Molecular Diagnostics


Table 1: Examples of types of changes occurring in genes or their protein products associated with tumours, which may predict for response to anti-cancer drugs


TYPE OF BIOCHEMICAL CHANGE ASSOCIATED WITH TUMOUR


GENE OR PROTEIN BIOMARKER


SOMATIC MUTATIONS


KRAS BRAF PIK3CA EGFR


INHERITED MUTATIONS POLYMORPHISMS BRCA1/2


UGT1A1 CYP450 Fc RII/III


GENE AMPLIFICATION OR COPY NUMBER VARIATION


GENE EXPRESSION (21 GENE MULTIPLEXED)


HER2 EGFR Top2A


OncotypeDx™ PROTEIN OVER-EXPRESSION


EGFR HER2 ERCC1 B-tubulin


PROTEIN LOSS; MUTATIONS, COPY NUMBER VARIATION


and the second (contributing to the first), was that the attrition rate for taking these drugs to licensing (most failing at the Phase II/III transition) was unacceptably high. For example, between 1990 and 2006 there were a total of 920 candidate ther- apeutics; of which 45% of these had been com- pleted by 2007, but only 32 had been approved by the FDA. This equates to a startlingly low overall success rate of 8%3.


The FDA suggested that new types of “tools” were required to deal with this unacceptable situa- tion. These fell into two categories:


l New molecular biomarkers, to be developed and incorporated into diagnostic assays. l Proteomic and genomic signatures for diagnos-


Drug Discovery World Spring 2011 PTEN MAY PREDICT RESPONSE TO


cetuximab; panitumumab; gefitinib; erlotinib cetuximab; panitumumab; gefitinib; erlotinib cetuximab; panitumumab; lapatinib; trastuzumab gefitinib; erlotinib


olaparib


irinotecan tamoxifen trastuzumab; rituximab; erbitux


trastuzumab gefitinib; erlotinib


anthracyline chemotherapy chemotherapy


cetuximab trastuzumab platinum compounds Taxanes


trastuzumab; hormone therapy, chemotherapy


tic, prognostic or predictive purposes, and for patient stratification and salvage of failed thera- peutic agents.


The modern paradigm therefore became that the predictive (or ‘companion diagnostic’ in some instances) would evolve as part of a rational drug discovery programme, and that the predictive would accompany the drug through its develop- mental arc; from discovery, through clinical trials where it would be used to stratify patients, finally to companion test on the label of the newly- licensed therapeutic. Current examples of this are the HER2 immunohistochemistry with reflex FISH test that accompanies prescribing of Herceptin™ (trastuzumab) for advanced breast


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