Prostate Cancer: Genes Predict Survival (CME/CE)

Authors: MedPage Today

By Kristina Fiore, Staff Writer, MedPage Today
Published: October 10, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Two different genetic signatures may offer some clue about prognosis in castration-resistant prostate cancer.

In one study, a six-gene panel distinguished between patients with longer and shorter survival rates (P<0.0001), according to William Oh, MD, of Mount Sinai School of Medicine in New York, and colleagues.

In a second study, Johann de Bono, MD, of Royal Marsden NHS Foundation Trust in Surrey, England, and colleagues identified a set of nine genes that predicted poor survival (P<0.0001).

The studies were published online in The Lancet Oncology.

Castration-resistant prostate cancer typically carries a high mortality rate -- though it is still highly variable -- and treatments, including treatment with newer agents such as sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone (Zytiga), usually extend life just a few months beyond expected survival.

Companies are still looking to develop treatments for this late-stage disease, but few genetic markers have been found that could serve as therapeutic targets.

Both groups of researchers conducted whole-blood gene profiling, looking for gene expression as measured for mRNA signatures.

Oh and colleagues used blood samples from 62 men with castration-resistant prostate cancer who were on various treatment regimens at Dana-Farber Cancer Institute in Boston to assess a panel of 168 inflammation-related and prostate cancer-related genes.

Ultimately, they derived a six-gene panel -- ABL2, C1QA, SEMA4D, TIMP1, ITGAL, and CDKN1A -- that separated patients in two groups: one low-risk group with a median survival of more than 34.9 months (the median survival actually was not reached in the trial) and a high-risk group with a median survival of 7.8 months (P<0.0001).

The panel's prognostic utility was validated in an independent cohort of 138 patients from Memorial Sloan Kettering Cancer Center in New York, they reported.

The difference in survival was less prominent in this validation cohort (9.2 versus 18.5 months, HR 2.3, 95% CI 1.39 to 3.70), but it was associated with a significantly higher area under the curve compared with a clinico-pathological model (0.90 versus 0.65, P=0.0067).

The model "suggests possible dysregulation of the immune system," they wrote. The protein products of ABL2, ITGAL, and SEMA4D are involved in T-cell motility, antigen surveillance, and T-helper-cell activity, while C1QA, CDKN1A, and TIMP1 are involved in macrophages and dendritic cells.

In the second study, de Bono and colleagues looked at mRNA expression in the blood of 64 patients with castration-resistant prostate cancer and compared it with that of 30 early prostate cancer patients who were slated for active surveillance, to come up with a nine-gene panel.

They found that patients in a certain genotype -- latent process decomposition 1 (LPD1) -- had features that were associated with poorer overall survival than those in other subgroups (LPD2, LPD3, and LPD4) (10.7 months versus 25.6 months, P<0.0001).

They confirmed the prognostic utility of the nine-gene panel in a validation cohort of 70 castrate-resistant prostate cancer patients and found that those in the LPD1 group had worse overall survival than the other three groups combined (9.2 months versus 21.6 months, P=0.001).

In an accompanying editorial, Karina Dalsgaard Sørensen, MD, of Aarhus University in Denmark, cautioned that the "biological relevance of these prognostic signatures, which are the first of their kind, is largely unknown."

She noted that further investigation of the underlying biological mechanisms is needed, and future studies need to clarify whether "any of the 15 signature genes are functionally relevant, or are surrogate markers for other processes."

"Whether these blood mRNA signatures will be true game changers for management of castration-resistant prostate cancer is too early to say," she wrote. While their simplicity is attractive, she said, "large-scale prospective studies are needed to validate their biomarker potential."

The Oh study was supported by MDx. The researchers reported relationships with MDx.

The de Bono study was supported by AstraZeneca, the Experimental Cancer Medicine Center, the Prostate Cancer Charity, and the Prostate Cancer Foundation. The researchers reported no conflicts of interest.

The editorialist reported no conflicts of interest.

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