Has discovery-based cancer research been a bust?

The completion of the human genome sequence sparked optimism about prospects for new anticancer drug development, but clinical progress over the last decade has proven slower than expected. Here it is proposed that unrealistically high expectations of first-generation discovery-based diagnostics have contributed to this problem. Hypothesis-based single-molecule tests (e.g., mutation screening of KRAS, EGFR, BRAF or KIT genes) continue to change clinical practice incrementally, whereas first-generation multiplex assays--such as gene expression profiling and proteomics--have identified few high-impact therapeutic targets despite numerous correlations with prognosis. To move forward, second-generation multiplex diagnostics should be based not on statistical patterns/associations alone, but on clinically interpretable ('high-signal-to-noise') data such as change-of-function mutations, gene amplifications, recurrent chromosomal anomalies, and abnormal phosphorylation profiles of ERK or mTOR signaling cascades.