Post-radical prostatectomy recurrence may be predicted by methylation status

Orlando, FL-Measuring paired-like homeodomain transcription factor 2 (PITX2) methylation status may aid in predicting the risk of biochemical recurrence after radical prostatectomy, according to findings from a multicenter study, which showed that high methylation status was associated with a higher risk of biochemical recurrence compared to low methylation status.

As such, PITX2 hypermethylation may identify those patients who might benefit from further therapeutic intervention for prostate cancer following prostatectomy, said first author Esmeralda Heiden, MD, PhD, a pathologist at Epigenomics AG in Berlin.

DNA methylation is an important regulator of gene transcription. Alterations in DNA methylation are common in several tumor types, notably breast and prostate tumors.

PITX2 is a transcription factor induced by the WNT pathway, and is required for cell-type-specific proliferation during development. PITX2 gene promoter methylation had already been shown to predict outcomes in patients with breast cancer and prostate cancer, Dr. Heiden said at the 2009 American Society of Clinical Oncology annual meeting. Epigenomics markets a prostate cancer prognosis test that is available under an early access program at select clinical centers in Europe. Its mPITX2 Detection Assay detects methylated DNA of the PITX2 gene isolated from formalin-fixed, paraffin-embedded tissue.

Hypermethylation, recurrence linked

"We made a discovery some years ago, checking tumor tissue, breast, and prostate tumors for abnormally methylated genes," Dr. Heiden told Urology Times.

"One of those genes is PITX2. We did a first study in prostate cancer with more than 600 patients using real-time polymerase chain reaction methodology detecting the methylation of the promoter of this gene, and we found that the hypermethylation of this promoter was significantly related to biochemical recurrence."

The validation study presented here included tumor tissue samples from more than 500 patients with pT2 or pT3 tumors. Biochemical recurrence was defined as at least two consecutive PSA measurements >0.2 ng/mL.

On univariate analysis, those with high methylation status had more than twice the risk of biochemical recurrence than those with low methylation status (hazard ratio [HR]: 3.0; p<.00001).

At 5 years, biochemical recurrence-free survival was 85% and 61% for men with low and high methylation status, respectively.

Among the patients with Gleason 7 tumors, high PITX2 imparted an HR of 2.0 (p=.005) for biochemical recurrence compared to low methylation status.

Hypermethylation of PITX2 was a significant predictor of recurrence independent of pathologic stage and margin status, said Dr. Heiden.

"In real practice, if the patient has positive margins or is Gleason 7 or has something else that would say this is high risk, the urologist is confronted with the possibility of recurrence," she explained. "We want to help define which patients may really benefit from further treatment."

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