Genetic Counseling Dilemma Debated at ESMO 21st Congress

VIENNA--The identification of genes that predispose to cancer raisestwo dilemmas for clinical oncologists. The first is whether to offer genetictesting to healthy relatives of cancer patients who carry a culprit gene,and the second, thornier problem is whether advice for healthy carriersshould 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% lifetimerisk of ovarian cancer, as well as a quadrupled risk of colon cancer anda 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 tumortypes.

For women who are BRCA1-positive and have an ominous family history,Jan Klijn, MD, PhD, of the Rotterdam Cancer Institute, often recommendsthe ultimate prevention--prophylactic mastect-omy or oophorectomy--afterextensive 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 atany 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 21stCongress of the European Society for Medical Oncology (ESMO).

A key issue in decision-making, Dr. Klijn said, is that in many BRCA1-positivefamilies, the onset of cancer occurs at a younger age in each succeedinggeneration.

Some crucial interplay between genetic and environmental factors issuggested by a study of 6 large Dutch cancer-prone families. This studyrevealed that early in the century, the risk of cancer in these familieswas only 1.4 times greater than that in the general population, but thishad risen to three times greater by mid-century, and is 10 times greatertoday.

"When you have a young woman with benign breast disease and a familyhistory of breast cancer, you have to be very careful," advised Dr.Klijn, noting that these individuals have an 11-fold increase in breastcancer risk.

He cited a 1990 study showing a 35% incidence of proliferative breastdisease in the first-degree relatives of patients with familial breastcancer, 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 benode-positive on screening, and at least one quarter to one third of allpatients with detected tumors will die of their disease within 10 yearsof diagnosis.

In the last 2 years, investigators at Rotterdam's Family Cancer Centerhave identified the BRCA1 gene or the BRCA2 gene in 22 of 150 familieswith suggestive cancer histories that have undergone DNA testing. Morethan

60 high-risk female members of these families, half of whom have previouslyhad breast cancer, have opted for prophylactic mastectomy, Dr. Klijn noted.

He also pointed out that the Rotterdam team found histologically normalovaries in only 72% of 18 BRCA-positive women who had undergone prophylacticoophorectomy, but in 93% of 26 women whose pedigrees were positive forovarian cancer.

The payoff from aggressive early intervention, Dr. Klijn contends, isthat prophylactic mastectomy slashes the risk of hereditary breast cancerfrom 87% to nearly zero, and prophylactic oophor-ectomy reduces the dangerof 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 makesthe value of prophylactic organ removal questionable, since patients maydevelop genetically linked cancers at other sites.

"The most extensive series published to date has shown about a2% risk of peritoneal carcinomatosis in women who have undergone ovariectomy,"he said, also pointing out that the failure rate of this preventive procedureis about 8%.

In addition, he said, there are no data to conclusively demonstratethat prophylactic mastectomy actually works, a statement that evoked strongdisagreement from Dr. Klijn.

Right Target, Wrong Timing

Another potential pitfall is choosing the right target but the wrongtiming, Dr. Janin commented. It may be unreasonable to remove both breastsat 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 relativelysmall.

Dr. Klijn responded that "we don't perform prophylactic mastectomyat 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-relatedsuccesses--cases of incomplete genetic penetrance in which cancer neverwould have developed even without surgery.

"It is also possible that the cancer would have occurred and beencured 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 testingbe performed only when there is certainty about penetrance, and that prophylacticorgan removal be reserved only for genetically high-risk women who requestit after extensive counseling.