Risk Assessment: Who Should Have BRCA Gene Testing

NEW ORLEANS--Most women with a family history of breast cancer have a familial predisposition to the disease, rather than true hereditary breast cancer. A comprehensive family history should guide the recommendations regarding testing for a genetic mutation, which, at about $2,400, should not be taken lightly, said speakers at an AMA-sponsored program on genetic medicine and the practicing physician.

Claudine Isaacs, MD, a medical oncologist and medical director of the Cancer Assessment and Risk Evaluation Program, Georgetown University Lombardi Cancer Center, and Maureen Smith, MS, director of genetic counseling, Baptist Cancer Institute, Memphis, offered some guidance regarding genetic testing of women for BRCA mutations.

Dr. Isaacs noted that about 5% to 10% of breast cancers are due to genetic mutations. BRCA1 mutations carry a breast cancer risk of 55% to 85% by age 70, a risk for contralateral breast cancer of up to 65%, and an ovarian cancer risk of 15% to 60%. Colon cancer risk may also be increased by up to fourfold, and prostate cancer risk increases in males who are carriers. BRCA2 mutations carry a breast cancer risk of 55% to 85%, an ovarian cancer risk of 15% to 20%, and possibly an increased risk for pancreatic cancer and other malignancies.

"By age 50, more than half of women with BRCA mutations develop breast cancer, half develop contralateral breast cancer, and 25% develop ovarian cancer," she said. The range of risks varies because studies have been based on different populations with differences in family history and other underlying factors.

Assessing Family History

Dr. Isaacs said that several characteristics strongly suggest when a BRCA mutation will be present in a breast cancer patient (see Table).

To thoroughly assess the risk of a mutation, Ms. Smith urged physicians to obtain information on all family members, if possible. Any reports of cancer in the family, as well as causes of death, should be documented. She pointed out that the family pedigree may not represent the family’s true risk profile if members have had prophylactic mastectomy or oophorectomy.

Smoking and drinking also introduce environmental toxins that impact the development of cancer, and premature deaths from accidents may preclude a potential cancer victim from being included in the profile.

"More often than not, there are no clear answers to many questions," Ms. Smith said.

Ethnicity is also vital to risk assessment. The odds of finding a BRCA1 mutation increase by fourfold for women of Ashkenazi Jewish ancestry (from central and eastern Europe), Dr. Isaacs pointed out. A population-based study found the carrier rate to be 1 in 45 (N Engl J Med 336:1401, 1997). The carrier frequency for BRCA1 mutations is only 1 in 833 in all other populations, she said.

Dr. Isaacs gave the following odds for detecting a BRCA1 mutation in a family of Ashkenazi Jewish descent as compared with the general population: For women developing breast cancer by age 45 to 49 years, 19% vs 5%; for breast cancer onset at age 35 to 49 years, 37% vs 12%; and for breast cancer onset before 35 years of age, 48% vs 17%.

Besides BRCA1 and 2, genes for Li-Fraumeni syndrome, Cowden syndrome, and ataxia telangiectasia are associated with hereditary breast cancer, she added.

When family history and disease patterns strongly suggest that a mutation may be present in the family, both speakers strongly advised the physician to seek the help of a genetics counselor in conveying the risk concept to the family.

While the advantages of knowing one’s risk status are obvious (including the risk of second malignancy), genetic testing often impacts strongly on the family dynamic. It also involves issues regarding privacy and the potential for insurance or employment discrimination, which need to be explored.

Said Dr. Isaacs: "Genetic counselors suggest that persons think through their reactions to both positive and negative results, to be sure they want to know. Comprehensive counseling before testing is very important, and physicians are not traditionally taught how to do this."

Ms. Smith noted that the physician’s office is usually not set up for extensive genetic counseling and follow-up of patients and other family members at risk. Thus, she advised referral when there is a strong suspicion of inherited cancer syndromes; a patient request for testing; the presence of more than one rare cancer in a family; excessive anxiety about cancer risk; or a need for genetic testing to clarify treatment choices and answer questions about risk for other relatives.

Furthermore, Dr. Isaacs said, genetic testing should be approached cautiously because it is not an easy, straightforward procedure. More than 200 different BRCA1 and BRCA2 mutations have been identified. This makes testing technically complex, cumbersome, expensive, and lengthy. Turnaround time varies from 1 month to 1 year, depending on the lab and the range of the testing.

While testing identifies 85% to 90% of all BRCA mutations, false-positive, false-negative, and inconclusive results often occur. False-positives can occur as a result of benign polymorphisms (normal variations in the gene), she said.

