Blood Test to Identify Poor-Prognosis Prostate Cancer

18-10-2012 18:09

October 9, 2012 — A blood test that can stratify patients with castration-resistant prostate cancer (CRPC) as high or low risk offers hope to patients for better outcome prediction and management, according to 2 studies published online October 9 in the Lancet Oncology.

Both studies describe whole-blood gene-expression profiling that found a distinct genetic signature (slightly different in each study) that appears to improve outcome prediction "significantly." It is too early to say whether these signatures will be "true game changers," according to an accompanying comment.

Although the "scarcity of prognostic markers presents a major challenge for the clinical management of castration-resistant prostate cancer and for stratification of patients into clinical trials...the biological relevance of these prognostic signatures, which are the first of their kind, is largely unknown," writes editorialist Karina Dalsgaard Sørensen, PhD, from the Department of Molecular Medicine at Aarhus University Hospital in Denmark.

"The technical simplicity of these tests is very attractive and could facilitate their translation into actual clinical use" in 3 to 5 years, Dr. Dalsgaard Sørensen told Medscape Medical News.

"The two studies provide proof-of-principle that such blood-based tests can be useful for the prediction of CRPC outcome, but additional independent validation studies are needed to confirm these initial and promising results," she explained.

"Importantly, future validation studies need to define in which exact clinical context(s) these tests might be useful. This is not completely clear at this time," she continued. "It is desirable to include such tests, as well as other developing candidate markers for CRPC, into phase 3 clinical trials, because this may allow definitive evaluation of their biomarker potential in a specific clinical setting," she added.

"If a simple blood test can be used to predict a patient's response to a particular drug and/or to determine which drug is the best for a given patient, it would be a very important step forward toward more individualized treatment of CRPC," Dr. Dalsgaard Sørensen said.

Better Predictor of Survival

In the first study, principal author William Oh, MD, from the Mount Sinai School of Medicine, Tisch Cancer Institute, in New York City, and colleagues report that a 6-gene signature can accurately stratify patients with CRPC into low or high risk.

"Our analysis predicts survival better than several routinely measured clinical variables alone," Dr. Oh and colleagues write.

Their study involved a training cohort of 62 men with CRPC being treated at the Dana-Farber Cancer Institute in Boston, Massachusetts, from August 2006 to June 2008, and a validation cohort of 140 patients with CRPC being treated at the Memorial Sloan-Kettering Cancer Center in New York City from August 2006 to February 2009.

A panel of 168 target genes was analyzed in whole blood (taken prospectively from the training cohort and banked from the validation cohort) to identify predictors of survival.

Using the 6-gene signature, there was a significant difference in median survival between low- and high-risk patients in the training cohort (hazard ratio, 9.7; >34.9 vs 7.8 months; P < .0001). There was also a significant difference in median survival between low- and high-risk patients in the validation cohort (18.5 vs 9.2 months; P < .0001), the researchers report.

When the prognostic ability of the 6-gene signature was compared with that of a model of clinicopathologic variables previously shown to be of prognostic significance in this population (J Clin Oncol. 2003;21:1232-1237), the 6-gene signature was associated with a significantly higher area under the curve (0.90 vs 0.65; P = 0.0067).

"The genes comprising our model suggest a biasing of the immune system towards macrophage differentiation, accompanied by a decrease in both cell-mediated and humoral immunity, in patients with higher mortality," Dr. Oh and colleagues write.

They note that the 6-gene signature is of clinical relevance. "First, such a test might assist with patient counseling. Second, the signature could be used to stratify patients enrolled in phase 3 trials. Finally, as the treatment armamentarium for castration-resistant prostate cancer has expanded to include immune modulation with sipuleucel-T, a natural extension of this work is to identify whether such a whole-blood signature could serve as a predictive biomarker," they explain.

"Could Add Prognostic Value"

In the second study, principal author Johann de Bono, MD, from the Institute of Cancer Research, in Sutton, United Kingdom, and colleagues used peripheral blood to identify a 9-gene signature that separated poor- and good-prognosis CRPC.

This 9-gene signature "could add prognostic value to other previously described clinicopathological risk factors for castration-resistant prostate cancer," they write, noting that the signature "was also associated with known prognostic biomarkers of CRPC, including high-alkaline phosphatase, PSA, lactate dehydrogenase, CTC counts, and low hemoglobin and albumin levels."

The first stage of the study involved 64 patients with CRPC and 30 with low-grade disease suitable for active surveillance who attended routine clinical appointments from August 2007 to April 2008 at The Royal Marsden Hospital NHS Foundation Trust in Sutton and the Beatson West of Scotland Cancer Centre in Glasgow, United Kingdom.

Using gene-expression studies and latent process decomposition (LPD), Dr. de Bono and colleagues identified 4 LPD subgroups. CRPC was evenly distributed in all subgroups of patients. However, a 9-gene signature was associated with significantly poorer overall survival in the LPD1 subgroup (approximately 25% of the patients) than in the other 3 LPD subgroups (10.7 vs 25.6 months; P < .0001).

The second stage of the study involved a validation group of 70 CRPC patients treated at the Memorial Sloan-Kettering Cancer Center from February 2007 to July 2011. In this group, the 9-gene signature was also associated with significantly poorer overall survival in the LPD1 subgroup (9.2 vs 21.6 months; P = .001).

Seven genes in the 9-gene signature could be sensitive early markers for bone marrow infiltration or failure, Dr. de Bono and colleagues note; the other 2 genes suggest altered immune function.

"The gene signature represented depressed T-helper cell and B-cell function and increased circulating erythroid progenitors, and indicates that decreased immune function is associated with worsened outcome from advanced prostate cancer," Dr. de Bono told Medscape Medical News in an email.

The study of the 6-gene signature was funded by Source MDx, which is no longer in business. Some of Dr. Oh's coauthors report relationships with Source MDx, as detailed in the paper. The study of the 9-gene signature was funded by AstraZeneca, Experimental Cancer Medicine Centre, Prostate Cancer Charity, and Prostate Cancer Foundation. Dr. de Bono and colleagues and Dr. Dalsgaard Sørensen have disclosed no relevant financial relationships.

Lancet Oncol. Published online October 9, 2012.