VIENNA--The identification of genes that predispose to cancer raises
two dilemmas for clinical oncologists. The first is whether to offer genetic
testing to healthy relatives of cancer patients who carry a culprit gene,
and the second, thornier problem is whether advice for healthy carriers
should extend beyond avoidance of risk factors and regular screening.
The predicament is especially acute when the gene involved is BRCA1,
which confers an 85% lifetime risk of breast cancer and a 63% lifetime
risk of ovarian cancer, as well as a quadrupled risk of colon cancer and
a threefold risk of prostate cancer.
When the gene involved is BRCA2, the risk of ovarian cancer is lower
(about 20%), but there is a slightly increased risk of several other tumor
For women who are BRCA1-positive and have an ominous family history,
Jan Klijn, MD, PhD, of the Rotterdam Cancer Institute, often recommends
the ultimate prevention--prophylactic mastect-omy or oophorectomy--after
extensive counseling of the patient.
In contrast, Dr. Nicolas Janin, of Institut Gustave-Roussy, Villejuif,
France, rejects prophylactic surgery as mutilating and of unproven benefit,
arguing that the oncologist's goal should not be to remove all risks at
any price but, rather, to help women who are at high risk live happily.
The two clinicians debated the issue at a special session at the 21st
Congress of the European Society for Medical Oncology (ESMO).
A key issue in decision-making, Dr. Klijn said, is that in many BRCA1-positive
families, the onset of cancer occurs at a younger age in each succeeding
Some crucial interplay between genetic and environmental factors is
suggested by a study of 6 large Dutch cancer-prone families. This study
revealed that early in the century, the risk of cancer in these families
was only 1.4 times greater than that in the general population, but this
had risen to three times greater by mid-century, and is 10 times greater
"When you have a young woman with benign breast disease and a family
history of breast cancer, you have to be very careful," advised Dr.
Klijn, noting that these individuals have an 11-fold increase in breast
He cited a 1990 study showing a 35% incidence of proliferative breast
disease in the first-degree relatives of patients with familial breast
cancer, compared with a 13% incidence among controls.
The most compelling reasons to consider prophylactic mastectomy, Dr.
Klijn said, are that some 10% to 30% of high-risk women will prove to be
node-positive on screening, and at least one quarter to one third of all
patients with detected tumors will die of their disease within 10 years
In the last 2 years, investigators at Rotterdam's Family Cancer Center
have identified the BRCA1 gene or the BRCA2 gene in 22 of 150 families
with suggestive cancer histories that have undergone DNA testing. More
60 high-risk female members of these families, half of whom have previously
had breast cancer, have opted for prophylactic mastectomy, Dr. Klijn noted.
He also pointed out that the Rotterdam team found histologically normal
ovaries in only 72% of 18 BRCA-positive women who had undergone prophylactic
oophorectomy, but in 93% of 26 women whose pedigrees were positive for
The payoff from aggressive early intervention, Dr. Klijn contends, is
that prophylactic mastectomy slashes the risk of hereditary breast cancer
from 87% to nearly zero, and prophylactic oophor-ectomy reduces the danger
of ovarian cancer from 17% to about 3% for those with BRCA2 and from 63%
to about 8% for those with BRCA1.
For Dr. Janin, however, the possibility of target-related failures makes
the value of prophylactic organ removal questionable, since patients may
develop genetically linked cancers at other sites.
"The most extensive series published to date has shown about a
2% risk of peritoneal carcinomatosis in women who have undergone ovariectomy,"
he said, also pointing out that the failure rate of this preventive procedure
is about 8%.
In addition, he said, there are no data to conclusively demonstrate
that prophylactic mastectomy actually works, a statement that evoked strong
disagreement from Dr. Klijn.
Right Target, Wrong Timing
Another potential pitfall is choosing the right target but the wrong
timing, Dr. Janin commented. It may be unreasonable to remove both breasts
at age 20, he said, when a cumulative risk of 80% is spread over many years,
and the risk of developing cancer in the next month or year is relatively
Dr. Klijn responded that "we don't perform prophylactic mastectomy
at the age of 20, but between ages 25 and 30 in the case of high-risk patients
(lifetime risk greater than 50%), as, for example, with gene mutation carriers."
Dr. Janin also highlighted the problem of questionable target-related
successes--cases of incomplete genetic penetrance in which cancer never
would have developed even without surgery.
"It is also possible that the cancer would have occurred and been
cured with conservative treatment," he said, stating that only 20%
to 25% of breast cancers are, in fact, very aggressive. Dr. Klijn, however,
believes that at least 50% of breast cancers are very aggressive and fatal,
based on survival curves from the Early Breast Cancer Trialist Group.
"Surgery is a very expensive form of life insurance," Dr.
Janin said. "The mutilation may be rendered more tolerable by reconstruction,
but this is not always the case." He recommends that genetic testing
be performed only when there is certainty about penetrance, and that prophylactic
organ removal be reserved only for genetically high-risk women who request
it after extensive counseling.