Researchers identify genetic signatures of castration-resistant prostate cancer
Genetic signatures that provide a significantly more accurate prognosis for patients with castration-resistant prostate cancer have been identified, data from two studies show.
Survival times for patients with castration-resistant prostate cancer are inconsistent, ranging from several months to several years. The reasons for such highly variable OS numbers remain elusive. Tests that determine whether a patient has castration-resistant prostate cancer exist, but they are only moderately accurate.
The ability to accurately predict prognosis in men with castration-resistant prostate cancer is critical to improve treatment, clinical trial design and drug development, according to background information provided in the two studies.
In the first study, David Olmos, MD, of the Institute of Cancer Research in Sutton, United Kingdom, and colleagues collected whole blood into PAXgene tubes from patients with castration-resistant prostate cancer and those with prostate cancer selected for surveillance. Olmos and colleagues obtained 118 blood samples from 100 patients. After quality control, the number dwindled to 94 patients.
In stage one, researchers assigned patients with castration-resistant prostate cancer (n=64) as cases and patients under surveillance (n=30) as controls.
In stage two — the validation phase — researchers assessed patients with castration-resistant prostate cancer. Olmos and colleagues used Bayesian latent process decomposition to analyze the expression profiles. They identified RNA expression profiles associated with castration-resistant prostate cancer subgroups.
Olmos and colleagues used the LPD analysis of mRNA expression data to divide patients into four groups. LPD1 consisted of all patients with castration-resistant prostate cancer (n=14). Researchers assigned 18 patients (17 with castration-resistant prostate cancer) to LPD2, 31 patients (15 with castration-resistant prostate cancer) to LPD3 and 21 patients (12 with castration-resistant prostate cancer) to LPD4.
Researchers identified and verified a nine-gene signature in the LPD1 group. The signature stratified patients with castration-resistant prostate cancer.
Patients with castration-resistant prostate cancer in the LPD1 subgroup demonstrated worse prognosis and poorer OS (10.7 months; 95% CI, 4.1-17.2) than patients with castration-resistant prostate cancer in other LPD subgroups (25.6 months; 95% CI, 18.0-33.4).
Patients identified with the distinctive nine-gene signature survived for an average of 9.2 months (95% CI, 2.1-16.4) compared with 21.6 months (95% CI, 7.5-35.6) for patients who did not test positive for the signature.
Johann de Bono
“We’ve shown it is possible to learn more about prostate cancer by the signs they leave in the blood, allowing us to develop a test that is potentially more accurate than those available now and easier for patients than taking a biopsy,” study researcher Johann de Bono, MD, of the drug development unit at The Royal Marsden NHS Foundation Trust in Sutton, United Kingdom, said in a press release. “Our test reads the pattern of genetic activity like a barcode, picking up signs that a patient is likely to have a more aggressive cancer. Doctors should then be able to adjust the treatment they give accordingly.”
In a similar study, researchers identified a different set of genes with predictive properties comparable to those discovered by Olmos and colleagues.
Robert W. Ross, MD, an instructor in medicine at Harvard University Medical School, and colleagues prospectively collected blood from 62 men with castration-resistant prostate cancer enrolled in a training set from August 2006 to June 2008.
The researchers also enrolled a validation cohort of 140 patients with castration-resistant prostate cancer from August 2006 to February 2009.
A six-gene model (ABL2, SEMA4D, ITGAL, C1QA, TIMP1 and CDKN1A) divided patients with castration-resistant prostate cancer into two risk groups: a low-risk group with a median survival of 34.9 months and a high-risk group with a median survival of 7.8 months (95% CI, 1.8-13.9). The low-risk group did not reach median survival.
The six-gene model was associated with a significantly higher area under the curve (AUC=0.9; 95% CI, 0.78-0.96) compared with a clinicopathological model (AUC=0.65; 95% CI, 0.52-0.78), according to results from the study.
Ross and colleagues hypothesized that gene expression profiling of whole blood could provide insight into the behavior of castration-resistant prostate cancer.
“Indeed, the peripheral blood six-gene model was capable of predicting survival in patients with castration-resistant prostate cancer,” Ross and colleagues wrote.
Due to lack of data, additional prospective validation of the six-gene signature — such as a randomized therapeutic trial — is needed, Ross and colleagues concluded.
“Scarcity of prognostic markers presents a major challenge for the clinical management of castration-resistant prostate cancer,” Karina Dalsgaard Sørensen, MD, of the department of molecular medicine at Aarhus University Hospital in Aarhus, Denmark, wrote in an accompanying editorial.
“These results suggest that a few selected genes in blood samples from patients with castration-resistant prostate cancer can significantly improve the prediction of outcomes,” Sørensen wrote. “However, the biological relevance of these prognostic signatures, which are the first of their kind, is largely unknown, and further investigation into the underlying biological mechanisms at work here could greatly advance our understanding.”
Olmos D. Lancet Oncol. 2012;13:1114-1124.
Ross RW. Lancet Oncol. 2012;13:1105-1113.
Sørensen KD. Lancet. 2012;13:1067-1068.
Olmos and colleagues report no relevant financial disclosures. Ross served as a consultant to Source MDx. Other researchers involved with that study report employment relationships with Source MDx. Sørensen reports no relevant financial disclosures.