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 familys 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 ones 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 physicians 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 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 patients
or familys 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
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,"
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
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 womans 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 patients 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
patients chart as a "starting point," but "you
may want to use caution about what information is kept in the
patients chart and is available to third parties."