Genetic Counseling

WHO IS A CANDIDATE FOR CANCER GENETIC COUNSELING?

Only 5% to 10% of most cancer is thought to be caused by single mutations within autosomal-dominant inherited cancer susceptibility genes.¹³ The key for clinicians is to determine which patients are at greatest risk to carry a hereditary mutation. There are seven critical risk factors in hereditary cancer (Table 35.2). The first is early age of cancer onset. This risk factor, even in the absence of a family history, has been shown to be associated with an increased frequency of germline mutations in many types of cancers.¹⁴ The second risk factor is the presence of the same cancer in multiple affected relatives on the same side of the pedigree. These cancers do not need to be of similar histologic type in order to be caused by a single mutation. The third risk factor is the clustering of cancers known to be caused by a single gene mutation in one family (e.g., breast/ovarian/pancreatic cancer or colon/uterine/ovarian cancers). The fourth risk factor is the occurrence of multiple primary cancers in one individual. This includes multiple primary breast or colon cancers as well as a single individual with separate cancers known to be caused by a single gene mutation (e.g., breast and ovarian cancer in a single individual). Ethnicity also plays a role in determining who is at greatest risk to carry a hereditary cancer mutation. Individuals of Jewish ancestry are at increased risk to carry three specific BRCA1/2 mutations.¹⁵ The presence of a cancer that presents unusually—in this case, breast cancer in a male—represents a sixth risk factor and is important even when it is the only risk factor present. Finally, the last risk factor is pathology. Certain types of cancer are overrepresented in hereditary cancer families. For example, medullary and triple negative breast cancers (where the estrogen, progesterone and Her2 receptors are all negative, often abbreviated ER-/PR-/Her2) are overrepresented in BRCA1 families,^16,17 and the National Comprehensive Cancer Network (NCCN) BRCA testing guidelines now include individuals diagnosed with a triple negative breast cancer <age 60 years.¹⁸ However, breast cancer patients without these pathologic findings are not necessarily at lower risk to carry a mutation. In contrast, patients with a borderline or mucinous ovarian carcinoma are at lower risk to carry a BRCA1 or BRCA2 mutation¹⁹ and may instead carry a mutation in a different gene. It is already well-established that medullary thyroid carcinoma, sebaceous adenoma or carcinoma, adrenocortical carcinoma before the age of 25 years, and multiple adenomatous, hamartomatous, or juvenile colon polyps are indicative of other rare hereditary cancer syndromes.^11,20 These risk factors should be viewed in the context of the entire family history, and must be weighed in proportion to the number of individuals who have not developed cancer. The risk assessment is often limited in families that are small or have few female relatives; in such families, a single risk factor may carry more weight.

A less common, but extremely important, finding is the presence of unusual physical findings or birth defects that are known to be associated with rare hereditary cancer syndromes. Examples include benign skin findings, autism, large head circumference^20,21 and thyroid disorders in Cowden syndrome, odontogenic keratocysts in Gorlin syndrome,²² and desmoid tumors or dental abnormalities in familial adenomatous polyposis (FAP).²³ These and other findings should prompt further investigation of the patient’s family history and consideration of a referral to genetic counseling.

In this chapter, the breast/ovarian cancer counseling session with a female patient will serve as a paradigm by which all other sessions may follow broadly.

COMPONENTS OF THE CANCER GENETIC COUNSELING SESSION

Precounseling Information

Before coming in for genetic counseling, the counselee should be informed about what to expect at each visit, and what information he/she should collect ahead of time. The counselee can then begin to collect medical and family history information and pathology reports that will be essential for the genetic counseling session.

Family History

An accurate family history is undoubtedly one of the most essential components of the cancer genetic counseling session. Optimally, a family history should include at least three generations; however, patients do not always have this information. For each individual affected with cancer, it is important to document the exact diagnosis, age at diagnosis, treatment strategies, and environmental exposures (i.e., occupational exposures, cigarettes, other agents).²⁴ The current age of the individual, laterality, and occurrence of any other cancers must also be documented. Cancer diagnoses should be confirmed with pathology reports whenever possible. A study by Love et al.²⁵ revealed that individuals accurately reported the primary site of cancer only 83% of the time in their first degree relatives with cancer, and 67% and 60% of the time in second and third degree relatives, respectively. It is common for patients to report a uterine cancer as an ovarian cancer, or a colon polyp as an invasive colorectal cancer. These differences, although seemingly subtle to the patient, can make a tremendous difference in risk assessment. Individuals should be asked if there are any consanguineous (inbred) relationships in the family, if any relatives were born with birth defects or mental retardation, and whether other genetic diseases run in the family (e.g., Fanconi anemia, Cowden syndrome), because these pieces of information could prove to be important in reaching a diagnosis.

