Elevated Immune Protein May Identify High-Risk Prostate Cancer

ROCHESTER, Minn., Aug. 15 -- Aggressive, high-risk prostate cancers have increased expression of an immumodulatory protein that predicts relapse after treatment, investigators reported.
Malignant and premalignant prostate tissue consistently expressed the B7-H3 at higher levels compared with those associated with benign or normal tissue, according to a study reported in the Aug. 15 issue of Cancer Research.
Increased B7-H3 intensity correlated with worse clinicopathologic features and a four-fold increased risk of progression after surgery, Eugene D. Kwon, M.D., of the Mayo Clinic here, and colleagues reported.
"B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery," the authors concluded.
"Moreover," they said, "B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well."
The B7 family of proteins interacts with various receptors to regulate T-cell activation and function. The authors speculated that B7-H3 might inhibit T-cell-mediated immune response against cancer cells.
The researchers had previously shown that expression of the B7-H1 protein by kidney and bladder cancers portends more aggressive disease and worse clinical outcome.
In the current study, they compared expression of B7-H3 and B7-H1 in 338 paraffin-embedded tissue samples from men who underwent radical prostatectomy for clinically localized disease.
At last follow-up, 93 (27.5%) had disease progression at a median of 3.9 years following surgery. The remaining 245 patients did not have progressive disease during a median follow-up of 9.1 years. Estimated progression-free survival was 95% at one year and 75.6% at seven years.
Dr. Kwon and colleagues reported that only three specimens (0.8%) had histologic evidence of B7-H1 expression. In one specimen, 5% of cells were B7-H1 positive, and the other two had 20% positive staining.
In contrast, all 338 cancer specimens tested positive for B7-H3 expression, and the proportion of involved cells ranged from 40% to 100%. In fact, 282 specimens exhibited 100% tumor expression of B7-H3. However, the intensity of expression varied substantially and was weak in 19.2% of cases, moderate in 61%, and marked in 19.8%.
All but two of the specimens contained areas of normal, atrophic, or hyperplastic prostatic epithelia. Examination of those areas revealed B7-H3 expression ranging from 20% to 100% of cells. However, the intensity of expression was weak in two-thirds of cases, and only one case (0.3%) demonstrated marked expression.
Intensity of B7-H3 expression correlated significantly with clinical and pathologic features. More intense expression was significantly associated with larger tumor volume, higher Gleason score, seminal vesicle involvement, and positive surgical margins. As an example, no tumor with weak B7-H3 intensity had a Gleason score of 8 or 9, compared with 10 (4.9%) in the moderate-intensity category, and 23 (34.3%) with marked B7-H3 intensity (P<0.001).
In univariate analysis, moderate-intensity B7-H3 expression increased the likelihood of progression after prostatectomy by 35% compared with weak expression, but the difference was not statistically significant. However, marked B7-H3 expression was associated with a progression risk ratio of 4.42 compared with weak expression (P<0.001).
After adjustment for clinical and pathologic features, marked B7-H3 expression remained significantly associated with disease progression (RR 2.23 versus weak expression (P=0.042).
"Collectively, these results show that B7-H3 is a novel and independent prognostic marker for the assessment of prostate cancer patients," the authors concluded.
"Thus," they said, "B7-H3 may prove useful for the clinical evaluation of patients who have, or are to undergo, surgical treatment for their cancer, especially to identify high-risk patients who are at increased risk of cancer progression and, therefore, most likely to benefit from early and aggressive adjunctive therapy."
Although the role of B7-H3 in prostate cancer has not been clearly established, the authors continued, "we surmise that B7-H3 functions as an inhibitor of T-cell-mediated immunity that promotes aggressive clinical behavior by adenocarcinomas of the prostate."
The authors noted that B7-H3 expression is not restricted to prostate tissues. Specifically, B7-H3 is expressed in other normal adult tissues, most notably within the liver.
As useful as B7-H3 may be as a diagnostic and prognostic marker, the researchers noted that many questions "will still need to be addressed in future mechanistic and prospective clinical studies, including strategies to preempt toxicity to the liver and other normal tissues that might occur consequent to the targeting of B7-H3 protein."
Several authors disclosed financial interests related to the research. The study was supported by the Richard M. Schulze Family Foundation, the Commonwealth Foundation for Cancer Research, the Helen and Martin Kimmel Foundation, the National Cancer Institute, and the Department of Defense.Primary source: Cancer ResearchSource reference: Roth TJ et al. "B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy." Cancer Res 2007;67:7893-7900.