CANCER GENES REVISITED

By Jeffrey Kluger

Cancer researchers aren't accustomed to breakthroughs, but three years ago, they thought they had scored a big one. That's when scientists revealed they had found and begun mapping the first of two genes that appeared to be behind most cases of inherited breast cancer. Suddenly it seemed possible that a woman's odds of getting the disease might be determined by simply scanning her genetic schematic. Thousands of women in the U.S. with a family history of breast cancer rushed to take blood tests designed to look for the rogue genes. Of those who tested positive, as many as 20% underwent prophylactic mastectomies.

In some cases that may have been premature. In papers published last week in the New England Journal of Medicine, investigators took a good look at the suspect genes and found them less guilty than originally charged. Women with positive screenings suddenly had cause to wonder whether the test result was a false alarm and whether any surgery they'd had was unnecessary.

Researchers spotted the two mutated cancer genes--BRCA1 and BRCA2--in 1994 and '95 and immediately realized they were dealing with a nasty pair of characters. Women with just one BRCA gene mutation appeared to have an 85% risk of developing breast cancer and a 60% risk of ovarian cancer.

Those findings were extremely sobering, but the new studies suggest they were considerably overstated. The 85% figure was derived by sampling women from families that already had a breast-cancer history. Researchers on two of this week's papers tried to determine whether stacking the statistical deck in this manner had skewed the results. When they looked at a broader population of women, the breast-cancer risk, even if a gene mutation was present, fell to 56%. National Institutes of Health geneticist Jeffrey Streuwig, who led one study, does not pretend this new number is the last word, but neither does he think the older, grimmer figure is a better one. "There is a lot of uncertainty," he says.

Things get murkier when researchers look at the BRCA mutations. Hundreds of base pairs may be strung along genes like Christmas-tree lights, but not every blown bulb affects the strand the same way. More than 200 mutations have been identified on the two BRCA genes, and one new study found that while BRCA2 mutations will show up on a test, they may be less likely to lead to disease than mutations on BRCA1 in young women.

Even if gene screening remains inconclusive, not everyone wants to toss the tests aside. High-risk women who have had preemptive mastectomies may not regret the decision, since the procedure can mean a 91% likelihood of remaining cancer free--attractive odds in families in which female relatives have repeatedly been claimed by the disease. Even women with a more benign genetic legacy may appreciate the increased knowledge that comes from a positive test and whatever relief comes from a negative one. For now, researchers say, the key may be to look at genetic testing not as firm forecasting but as mere oddsmaking. As with all rolls of the dice, the outcome is never a sure thing.

--By Jeffrey Kluger. Reported by Dick Thompson/Washington

With reporting by Dick Thompson/Washington