The traditional trial and error practice of medicine is progressively eroding in favor of more precise marker-assisted diagnosis and safer and more effective molecularly guided treatment of disease. For the pharmaceutical industry there appears an equally desirable outcome of this approach: increased efficiency, productivity, and product lines. For the diagnostics industry this represents an unprecedented opportunity for integration, increased value and commercial opportunities for molecularly derived tests. The realization of the integration of diagnostics with therapeutics and the transition to personalized medicine are not without challenges, yet many of these challenges are being addressed. As patients continue to take on more and more of the burden of their own health and well being, educational forums must be developed for patients and providers alike to understand the complex nature of the genomic, epigenomic and proteomic information that is now driving biomarker-based drug development and the future introduction of integrated diagnostics and therapeutics.

According to the Tufts Center for the Study of Drug Development, the cost of developing a new drug has surpassed $900 million. Under intense pressure to control development costs, most companies are evaluating novel approaches. A majority of development costs occur during clinical trials. Compounding the problem is that < 1/4 NCE’s are approved for marketing. For these reasons, finding early evidence of in vivo, target-specific effects would clearly assist in decision-making. Recently, emphasis has grown in the development of drug activity biomarker assays. This presentation will describe how flow cytometry was utilized as an effective tool for biomarker analysis in both pre-clinical and clinical development. Background concepts, assay development, validation and application of several flow cytometric biomarker assays will be described in this presentation. Biomarker assay results on cells taken after in vivo treatment with anti-cancer (zosuquidar trihydrochloride and enzastaurin) and an anti-inflammatory agent (LY293111) will be described.

In breast cancer, prognostic and predictive markers are urgently needed in order to individualize therapy concepts and thus avoid over- or undertreatment. Using a DNA methylation microarray, we found that DNA methylation of PITX2 correlates strongly with the risk of recurrence in breast cancer after adjuvant tamoxifen therapy. PITX2 methylation contributed significant information to conventional factors (e.g. grade, age, tumor size). PITX2 methylation was subsequently validated in an independent population (n=236) using the same microarray approach (Cox proportional hazard model, p<0.05). Independent methodological validation (PCR) was also performed. For the first time, DNA methylation was thus validated both clinically and methodologically as a clinically relevant prognostic and predictive marker in breast cancer. Results from a currently ongoing independent multicenter study, including over 800 tamoxifen treated as well as untreated node-negative breast cancer patients will be presented, and the potential of DNA methylation markers for personalized medicine will be discussed.