Biomedical Engineering Reference
In-Depth Information
to assist in personalized treatment decisions. An excellent example is
the development of OncoType Dx for prognostic prediction of patients
with breast cancer. In the context of MTA against key molecular targets
and pathways, it is conceivable that gene expression signatures of
pathway activations (e.g., MAPK or PI3K) may be potential candidates
of predictive markers. However, development and validation of non-
DNA based multi-analyte markers are technically and statistically
challenging. In an analysis by Subramanian and Simon of 16 studies
for gene expression-based prognostic signatures for non-small cell
lung cancer,
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there was little evidence that any of the reported
gene expression signatures were ready for clinical application. More
importantly, there were serious problems in the design and analysis
of many of the studies. Guidelines have now been proposed to aid
the proper trial design, validated assays and unbiased analysis and
validation.
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Another challenge is the longitudinal evolutions of the molecular
and clonal profiles through the tumor progression, particularly
under the selective pressure of various drug therapies. Therefore
tumor tissues obtained from the time of diagnosis, may not reflect the
molecular features at the time of new drug clinical trials. Exploration
of predictive markers based on these distant tumor specimens can
be misleading. However, fresh biopsies for current tumor tissues
are costly and not always feasible in patients in advanced stage of
cancer.
With the increasing realization of the important of predictive
markers for drug development and personalized medicine, there is
an enhanced awareness and investment in the biomarker studies,
including the search of predictive marker hypotheses in preclinical
development of new drugs. The rapidly evolving sequencing
technologies have also made it possible to perform genetic
characterizations with increasing efficiency and decreasing cost.
As exemplified by the BATTLE trials, it is now feasible to screen a
patient for potential clinical trials and therapeutic options through
multiplexed platforms of genetic characterizations of multiple genes.
Currently such “snapshot” approach to patient characterizations can
be established for hot-spot mutations in many “actionable” genes. It
can be envisioned that in the future, such approach can be extended
to characterization of whole-exome sequencing or RAN- and protein-
based assays in a real time efficient manner.
