Abstract
Molecular prognostic markers are urgently needed in order to improve therapy decisions in prostate cancer. To better understand the requirements for biomarker studies, we re-analyzed prostate cancer tissue microarray immunohistochemistry (IHC) data from 39 prognosis markers in subsets of 50 – >10,000 tumors. We found a strong association between the “prognostic power” of individual markers and the number of tissues that should be minimally included in such studies. The prognostic relevance of more than 90% of the 39 IHC markers could be detected if ≥6400 tissue samples were analyzed. Studying markers of tissue quality, including immunohistochemistry of ets-related gene (ERG) and vimentin, and fluorescence in-situ hybridization analysis of human epidermal growth factor receptor 2 (HER2), we found that 18% of tissues in our tissue microarray (TMA) showed signs of reduced tissue preservation and limited immunoreactivity. Comparing the results of Kaplan-Meier survival analyses or associations to ERG immunohistochemistry in subsets of tumors with and without exclusion of these defective tissues did not reveal statistically relevant differences. In summary, our study demonstrates that TMA-based marker validation studies using biochemical recurrence as an endpoint require at least 6400 individual tissue samples for establishing statistically relevant associations between the expression of molecular markers and patient outcome if weak to moderate prognosticators should also be reliably identified.
Highlights
Prostate cancer is the most frequent malignancy in men
ets-related gene (ERG) is a member of the E26 transformation-specific (ETS) transcription factor family that is expressed in endothelial cells
ERG had been extensively studied in our tissue microarray (TMA) before since it is strongly expressed in about 50% of prostate cancers [47], and has been linked to early onset prostate cancer [48]
Summary
Prostate cancer is the most frequent malignancy in men. The clinical behavior ranges from slowly growing indolent tumors to highly aggressive and metastatic cancers. These tests are based on mRNA expression profiling of defined gene sets, allow for estimating the biological aggressiveness of a cancer and, may aid in therapy decisions [2,3,4]. The example of HER2 immunohistochemistry analysis of breast cancer demonstrates that a considerable (but not a complete) degree of assay standardization can be achieved [23] Even in such a highly standardized analysis including various controls, the quality of the tissues samples will impact the results. We took advantage of our very large prostate cancer tissue microarray comprising more than 12,000 tissue spots and molecular data from more than one hundred proteins analyzed by means of immunohistochemistry to better understand the impact of the sample size and the tissue quality on the outcome of TMA studies for marker validation purposes. This reason for this is that PSA recurrence is the “easiest” (most frequent) clinical endpoint to analyze in prostatectomy studies and it is strongly associated with other clinical endpoints such as metastasis or cancer-related death
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