Tantalizing Clues to a Lethal Legacy

By J. Madeleine Nash/Chicago

To most women, the notion of undergoing a mastectomy in order to prevent breast cancer smacks of wild paranoia. But for Maria Burkhardt of Covington, La., the unthinkable slowly became the inevitable. Twenty years ago, an aunt was stricken with the disease. Her mother died from it a decade later. In 1986 Maria's younger sister Jo Ann began fighting for her life. Next her older sister Rose developed an aggressive tumor. Maria consulted a doctor and was told she was "a ticking time bomb." Ominously, her tissues were judged too dense for mammograms to scan reliably.

So last summer, at 47, Maria decided to have both breasts removed. Her own graceful curves were replaced with silicone implants that harbored no trace of her family's lethal legacy. A short time later, Maria received a report that vindicated her decision. A postoperative examination of her breast tissue had found precancerous lesions. "I just broke down and cried," she recalls. "I'd done this knowing I might never know if I'd made the right choice."

Families like Maria Burkhardt's are rare, accounting for a tiny fraction of breast-cancer cases. But the malevolent genes they pass down through the generations are beginning to yield important clues to all breast malignancies. "Cancer," declares celebrated molecular biologist James D. Watson, "is a disease of the DNA," the master molecule that encodes the genetic blueprint for every living cell. Tumors develop as the result of rearrangements in DNA, specifically in the genes that govern cell growth.

In most cases, the changes that lead to breast cancer begin accumulating after birth, perhaps triggered by some set of environmental stresses, whether random cosmic rays or a dietary factor. Some women, however, start out with the genetic deck stacked against them. Like Burkhardt and her sisters, they stand a greater risk of developing breast cancer, in both breasts and at an earlier age, than other women.

Recent months have brought a series of discoveries about the genetic mutations involved in breast cancer. "Information is accumulating at an astounding rate," says University of Utah geneticist Mark Skolnick. Changes in at least two types of genes play a role: those that direct cells to grow and divide; and those that issue commands to halt growth. Much of the research has focused on a growth-enhancing gene on chromosome 17, often referred to as the HER-2/neu oncogene. An estimated 30% of breast-cancer patients have somehow acquired abnormal quantities of this gene -- as many as 50, as opposed to the normal two.

The extra copies are a bad omen. Patients that have them suffer three times the rate of cancer recurrence of other patients, says UCLA oncologist Dr. $ Dennis Slamon. Such patients, he says, should "absolutely" get further treatment. But one genetic abnormality is not enough to transform healthy, law-abiding breast cells into anarchic tumors. "The genes responsible for this disease are like pieces of a patchwork quilt," says geneticist Mary- Claire King of the University of California, Berkeley. The patchwork pattern may vary from one woman to the next, but each case probably involves five or six separate mutations occurring over a period of years.

Researchers at the Cancer Institute in Tokyo have implicated five genes on four different chromosomes. Dr. Yusuke Nakamura speculates that the loss of a growth-suppressing gene on chromosome 17 may be one of the earliest changes on the road to malignancy. Other groups have also pointed to sites on chromosome 17. Last November a team led by scientists at Massachusetts General Hospital Cancer Center identified one such gene as the likely cause of Li-Fraumeni syndrome, a rare genetic disorder that increases susceptibility to breast cancer and other malignancies. Since then, King and her colleagues at Berkeley have identified another segment of chromosome 17 that is associated with familial breast cancer. Other researchers, including a group in Strasbourg, France, are unraveling the genetics behind the deadly process of metastasis.

The flood of insights into the genetics of breast cancer will ultimately provide physicians with more effective weapons. This year Dr. Slamon and his colleagues hope to begin clinical trials of a genetically engineered antibody that locks onto the protein made by the HER-2/neu oncogene, interfering with its function. This antibody has already been shown to inhibit tumor growth in mice.

Researchers like Berkeley's King dream of diagnostic tools powerful enough to identify abnormal genes in breast cells long before they become fully cancerous. Such tools could begin to lift the burden of uncertainty from women who, like Maria Burkhardt, come from cancer-prone families and wonder if they carry the dreaded trait. Someday, if King has her way, tests for breast-cancer genes could become as commonplace as Pap smears. And then, she says optimistically, "no one need die of breast cancer anymore."

With reporting by James Willwerth/ Los Angeles