Tissue microarrays for rapid linking of molecular changes to clinical endpoints

Advances in genomics and proteomics are dramatically increasing the need to evaluate large numbers of molecular targets for their diagnostic, predicti ve or prognostic value in clinical oncology. Conventional molecular patholo gy techniques are often tedious, time-consuming, and require a lot of tissu e, thereby limiting both the number of tissues and the number of targets th at can be evaluated. Here, we demonstrate the power of our recently describ ed tissue microarray (TMA) technology in analyzing prognostic markers in a series of 553 breast carcinomas. Four independent TMAs were constructed by acquiring 0.6 nun biopsies from one central and from three peripheral regio ns of each of the formalin-fixed paraffin embedded tumors. Immunostaining o f TMA sections and conventional "large" sections were performed for two wel l-established prognostic markers, estrogen receptor (ER) and progesterone r eceptor (PR), as well as for p53, another frequently examined protein for w hich the data on prognostic utility in breast cancer are less unequivocal. Compared with conventional large section analysis, a single sample from eac h tumor identified about 95% of the information for ER, 75 to 81% for PR, a nd 70 to 74% for p53. However, all 12 TMA analyses (three antibodies on fou r different arrays) yielded as significant or more significant associations with tumor-specific survival than large section analyses (p < 0.0015 for e ach of the 12 comparisons). A single sample from each tumor was sufficient to identify associations between molecular alterations and clinical outcome . It is concluded that, contrary to expectations, tissue heterogeneity did not negatively influence the predictive power of the TMA results. TMA techn ology will be of substantial value in rapidly translating genomic and prote omics information to clinical-applications.