The most common misconception in family history taking is that somehow a maternal family history of breast, ovarian, or uterine cancer is more significant than a paternal history. Conversely, many still believe that a paternal history of prostate cancer is more significant than a maternal history. Few cancer genes discovered thus far are located on the sex chromosomes and, therefore, both maternal and paternal history are significant and must be explored thoroughly. It has also become necessary to elicit the spouse’s personal and family history of cancer. This has bearing on the cancer status of common children, but may also determine if children are at increased risk for a serious recessive genetic disease such as Fanconi anemia.²⁶ Children who inherit two copies of a BRCA2 mutation (one from each parent) are now known to have this serious disorder characterized by defective DNA repair and high rates of birth defects, aplastic anemia, leukemia, and solid tumors.²⁶ Patients should be encouraged to report changes in their family history over time (e.g., new cancer diagnoses, genetic testing results in relatives), because this may change their risk assessment and counseling.

A detailed family history should also include genetic diseases, birth defects, mental retardation, multiple miscarriages, and infant deaths. A history of certain recessive genetic diseases (e.g., ataxia telangiectasia, Fanconi anemia) can indicate that healthy family members who carry just one copy of the genetic mutation may be at increased risk to develop cancer.^26,27 Other genetic disorders, such as hereditary hemorrhagic telangiectasia, can be associated with a hereditary cancer syndrome caused by a mutation in the same gene—in this case, juvenile polyposis.²⁸

Dysmorphology Screening

Congenital anomalies, benign tumors, and unusual dermatologic features occur in a large number of hereditary cancer predisposition syndromes. Examples include osteomas of the jaw in FAP, palmar pits in Gorlin syndrome, and papillomas of the lips and mucous membranes in Cowden syndrome. Obtaining an accurate past medical history of benign lesions and birth defects, and screening for such dysmorphology can greatly impact diagnosis, counseling, and testing. For example, BRCA1/2 testing is inappropriate in a patient with breast cancer who has a family history of thyroid cancer and the orocutaneous manifestations of Cowden syndrome.

Risk Assessment

Risk assessment is one of the most complicated components of the genetic counseling session. It is crucial to remember that risk assessment changes over time as the person ages and as the health statuses of their family members change. Risk assessment can be broken down into three separate components.

■ What is the chance that the counselee will develop the cancer observed in his/her family (or a genetically related cancer such as ovarian cancer due to a family history of breast cancer)?

■ What is the chance that the cancers in this family are caused by a single gene mutation?

■ What is the chance that we can identify the gene mutation in this family with our current knowledge and laboratory techniques?

Cancer clustering in a family may be due to genetic and/or environmental factors, or may be coincidental because some cancers are very common in the general population.²⁹ Although inherited factors may be the primary cause of cancers in some families, in others, cancer may develop because an inherited factor increases the individual’s susceptibility to environmental carcinogens. It is also possible that members of the same family may be exposed to similar environmental exposures due to shared geography or patterns in behavior and diet that may increase the risk of cancer.³⁰ Therefore, it is important to distinguish the difference between a familial pattern of cancer (due to environmental factors or chance) and a hereditary pattern of cancer (due to a shared genetic mutation). Emerging research is also evaluating the role and clinical utility of more common low-penetrance susceptibility genes and single nucleotide polymorphisms (SNP) that may account for a proportion of familial cancers.³¹

Several models are available to calculate the chance that a woman will develop breast cancer, including the Gail and Claus models.^32,33 Computer-based models are also available to help determine the chance that a BRCA mutation will be found in a family.³⁴ At first glance, many of these models appear simple and easy to use, and it may be tempting to exclusively rely on these models to assess cancer risk. However, each model has its strengths and weaknesses, and the counselor needs to understand the limitations well and know which are validated, which are considered problematic, when a model will not work on a particular patient, or when another genetic syndrome should be considered. For example, none of the existing models are able to factor in other risks that may be essential in hereditary risk calculation (e.g., a sister who was diagnosed with breast cancer after radiation treatment for Hodgkin disease).

The risk of a detectable mutation will also vary based on cancer history and the degree of relationship to an affected family member. For example, family members with early-onset breast cancer have a higher likelihood of testing positive than unaffected family members. Therefore, the risk assessment process should include a discussion of which family member is the best candidate for testing.