Inconclusive Results

Inconclusive results can occur when BRCA testing is negative yet history is strongly suggestive of hereditary cancer, Dr. Isaacs said. If only partial testing has been done (not a complete gene sequencing), it is possible that a mutation is present in an untested portion of BRCA1 or 2; if complete testing has been performed, a mutation could be present in either a regulatory region of the gene or in a different gene predisposing to hereditary breast cancer.

A second type of inconclusive result occurs when a BRCA1 or 2 alteration is identified but is of unknown significance. This alteration may be a polymorphism or a deleterious mutation, Dr. Isaacs said. "Given the large size of these genes and the number of different and often unique mutations, it may be difficult to distinguish these," she added.

Confusion can be minimized by performing a protein truncation assay if the mutation is being seen for the first time. If the results are positive, the mutation is likely disease-conferring. The likelihood of finding a mutation is enhanced by initially testing the family member who is most suggestive of the mutation, eg, one with early onset or multiple cancers.

Consulting Risk Tables

Ms. Smith said the traditional concept that having two first-degree relatives with breast cancer constitutes genetic risk is not sound. "You need at least a three-generation pedigree from both the maternal and paternal sides of the family," she said, since the gene mutation can be inherited from either parent.

Published risk tables can be consulted to estimate the patient’s or family’s chances of carrying a genetic mutation. Ms. Smith recommended that genetic testing not be performed unless such tables show the risk of mutation to be 10% or more (see case studies).

Patients should fully understand the risks, benefits, and limitations of genetic testing, the speakers stressed, and should know that a negative or inconclusive result does not change the picture dramatically when the history is striking. Ms. Smith noted that women with a true-positive result have a 50% chance of passing the mutation to their offspring.

There are few data regarding the benefit of enhanced surveillance and prevention options in women with BRCA mutations, the speakers said, but several means are often discussed with patients, including chemoprevention with tam-oxifen (Nolvadex).

The Breast Cancer Prevention Trial of tamoxifen includes 13,000 women, some of whom have BRCA mutations, Dr. Isaacs noted. [The interim results of this trial, which showed a 45% reduction in breast cancer incidence among the women taking tamoxifen compared with placebo, were not available at the time of Dr. Isaacs’ presentation.]

Prophylactic mastectomy does appear to substantially reduce predicted risk of breast cancer, Dr. Isaacs said. A Mayo Clinic study of 17 years median follow-up found a 90% reduction in risk, and an M.D. Anderson study of 510 women found that only 1.2% developed breast cancer after prophylactic mastectomy.

While prophylactic mastectomy does not provide complete protection, prophylactic oophorectomy is even less foolproof, since it does not protect against primary peritoneal carcinomatosis. A study in 12 early-onset breast/ovarian cancer families found a 24-fold excess risk of ovarian cancer in non-oophorec-tomized patients and a 13-fold excess risk in oophorectomized patients, "so the data suggest about a 50% reduced risk of ovarian cancer with oophorectomy," she said.

Increased surveillance will certainly protect against breast cancer, but screening for ovarian cancer is generally poor, Dr. Isaacs said. Some experts recommend monthly breast self-examination beginning at age 18 to 21, clinical breast examination every 6 to 12 months starting at age 25 to 35, and annual mammography starting at age 25 to 35.

For ovarian cancer, the recommendation is CA-125 testing and ultrasonog-raphy every 6 to 12 months, starting at age 25 to 35 years for BRCA1 carriers, and possibly for BRCA2 carriers (who have less risk).

Dr. Michael Kaback, professor of reproductive medicine, University of California, San Diego, raised the question of whether early and repeated mammog-raphy could increase a high-risk woman’s chance of radiation-induced cancer. "We may be creating the very thing we are screening for," he commented.

The influence of hormone replacement therapy and birth control pills in these high-risk women is likewise still being debated, Dr. Isaacs said. She stressed that genetic testing is not recommended in minors, nor is early intervention. Breast cancer risk starts rising in the 30s, although the cancer occasionally occurs earlier. Ovarian cancer usually does not occur before the 40s, so women may bear children before considering oophorec-tomy. The severity of the family history should help guide decisions regarding when to start screening and when to consider prophylactic surgery, she said.

Regarding documentation, Dr. Isaacs said she does not record genetic test results in the patient’s chart but does indicate that hypothetical situations were discussed, for example, what she would suggest if the patient were to test positive.

Ms. Smith said the initial family history information goes into the patient’s chart as a "starting point," but "you may want to use caution about what information is kept in the patient’s chart and is available to third parties."