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Researchers identify genetic signatures of castration-resistant prostate cancer
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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.”
References:
Olmos D. Lancet Oncol. 2012;13:1114-1124.
Ross RW. Lancet Oncol. 2012;13:1105-1113.
Sørensen KD. Lancet. 2012;13:1067-1068.
Disclosures:
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.
Perspective
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Donald L. Trump, MD, FACP
Two papers published online in The Lancet Oncology provide a glimpse into the potential for disease classification based on analysis of peripheral blood derived mRNA. Both studies examined the hypothesis that it is possible to develop gene expression profiles predictive of prognosis among men with castration-resistant prostate cancer (CRPC). The question is highly relevant as there is marked heterogeneity in survival among men with CRPC — or castration-sensitive prostate cancer (CSPC), for that matter —
regardless of which current risk estimation algorithm is used. All such algorithms are based on clinical and/or biochemical parameters. Illustrative of this situation is the discussion regarding a recent intergroup study (Hussain M. Abstract#4. Presented at: The 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago). Researchers reported "equivalence" of intermittent and continuous androgen deprivation in men with "extensive" CSPC but inferiority of intermittent androgen deprivation among men with "limited" (axial skeletal, prostate-specific antigen <20) disease. However, there was anything but broad agreement on the validity of this "limited" vs. "extensive" classification.
As pointed out in the editorial by Professor Sørensen that accompanied these two papers, the ability to delineate prognosis and choose treatment based on a prognostic classification derived from sound biology and using readily accessible techniques is much desired. The two papers utilized a similar approach, validated with rigorous statistical techniques, including training and validation patient data sets. Both studies were conducted by leaders in the clinical study of prostate cancer and involved multiple institutions. Both analyses defined peripheral blood-derived, mRN-based gene expression profiles, which provided substantial discriminatory power to distinguish favorable and unfavorable prognostic groups. Good prognosis patients had as much as a 2.5- to 3-fold better survival in some analyses. Olmos and colleagues and Ross and colleagues are to be congratulated for very intriguing studies, which — like all good studies — raise more questions:
• What is the performance of such assays in more homogeneous groups of patients?
• Where do these expressed genes come from and what do they mean? Because they are derived from the peripheral blood, presumably they are not directly cancer-derived because insufficient numbers of circulating cancer cells are present to yield these profiles.
• Which cells release these mRNAs?
• To which biologic processes are these mRNAs linked? Immune response? Inflammatory response? Metabolic response?
• Are we sure such mRNAs are not released directly from tumor cells in metastatic sites?
Interestingly, the two groups of investigators described two non-overlapping sets of genes, nine from the Olmos group and six from the Ross group. This raises the substantial question as to how these patterns compare and how many other patterns exist. Finally, the development of molecular diagnostics that are associated with cancer prognosis and on which treatment choices can be based is complex and fraught with biostatistical, analytic, ethical and biologic challenges (ie, the recent Institute of Medicine report on the development of molecular "omics" tests). These two groups are to be congratulated for the first studies of mRNA-based prognostic model development in CRPC. Their work is rigorous and thought provoking and could be among the first steps to truly personalized treatment choice in men with prostate cancer — personalized based on the molecular characteristics of the cancer and the patients interface with that cancer, rather than morphology and clinical parameters.
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