New Markers May Help Predict Course of Prostate Carcinoma

SEATTLE-Current screening techniques allow the early detectionof prostate cancer in large numbers of men every year. The problemis that prostate cancer appears to be an almost ubiquitous malignancyin men over the age of 50. The question, then, is which patientsrequire intervention to prevent their cancer from becoming lifethreatening?

Three commonly used parameters are somewhat helpful in this regard:Gleason grade, tumor volume, and extent of tumor infiltration,said Michael Brawer, MD, of the University of Washington, Seattle.

In his presentation at the Pacific Northwest Cancer FoundationMeeting on Transperineal Brachytherapy for Early Stage ProstateCancer, Dr. Brawer noted that a number of new markers such asoncogenes and tumor microvasculariza-tion are currently beingevaluated.

Histologic (Gleason) grading does work, he said, in predictingthe probability of metastasis. The problem is, the majority ofcancers that are detected by early screening fall into a middleground where the picture is not so clear.

He said that tumor volume is also helpful in predicting metastaticdisease and seminal vesicle invasion. But it is difficult to assessthe shape and volume of a tumor by remote methods. Although transurethralultrasound (TRUS) is helpful in visualizing the extent of thetumor outside of the capsule, it is not otherwise useful in stagingthe cancer. "Pathologic stage and echogenicity may indicatehigher grade cancer," Dr. Brawer said, "but so far wehaven't seen any difference."

Biopsy is used to determine the extent of the tumor, ie, whetherthe cancer is found on one side of the prostate (B1), both sides(B2), or shows extracapsular extension. The more biopsy sitesthat contain cancer cells, the larger the tumor volume, whichworsens the prognosis.

The best combination at present for determining prostate cancerprognosis is biopsy, histological staging, and PSA values, hesaid.

The position of the tumor may have some predictive value, butnot a great deal. "Prostate cancer likes to escape the glandalong the neurovascular bundle," Dr. Brawer said. "Cancerin the apex has a preferred position for exiting, so this maybe a slightly worse area to find the tumor, but this hasn't beenhighly predictive." He noted that DNA heterogeneity (ploidy)also has not proved to be useful.

Newer Techniques

An area that needs further study is that of neuroendocrine differentiationof the tumor, Dr. Brawer said. Apparently an increase in the subsetof prostate cancer cells that express neuroendocrine markers hasbeen correlated with an increased rate of tumor progression insome studies, but others have shown no such correlation. Expressionof the oncogenes bcl-2 and p53 may also indicate greater tumorprogression, but again results have been mixed.

A parameter that seems especially promising, Dr. Brawer said,is the extent of microvascularization of a particular tumor. "Tumorangiogenesis is extremely important," he said. "Oncea neoplasm is greater than 1 mm in diameter, it has to inducea blood supply from the surrounding tissue."

Dr. Brawer and his colleagues have quantitated microvessel densityvia computer and correlated this with pathologic stage. They foundthat this technique yielded a significant increase in their abilityto detect which cancers had progressed beyond the prostate, particularlywhen microvessel density was more than 120 vessels/mm.

Another technique for detecting ex-traprostatic disease that hasshown good preliminary results uses reverse transcriptase PCR(polymerase chain reaction), Dr. Brawer said. The researchersused primers against PSA and prostate membrane antigen to probefor small numbers of circulating cancer cells.

"There's nothing new here," he said. "We've knowncancer cells circulate. The question is, are these circulatingcells able to give rise to metastases and predict a negative outcome?"

Dr. Brawer noted that the PCR technique thus far is about 72%to 88% as sensitive as PSA levels in predicting extraprostaticmetastases. These are encouraging results, but he noted that furthermarkers need to be developed to prove that those cancer cellsthat can be detected actually have the potential to cause metastaticmalignancy.