testing and testing laboratory

* Determination of best strategy for testing within the family

* Interpretation of genetic test results

* Provision of ongoing emotional support and assistance in informing family members

* Assistance in developing a plan for cancer screening and risk reduction, when appropriate

* Detailed summary letters sent to patients and their physicians

* Referrals to research and local and national support organizations, when appropriate

Genetic counseling appointments typically last between 45 minutes and an hour. Interested family members are usually welcome to attend. The genetic counselor usually begins the appointment by listening to the patient's goals, expectations, and concerns to understand how best to meet the patient's needs.

Information about the family history is collected and documented either prior to or during the appointment. The counselor explains the basic principles of genetics and hereditary cancer, including what clues might indicate that the cancer seen within that family could be hereditary.

The patient and counselor review and assess the patient's family history of cancer together. Many genetic counselors provide a numeric estimate of the likelihood that the patient will carry a gene mutation generated by a validated risk assessment tool.

Genetic testing is discussed in detail, including whether testing is indicated for a particular patient, the most useful strategy for testing within the family, possible test results for the patient and the family, and insurance coverage. Many options for genetic testing are now available, ranging from analysis of a single gene mutation to testing dozens of genes simultaneously. The counselor reviews appropriate testing options and answers any questions that the patient has.

Genetic testing can usually be performed on a blood or saliva specimen, and results are usually available in 1 to 5 weeks. Once the results of testing are available, the genetic counselor reviews them with the patient, either in person or by telephone. The genetic counselor discloses to the patient whether a gene mutation was found. In addition, the patient's chance of developing cancer is discussed, and recommendations for screening and risk reduction are reviewed. If a gene mutation is found, the counselor offers assistance on how to discuss this information with family members and provides information about support groups, cancer gene registries, and other resources that may be helpful to the patient.

Many myths exist about genetic counseling and can affect use of genetic counseling and testing. It is important to dispel these myths and address them whenever possible with patients and clinicians. Some of the more common myths and misperceptions about genetic counseling are listed in Table 1.

Conclusions

Primary care clinicians are in a unique position to identify individuals at increased risk for development of hereditary or familial breast cancer. Using a protocol-driven evaluation of personal and family risk factors and genetic testing for breast cancer, clinicians are able to manage patients at increased risk of developing breast cancer in a primary care setting.

Patients who are suspected of having an inherited syndrome should be referred to genetic counseling and testing, which allows appropriate risk stratification and management in those found to carry a genetic mutation. If a hereditary breast cancer syndrome is identified, early evaluation and additional interventions can substantially decrease the mortality and morbidity associated with breast cancer.

Case 1

AB came in for genetic counseling at age 40, due to her concern about her mother's history of breast cancer at age 44 and her wish to be proactive in surveillance and prevention measures. Her mother's only sister died at age 60, and her maternal grandmother died at age 86; neither of them had been diagnosed with cancer of any kind. There was also a history of colon cancer in AB's father at age 62.

AB's family pedigree, which is a chart that enables a genetics professional to visualize the appearance and phenotype of a particular gene, is shown in Figure 1. Family members affected by breast and colorectal cancer are indicated and standard symbols are used to represent women (circles) and men (squares).

According to guidelines from the National Comprehensive Cancer Network, AB met the criterion for testing hereditary breast and ovarian cancer (a first- or second-degree relative with breast cancer at age 45 or younger). However, due to significant limitations in the ability to interpret test results in an individual without cancer, it is recommended that in any family, testing begin with the family member with the highest likelihood of a mutation. If a mutation is identified in that individual, then other family members can be tested for that specific mutation. If no mutation is detected, then testing is usually not indicated for other family members.

AB's mother, now age 62, was the ideal candidate for testing, and she agreed to be tested. Analysis revealed a mutation in the BRCA2 gene. It was therefore recommended that she undergo risk-reducing salpingo-oophorectomy and be screened with breast magnetic resonance imaging (MRI) and mammography annually, or consider risk-reducing bilateral mastectomy or other risk-reducing measures. Her initial breast cancer had been treated with lumpectomy followed by radiation therapy.

For AB, the following information was now clear: the cancer in her mother was hereditary, and the specific mutation had been identified. AB was tested for the mutation found in her mother, and the results showed that AB did not inherit the mutation. These results were interpreted as a "true negative." Her risk for hereditary breast cancer having been ruled out, she was advised that she was expected to have the same risk for breast and ovarian cancer as a woman at average risk and should be screened accordingly. In addition, due to the history of colon cancer in her father, AB was advised to begin screening via colonoscopy at age 40, rather than at age 50.

Case 2

GG is a 34-year-old woman who has come to the clinic for her annual well woman examination. She has not had a diagnosis of breast cancer, but she is concerned that she is at high risk of developing breast cancer because she has an older sister (GA) who was diagnosed with breast cancer at age 35. She has a younger sister (GB) who was diagnosed with breast cancer at age 31. On the paternal side of her family, she had an aunt who was diagnosed with breast cancer at age 78 and died at age 82.

Why is this patient an appropriate candidate for genetic counseling?

