When cancer is bone deep
Bone enzymes point the way to prostate cancer outcomes
For 29 years, Lee Stram was a production supervisor and avionics operations engineer for an aerospace manufacturer. A family man with two children, Stram was also a product-support engineer on electronic systems for planes, and his company flew him around the world to troubleshoot problems on malfunctioning commercial aircraft.
But in 2004, the then-68-yearold Stram encountered a problem he couldn't fix alone. A routine visit to the doctor revealed a worrisome jump in his prostate-specific antigen — or PSA — level. A high PSA is a common early warning sign of prostate cancer. A biopsy confirmed Stram's worst suspicions: He had cancer.
Stram is just one of the estimated 200,000 men diagnosed each year in the United States with prostate cancer. The disease is the most common cancer among American men, accounting for more new cancer cases than lung, colorectal, pancreas and kidney cancer combined. For Stram, additional diagnostic tests at the time of his diagnosis delivered even more unpleasant news.
"I found out through a bone scan that the cancer had already metastasized to my hip and ribs," he says.
Several rounds of intermittent anti-androgen therapy administered by his primary oncologist, Ralph deVere White, kept Stram's cancer at bay for years. Most prostate cancers, at least initially, require male hormones such as testosterone in order to grow, and anti-androgen therapy medications slow that process. But in 2008, Stram's PSA levels began rising again — a sign that his cancer was now resisting this line of treatment.
Overcoming treatment resistance
Stram's story is all too common among prostate cancer patients. After initial treatments involving drugs, surgery, radiation or some combination of these, approximately a third of patients will eventually relapse. The cancer in most of these patients eventually spreads into bone. Stram was among the 10 percent of prostate cancer patients with skeletal metastases when first diagnosed.
Bone metastases are bad news for any cancer patient. For one thing, they push the body's bone maintenance system out of whack. New bone is constantly formed while old bone is resorbed as part of normal skeletal maintenance. The two processes are normally well-balanced.
"We realized that tracking these enzymes could be a way to increase our ability to detect and follow prostate cancer cells in bone. The would allow us to get an early glimpse of whether or not therapies were actually helping patients."
— Primo Lara
"But when cancer enters the bones, the cancer cells destroy other cells, and we find that bone degradation goes on much faster than bone formation," says Marta Van Loan, a research physiologist at the U.S. Department of Agriculture's Western Human Nutrition Center based at UC Davis and an expert in bone metabolism.
As if that weren't bad enough, says Primo Lara, associate professor of hematology and oncology at UC Davis Cancer Center and an expert in genitourinary cancer, "prostate cancer treatment also contributes to the loss of bone integrity. Androgen-elimination therapy often causes abnormally low bone density and osteoporosis, which weakens bone."
Bone pain and even fractures are common among people whose cancers have spread to the skeleton, "things patients don't need when they're battling cancer," Lara says.
But diagnosing cancer in bone can be tricky. Bone scans often fail to detect areas of degradation, and frequently cannot show how well a patient is responding to chemotherapy.
Now Lara, Van Loan and their colleagues throughout the United States may have found a better way to both diagnose bone metastases and predict survival outcomes. Requiring only a blood sample, the new test could offer a better means to track bone metastases and tailor treatments to each patient's type of disease.
"The test could apply to any cancer in general that has metastasized," Van Loan says. "It could potentially become a standard of treatment."
A new predictor
The researchers hit upon the idea unexpectedly. Several years ago, Lara was conducting a small pilot study of a new prostate cancer drug. The drug was also reported to affect bone health. For this reason, Lara took the extra step of monitoring the patients' bone metabolism. To do this, they measured blood levels of enzymes associated with bone turnover.
Though the drug failed to help the prostate cancer patients, the team stumbled onto something else. Patients with lower levels of bone resorption enzymes tended to survive longer, plus their disease was less likely to progress during the four-month study period. Patients whose enzyme levels dropped over time also had better outcomes. In other words, the test monitored how well patients were responding to therapy and predicted how they would fare on the treatment.
"It was like looking into a crystal ball," Lara says. "We realized that tracking these enzymes could be a way to increase our ability to detect and follow prostate cancer cells in bone. They would allow us to get an early glimpse of whether or not therapies were actually helping patients."
The approach is now being tested as part of a much larger clinical trial on patients whose prostate cancer is resistant to anti-androgen therapy and has spread to bone. More than 900 prostate cancer patients are enrolled in this nationwide double-blind study of a promising new cancer therapy and the bone-enzyme test.
The patients are given docetaxel, a drug that inhibits cell division, and prednisone, a steroid that reduces the pain of cancer in bone. Half of the subjects will also be given atrasentan, an experimental drug for metastatic cancers that inhibits a cancer-advancing protein. All study subjects also will have their bone enzymes monitored to determine if the bone-health measures correlate with patient responses and outcomes.
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"We felt this was the opportunity we were looking for — to test the hypothesis that bone markers have potential prognostic value," says Lara, the study's principal investigator.
If the bone-enzyme test proves valid, it could mean major improvements in many areas of cancer care, ranging from case monitoring to treatment and counseling. It could also benefit more than just prostate cancer patients.
"Because the test could give doctors a means to track the progression of cancer in bone, it could serve as a screening tool for cancer patients as they try different therapies. Those whose test results indicate they are not responding to standard treatments or whose disease is more advanced could be considered eligible for newer, more experimental therapies like atrasentan," Van Loan says.
The path to personalized treatment
The test could also pave the way toward personalized cancer care.
"Right now, everybody with prostate cancer is treated with the same standard therapy," Lara says. "This test could help us treat only those most likely to benefit, and we could focus on finding more effective therapies for those who are not likely to benefit. Patients could avoid having to take drugs unsuited to their particular form of cancer."
The newfound ability to gauge patient survival could help doctors further tailor the choice of therapies with the goal of longer-term survival.
Stram is enrolled in the study and already feels it is making a difference. Three weeks after his first clinical trial treatment, he visited Lara for a checkup.
"He said, 'We did it, the cancer stopped growing.' And I lit up like a Christmas tree," Stram says, and adds his appreciation for his physicians: "I am so grateful to UC Davis and doctors deVere White and Lara for my health care and well-being."