DNA Testing

DNA testing is now available for a variety of hereditary cancer syndromes. However, despite misrepresentation by the media, testing is feasible for only a small percentage of individuals with cancer. DNA testing offers the important advantage of presenting clients with actual risks instead of the empiric risks derived from risk calculation models. DNA testing can be very expensive; full sequencing and rearrangement testing of the BRCA1/2 genes currently averages $2,500, and full panel testing costs up to $7,000 per patient. Importantly, testing should begin in an affected family member whenever possible to maximize scientific accuracy. Most insurance companies now cover cancer genetic testing in families where the test is medically indicated.

One of the most crucial aspects of DNA testing is accurate result ordering and interpretation. Unfortunately, errors in ordering and interpretation are the greatest risk of genetic testing and are very common.³⁵ Emerging data reveal that between 30% to 50% of genetic tests are ordered inappropriately, which is problematic for patients, clinicians, and insurers.^36–38 Recent data demonstrate that many medical providers have difficulty interpreting even basic pedigrees and genetic test results.^33–35 Additional studies have demonstrated that an inaccurate interpretation of genetic testing has been shown to result in inappropriate medical management recommendations, unnecessary prophylactic surgeries, a massive waste of health-care dollars, psychosocial distress, and false reassurance for patients.^2,3

Interpretations are becoming increasingly complicated as more tests and gene panels become available. For example, one study demonstrated that approximately 25% of high-risk families that were BRCA1 and BRCA2 negative by commercially available sequencing were found to carry a deletion or duplication in one of these genes, or a mutation in another gene.³⁹

This is particularly concerning in an era in which testing companies are canvassing physicians, and now mammography technicians, and encouraging them to perform their own counseling and testing. The potential impact of test results on the patient and his/her family is great and, therefore, accurate interpretation of the results is paramount. Professional groups have recognized this and have adopted standards encouraging clinicians to refer patients to genetics experts to ensure proper ordering and interpretation of genetic tests. The U.S. Preventive Services Task Force recommends that women whose family history is suggestive of a BRCA mutation be referred for genetic counseling before being offered genetic testing.⁴⁰ The American College of Surgeons’ Commission on Cancer standards include “cancer risk assessment, genetic counseling and testing services provided to patients either on site or by referral, by a qualified genetics professional.”⁴ In an effort to reduce errors, some insurance companies are requiring genetic counseling by a certified genetic counselor before testing for hereditary breast or colon cancer syndromes.¹²

Results can fall into a few broad categories. It is important to note that a negative test result can actually be interpreted in three different ways, detailed in #2, #3, and #4, which follows.

1. Deleterious mutation “positive.” When a deleterious mutation in a well-known cancer gene is discovered, the cancer risks for the patient and her family are relatively straightforward. However, with the development of multigene panels and the inclusion of many lesser known genes, the risks of detecting a mutation within a gene whose cancer risks are ill defined and medical management options unknown is much greater. Even for well-known genes, the risks are not precise and should be presented to patients as a risk range.^41,42 When a true mutation is found, it is critical to test both parents (whenever possible) to determine from which side of the family the mutation is originating, even when the answer appears obvious.

2. True negative. An individual does not carry the deleterious mutation found in her family, which ideally, has been proven to segregate with the cancer family history. In this case, the patient’s cancer risks are usually reduced to the population risks.

3. Negative. A mutation was not detected, and the cancers in the family are not likely to be hereditary based on the personal and family history assessment. For example, a patient is diagnosed with breast cancer at age 38 years and comes from a large family with no other cancer diagnoses and relatives who died at old ages of other causes.

4. Uninformative. A mutation cannot be found in affected family members of a family in which the cancer pattern appears to be hereditary; there is likely an undetectable mutation within the gene, or the family carries a mutation in a different gene. If, for example, the patient developed breast cancer at age 38 years, has a father with breast cancer, and has a paternal aunt who developed breast and ovarian cancers before age 50 years, a negative test result would be almost meaningless. It would simply mean that the family has a mutation that could not be identified with our current testing methods or a mutation in another cancer gene. The entire family would be followed as high risk.

5. Variant of uncertain significance. A genetic change is identified, the significance of which is unknown. It is possible that this change is deleterious or completely benign. It may be helpful to test other affected family members to see if the mutation segregates with disease in the family. If it does not segregate, the variant is less likely to be significant. If it does, the variant is more likely to be significant. Other tools, including a splice site predictor, in conjunction with data on species conservation and amino acid difference scores, can also be helpful in determining the likelihood that a variant is significant. It is rarely helpful (and can be detrimental) to test unaffected family members for such variants. The rates of variants of uncertain significance vary greatly depending on the reporting protocols of the lab and the genes analyzed. Creation of open databases through a nationwide movement called Free the Data will likely improve variant reporting for all laboratories.