A. A known mutation in a breast cancer susceptibility gene within the family

B. A family history suggestive of a BRCA mutation

C. More than one first-degree relative with breast cancer diagnosed at an age younger than 45

D. More than two family members with primary breast cancer

The best answers are C and D. This patient is an appropriate candidate for genetic counseling, because she has 1 or more first-degree relatives who have been diagnosed with breast cancer at age 45 or younger and 2 or more individuals with primary breast cancer on the same side of the family.

You receive a report from the genetic counselor after GG's appointment. The genetic counselor appropriately recommended which of the following for GG and her family?

A. Genetic testing for GG

B. No testing at this time

C. Genetic testing on a family member who has developed breast cancer

D. Tumor testing on GA and GB

The best answer is C. The genetic counselor recommended genetic testing on an affected member of GG's family.

Subsequently, GG's older sister GA undergoes genetic testing and is found to have a BRCA1 mutation. The genetic counselor appropriately makes which of the following recommendations for GG and her family?

A. No further testing should be done on this family

B. Single-site genetic testing for all of GG's siblings

C. Single-site genetic testing for GG and all of her siblings

D. Tumor testing for GA to establish risk-reduction recommendations

The best answer is C. Single-site genetic testing for GG and her siblings is the most appropriate next step.

GG's genetic test results are negative for the familial BRCA1 mutation. As her clinician, what do you recommend?

A. Educate GG about the fact that she is considered to be at average risk and should therefore follow recommendations for an average-risk individual.

B. Suggest a complete genetic panel for GG because something may have been missed.

C. Recommend annual breast magnetic resonance imaging because GG is now considered at elevated risk.

The best answer is A. Education on GG's status as a woman at average risk should be provided, and guidelines and screening for an average-risk individual should be followed.

Case 3

HH is a 44-year-old patient who presents to your office after a recent diagnosis of breast cancer. She decided to transfer her care to you because she made a recent move from another state. She reports that she has a sister, age 55, who was diagnosed with breast cancer at age 51. She also has an aunt on her paternal side, now in her 60s, who was diagnosed with breast cancer 1 year earlier. No one in HH's family has had genetic counseling or testing, and HH does not know what genetic counseling is.

What should you do first?

A. Recommend genetic testing to HH

B. Recommend genetic testing of HH's sister

C. Recommend no genetic testing at this time

D. Recommend that HH have genetic counseling

The best answer is D. You should recommend that HH have genetic counseling; she is an appropriate genetic testing candidate because she has breast cancer that was diagnosed at an early age.

You receive genetic testing results for HH, and you note that no mutations were detected. Given these results, what risk management recommendations should you make for your patient?

A. Recommend risk-reducing bilateral salpingooophorectomy.

B. Review recommendations for contralateral breast cancer risk, including prophylactic mastectomy and screening.

C. Recommend genetic testing of HH's sister.

D. No recommendations should be made because the patient had negative test results and is not at high risk for another breast cancer.

The best answer is B. You should review the recommendations for contralateral breast cancer risk, including prophylactic mastectomy and screening. This is an important consideration, as the patient still may have an increased risk of breast cancer due to both her personal and family history, even though she had negative genetic test results. As a clinician, it is important to consider family history when making recommendations for contralateral breast cancer risk. You should also consider whether this is a family that is affected by only breast cancer or whether the family is affected by breast and ovarian cancer, as this may influence your recommendations for screening and prophylactic surgery.

All electronic documents accessed December 2, 2015.

References

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9. Tracy KA, Quillin JM, Wilson DB, et al. The impact of family history of breast cancer and cancer death on women's mammography practices and beliefs. Genet Med. 2008;10(8):621-625.

10. Owens WL, Gallagher TJ, Kincheloe MJ, Ruetten VL. Implementation in a large health system of a program to identify women at high risk for breast cancer. J Oncol Pract. 2011;7(2):85-88.

11. NCCN Clinical Practice Guidelines in Oncology. Breast cancer screening and diagnosis. V. 1.2015. National Comprehensive Cancer Network website. http://www.nccn.org/professionals/physician_gls/PDF/ breast_risk.pdf

12. BRCA1 and BRCA2: Cancer risk and genetic testing. National Cancer Institute website. http://www.cancer.gov/cancertopics/causes-prevention/ genetics/brca-fact-sheet

13. BRCA-related cancer: risk assessment, genetic counseling, and genetic testing. US Preventive Services Task Force website. http://www.uspreventiveservicestaskforce.org/Page/Name/ uspstf-a-and-b-recommendations

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15. Brierley KL, Blouch E, Cogswell W, et al. Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications. Cancer J. 2012;18(4):303-309.

16. Bonadies DC, Brierley KL, Barnett RE, et al. Adverse events in cancer genetic testing: the third case series. Cancer J. 2014;20(4):246-253.

Karen Herold, DNP, WHCNP-BC, FNP-BC, is the High Risk Breast Cancer Nurse Practitioner for the Hoag Breast Center in Newport Beach, and Jeanne Homer, MS, CGC, is a genetic counselor at the Hoag Family Cancer Institute of Hoag Memorial Hospital Presbyterian in Orange County, Calif.