(SACRAMENTO, Calif.) —Biomarkers for bone formation and resorption predict outcomes for men with castration-resistant prostate cancer, a team of researchers from UC Davis and their collaborators have found. Their study, published online in the Journal of the National Cancer Institute, also found that the markers identified a small group of patients who responded to the investigational drug atrasentan. The markers' predictive ability could help clinicians match treatments with individual patients, track their effectiveness and affect clinical trial design.
Castration-resistant prostate cancer does not respond to hormone treatments and often metastasizes to bone. This led researchers to wonder if increased bone turnover markers might predict the course of the disease.
"We found that patients with high levels of these markers in the blood had a much shorter lifespan compared to patients with low levels," said lead author Primo Lara, associate director for translational research at the UC Davis Comprehensive Cancer Center. "By measuring bone turnover in prostate cancer patients, we can determine how well they do."
Healthy bone maintains a balance between formation and resorption, generating new bone while recycling old. Prostate cancer throws off this balance. Researchers hoped this mechanism would help them track the cancer. To investigate this potential link, the team tested blood serum in 778 patients for both resorption (N-telopeptide, pyridinoline) and formation markers (C-terminal collagen propeptide, bone alkaline phosphatase) and found elevated levels of each of the markers predicted poor prognosis.
Perhaps most interesting, elevated marker levels also predicted whether patients would respond to a specific drug. About 6 percent of patients with the highest marker levels responded to atrasentan, and investigational drug abandoned because it failed in clinical trials. Lara and colleagues believe this may be related to study design.
"Atrasentan kept coming up short in randomized trials because the drug only works for a small group," Lara said. "Because certain drugs only succeed in a fraction of patients, drug makers need to factor in these bone metabolism markers in their trial design. They need to target the patients most likely to benefit."
In addition to determining which patients might respond best to a specific treatment, these markers could be used to track their response during treatment. Marker status could also stratify patients equally within different study arms. Balancing these studies could potentially make them more accurate and identify the niche value of drugs like atrasentan whose effectiveness is not evident in large populations.
"I think the days of doing empirical studies on all comers should end," Lara said. "You need to have an appropriate database of patients and perform a rigorous analysis to find the subset who will benefit from an investigational drug."
The study's title is Serum Biomarkers of Bone Metabolism in Castration-Resistant prostate Cancer Patients With Skeletal Metastases: Results From SWOG 0421.
Other researchers included: Philip C. Mack of the UC Davis Comprehensive Cancer Center, Erik Gertz and Marta D. Van Loan of the USDA Western Human Nutrition Center at UC Davis; Benjamin Ely and Catherine Tangen of the Southwest Oncology Group Statistical Center in Seattle; David I. Quinn and Amir Goldkorn of the University of Southern California Norris Cancer Center; Przemyslaw W. Twardowski of the City of Hope; Maha Hussain of the University of Michigan; Nicholas J. Vogelzang of US Oncology; and Ian M. Thompson of the Cancer Treatment and Research Center, University of Texas, San Antonio.
This research was funded by grants from the National Institutes of Health: 5R01-CA120469, CA32102, CA38926 and NCT00134056.
UC Davis Comprehensive Cancer Center is the only National Cancer Institute-designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its specialists provide compassionate, comprehensive care for more than 10,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit cancer.ucdavis.edu.
JNCI Journal of the National Cancer Institute