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. Author manuscript; available in PMC: 2012 Jul 29.
Published in final edited form as: Urol Oncol. 2010 Jul-Aug;28(4):389–400. doi: 10.1016/j.urolonc.2010.02.011

Table 2.

Challenges to and advances that may facilitate the development of clinically useful bladder cancer biomarkers

CHALLENGES
Biologic factors

  • Progressive biologic heterogeneity with transient expression of certain features is a characteristic of tumor cells. Biological heterogeneity is present both among cells within the tumor at a given time and in cells during the development of the tumor from earlier to later points in time. In addition, biomarkers may be affected by therapy and as yet uncharacterized, host factors. Biological heterogeneity includes multiple pathways to the same endpoints and the variable metabolism of biomarkers, including post-translational trans-modifications.

  • Age and the presence of other diseases also introduce variation in biomarker levels between individuals. Other physiologic or pathologic processes may generate biomarker profiles similar to those found in patients with tumor disease states.

  • Exogenous substances that affect biomarker presence and concentration. Foods, drugs, and natural alternative therapies are well known interferences.

Clinical pathologic factors

  • Requirement to define and standardize more precisely concepts of the biological events against which biomarkers are to be measured (e.g., normal variation, different disease states). New tools for accurate detection of pre-neoplastic neoplasia, micrometastatic spread, and states of early and/or aggressive cancer recurrence need to be developed.

Analytical sensitivity and detection limit

  • Assay sensitivity needs to be sufficiently high to allow biomarker quantitation at concentrations that have biologic relevance. Clinical detection and measurement of biomarkers of this type, at worst, could lead to unnecessary investigation and therapy or, at best, unnecessary chronic anxiety for the patient.

  • There is a lack of definition of standard procedures, standard reference materials, and quality control schemes necessary to assure accuracy and reproducibility.

  • There is a lack of clear guidelines for good manufacturing/laboratory practice and quality control requirements for all phases of biomarker development.

Intellectual property

  • Ownership of a biomarker is a key element of its commercialization. Considering the cost of developing and validating a biomarker, no company will invest in a biomarker for which they can not be assured a reasonable return on investment by means of protection of intellectual property. Only a very small fraction of candidate biomarkers demonstrate real clinical utility, such that the demand for return on investment is similar to the drug development models. These issues are well appreciated by bio-industry, and demonstrated by their lack of interest in commercialization of the plethora of candidate biomarkers in the literature.

Health service factor

  • It is not sufficient for a tissue biomarker to detect a particular phase of neoplasia. To be successful, the biomarker must also fit within the profile of health service factors with respect to cost-effectiveness, cost benefit, and relative value of biomarker strategy for cancer burden reduction.

FACTORS TO SUPPORT ADVANCES
Defining the biology of bladder cancer and its processes with precision

  • Enhanced interaction among investigators of different disciplines and institutions.

  • Greater appreciation of the biokinetics of both cancer and its biomarkers permitting more dynamic views of how cancers evolve.

Defining host biology: pharmaco-genomics and pharmaco-proteinomics

  • Biological profiling does have the prospect of individualizing therapy, maximizing efficacy, and minimizing toxicity. Ideal markers would reflect both cancer activity and individual sensitivity to therapy.

Defining biomarkers and surrogate endpoints

  • Need for developing a consensus about definitions that are widely accepted and applied.

Creating guidelines for appropriate clinical employment of each biomarker

  • Plan a series of national multidisciplinary initiatives aimed at (1) surveying the QC programs, (2) coordinating from a scientific point of view the activities in this area and producing guidelines for the clinical employment of cancer biomarkers, (3) standardizing the procedures, and (4) developing laboratory QC programs for the analysis of cancer biomarkers of validated clinical relevance in multicenter clinical protocols.

Standardization and stringency of analytical technology

  • Further standardize pre-analytical, analytical, post-analytical methodology. However standardization of biomarker assay technology involves considerations beyond analytical sensitivity and specificity. For example, advancing toward standardized technology, the advantages of comparability between various studies must be weighted against the desire and need for innovation and conditions that require protocol flexibility.

High-quality specimen and clinical data repository

  • Need for specimen and data repositories that address in a bioethical manner patient consent, confidentiality, specimen provenance, technical preparation, and storage.