Genomics, studies try to uncover prostate cancer

For researchers, physicians - and patients - prostate cancer has always been among the most maddening and elusive of foes.

The third-most common cancer in the United States, behind breast and lung cancers, its course is less predictable than either.

It can remain dormant in a man's body until he dies decades later from something else. Or it can spread aggressively and kill.

The riddle has been how to tell one cancer from another. Now researchers at Thomas Jefferson University and elsewhere think they are coming closer to solving it through increasingly sophisticated genetic studies.

The payoff would be in saving lives, and also in avoiding the overuse of surgery, radiation, and other treatments that have debilitating side effects. Additionally, genetic testing may help unlock another mystery of the disease: why African American men are more likely than others to suffer the most aggressive forms of it.

"This whole area of genomics is taking everything by storm right now," says Leonard Gomella, who is the Chair of the Department of Urology, and Director of the Sidney Kimmel Cancer Network at Jefferson. "It's had a major impact on urology over the past two or three years."

In a study published in July in the Journal of Clinical Oncology, researchers at Jefferson and three other institutions reviewed clinical records of almost 400 men who had undergone radical prostatectomies and found 20 genes, known as biomarkers, associated with prostate cancer.

Some of the genes were associated with a particularly aggressive form of the disease that tends to spread to the lymph nodes or liver even after surgery.

Two months earlier, in the journal Cell, scientists at the Institute of Cancer Research in London said they had created a comprehensive map of genetic mutations found in metastatic prostate cancer. Coauthor Johann de Bono described the study as "prostate cancer's Rosetta Stone."

"Now we can tell patients the chances of biochemical recurrence in three years, five years from surgery," says Robert Den, a Jefferson radiation oncologist and coauthor of the first paper. "We might be able to tailor postoperative treatments better, and determine the best therapy for each man."

In many cases, he said, it will be limited treatment. Radiation can bring side effects such as fatigue, damage to the bladder and rectum, diarrhea, and erectile dysfunction.

"We overradiate some people who don't need it and we wait too long to radiate other people," says Gomella. "Today, most people are overtreated. We're trying to dial it back.

"Up until now, everything has been what you see under the microscope. This takes it beyond what you see under the microscope."

Den said he found the paper in Cell very interesting and encouraging, but cautioned that "just because there is a mutation present, it doesn't mean that targeting it will result in a cure. Some mutations are just challenging to inhibit at this point."

One in six American males is likely to develop prostate cancer in his lifetime, but African American men are 1.6 times as likely as Caucasian men to get it and 2.4 times as likely to die from it, according to the Prostate Cancer Foundation.

True to that pattern, the most aggressive form of cancer found in the Jefferson study was most likely to occur in African American men.

Disparities in medical treatment and diagnosis have been blamed for the disease's greater impact on black men. But the Jefferson researchers cite this study as part of a growing body of evidence that isn't the whole story.

"Part of it is biology, but another large component is socioeconomic, and access to care," Den said. "But even teasing out those differences, there are differences in the biology."

Until now, he said, biomarker studies have been retrospective, using medical databases to reconstruct history rather than the preferred prospective studies that follow patients as they live with the disease. Partly that is due to the length of time a man may have prostate cancer before it affects his overall health. "You're talking thousands of patients, and not one decade, but two decades of follow-up," he said.

But the work he and others are doing could mean trials that follow diagnosed patients for shorter periods, yielding a fuller picture.

"It's amazing," he said, "that we have a disease that's so common, that affects so many men, and there's still so much uncertainty."

The most recent victories against prostate cancer left Virgil Simons with mixed feelings.

He was pleased, of course, with new research that could prolong the lives of fellow survivors of the disease, particularly African Americans like himself.

Yet the businessman, who has dedicated years to raising awareness and money, knows well how tough the fight against prostate cancer is and how far it still needs to go.

"We need to know more," he said in an interview from Barcelona, Spain, where he now lives. "We still don't know what the triggers [of the disease] are."

In 1998, Simons established prostate.net, a nonprofit patient and advocacy organization that seeks to spread knowledge of the disease, possible treatments, and to encourage men to get screened and participate in clinical trials.

But Simons notes that many African Americans are deeply reluctant to participate in medical trials of all kinds.

Partly, he says, it's due to mistrust of the health-care system stemming in large part from the infamous Tuskegee study. From 1932 to 1972, black men in rural Alabama with syphilis were observed by researchers - but left untreated - while being told they were receiving free government health care.

"Everybody knows about Tuskegee," says Simons, 69. "It's passed down from generation to generation as a reason not to trust the system."

Simons has called for research organizations and hospitals to send outreach workers to barbershops and churches to educate men.

Increasing African American participation in clinical trials is particularly critical in prostate cancer because the largest databases available to researchers come from Scandinavian countries, whose national health systems have excellent record-keeping - and nearly all-Caucasian populations.

"We need patients who have been followed for 15, 16 years," he said.