Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 38

in the surrogate marker is sufficient for approval. In the oncology field, the lack of such well-
established surrogate biomarkers of anti-tumor activity or overall survival has hampered
early clinical development of new therapies/therapeutic combinations.
The enumeration and characterization of circulating tumor cells (CTCs) prior to and dur-
ing various treatment regimens have the potential to become a surrogate endpoint that could
accelerate development of new anti-tumor agents. CTCs are present in the blood of many
patients with cancer and can be detected/quantified using the FDA approved CellSearch sys-
tem from Veridex [117] . The number of CTCs per 7.5 mL of blood has been identified as a
prognostic biomarker across a range of indications, including breast, colorectal, and prostate
cancer. Studies are currently ongoing to measure changes in CTCs following multiple thera-
pies both to evaluate its utility as a predictive biomarker and evaluate its association with
established clinical endpoints, such as disease-free survival and overall survival. Despite
considerable effort in this area, the use of CTC numbers as a surrogate biomarker/surrogate
endpoint for antitumor activity or as a guide for therapeutic intervention is not yet part of
routine clinical practice [118] . Limitations currently exist in the detection of CTC, in that the
use of anti-EpCAM-coated beads to identify circulating epithelial cells from various tumors
does not work when EpCAM expression levels are low [118] . Furthermore, the need for fresh
blood samples and the inability to both enumerate CTCs and evaluate their molecular phe-
notype in a clinical setting add to the challenges of utilizing CTCs as surrogate biomarkers.
Nonetheless, as technology improves to overcome these current limitations, the association
of CTCs with clinical benefit and utility as a surrogate biomarker may be possible [117-119] .
Having such a surrogate endpoint will aid clinical decision making and positively impact
drug development timelines in early phase trials where it is challenging to assess overall sur-
vival due to lengthy timelines.
2.3 COMPANION DIAGNOSTICS
Most of the biomarkers that have successfully reached the clinic have been identified
though retrospective analyses. Existing knowledge of mutations and other molecular data
available early in the drug development process has yet to become a routine aspect of pro-
spective trials. Thus, the challenge is to use current techniques and knowledge to pursue
opportunities for predictive biomarkers to be identified prospectively or co-developed as
companion diagnostics.
Companion diagnostics are in vitro diagnostic (IVD) tests that are intended to insure that
therapeutic products are used according to their label and are safe and effective [120-122] .
Additionally, they are of substantial importance in patient selection for certain treatments
and in preventing undue safety risk that may arise from patients receiving treatments
unlikely to work. The term 'companion diagnostic' can be used independently of where
in the drug development cycle the diagnostic test is introduced. For example, a compan-
ion diagnostic can be developed with a new drug, as in the case of HER2 for trastuzumab /
Herceptin [18] . A new diagnostic test can be developed for an existing drug, as in the case of
UGT1A1 for the chemotherapeutic irinotecan [73,75,76] . Finally, an existing diagnostic test
could be applied for a new drug. Since 1994, approximately 100 molecular IVD tests have
received pre-market authorization from the FDA, with about a quarter of these tests relying