In order to pinpoint the mutation in a family, an affected individual most likely to carry the mutation should be tested first whenever possible. This is most often a person affected with the cancer in question at the earliest age. Test subjects should be selected with care, because it is possible for a person to develop sporadic cancer in a hereditary cancer family. For example, in an early-onset breast cancer family, it would not be ideal to first test a woman diagnosed with breast cancer at age 65 years because she may represent a sporadic case.

If a mutation is detected in an affected relative, other family members can be tested for the same mutation with a great degree of accuracy. Family members who do not carry the mutation found in their family are deemed true negative. Those who are found to carry the mutation in their family will have more definitive information about their risks to develop cancer. This information can be crucial in assisting patients in decision making regarding surveillance and risk reduction.

If a mutation is not identified in the affected relative, it usually means that either the cancers in the family are (1) not hereditary, or (2) caused by an undetectable mutation or a mutation in a different gene. A careful review of the family history and the risk factors will help to decipher whether interpretation 1 or 2 is more likely. Additional genetic testing may need to be ordered at this point. In cases in which the cancers appear hereditary and no mutation is found, DNA banking should be offered to the proband for a time in the future when improved testing may become available. A letter indicating exactly who in the family has access to the DNA should accompany the banked sample.

The genetic counseling result disclosure session should also include a detailed discussion of which other family members would benefit from genetic counseling and testing and referral information. This can apply not only to families who have been found to carry a deleterious mutation, but may also prove useful in other families (e.g., test a higher risk relative or determine segregation of a variant within a family).

The penetrance of mutations in cancer susceptibility genes is also difficult to interpret. Initial estimates derived from high-risk families provided very high cancer risks for BRCA1 and BRCA2 mutation carriers.⁴³ More recent studies done on populations that were not selected for family history have revealed lower penetrances.⁴⁴ Because exact penetrance rates cannot be determined for individual families at this time, and because precise genotype/phenotype correlations remain unclear, it is prudent to provide patients with a range of cancer risk and to explain that their risk probably falls somewhere within this spectrum. This can prove challenging for genes that lack published long-term data on cancer associations and risks.

Female carriers of BRCA1 and BRCA2 mutations have a 50% to 85% lifetime risk to develop breast cancer and between a 15% to 60% lifetime risk to develop ovarian cancer.^15,42,43 It is important to note that the classification “ovarian cancer” also includes cancer of the fallopian tubes and primary peritoneal carcinoma.^44,45 BRCA2 carriers also have an increased lifetime risk of male breast cancer, pancreatic cancer, and possibly, melanoma.^46,47

Options for Surveillance, Risk Reduction, and Tailored Treatment

The cancer risk counseling session is a forum to provide counselees with information, support, options, and hope. Mutation carriers can be offered: earlier and more aggressive surveillance, chemoprevention, and/or prophylactic surgery. Detailed management options for BRCA carriers are discussed in this chapter.

Surveillance recommendations are evolving with newer techniques and additional data. At this time, it is recommended that individuals at increased risk for breast cancer, particularly those who carry a BRCA mutation, have annual mammograms beginning at age 25 years, with a clinical breast exam by a breast specialist, a yearly breast magnetic resonance imaging (MRI) with a clinical breast exam by a breast specialist, and a yearly clinical breast exam by a gynecologist.^48,49 It is suggested that the mammogram and MRI be spaced out around the calendar year so that some intervention is planned every 6 months. Recent data suggest that MRI may be safer and more effective in BRCA carriers <40 years of age and may someday replace mammograms in this population.⁵⁰

BRCA carriers may take a selective estrogen-receptor modulator (SERM) or aromatase inhibitor in hopes of reducing their risks of developing breast cancer. These medications have been proven effective in women at increased risk due to a positive family history of breast cancer.^51–53 There are limited data on the effectiveness of such medications in unaffected BRCA carriers^54–56; however, there are some data to suggest that BRCA carriers taking tamoxifen as treatment for a breast cancer reduce their risk of a contralateral breast cancer.⁵⁷ Additionally, the majority of BRCA2 carriers who develop breast cancer develop an estrogen-positive form of the disease,⁵⁸ and it is hoped that this population will respond especially well to chemoprevention. Further studies in this area are necessary before drawing conclusions about the efficacy of chemoprevention in this population. Prophylactic bilateral mastectomy reduces the risk of breast cancer by >90% in women at high-risk for the disease.⁵⁹ Before genetic testing was available, it was not uncommon for entire generations of cancer families to have at-risk tissues removed without knowing if they were personally