Overcoming tumor heterogeneity in the molecular diagnosis of urological cancers

Abstract

Our understanding of tumor heterogeneity and impact on treatment response is still in its infancy, presenting significant challenges to the molecular pathologist, treating physician and ultimately for the patient. Given that tumor recurrence due to treatment resistance is the most common cause of cancer death, there remains a critical unmet need to change the current paradigm. The mechanisms which underlie tumor heterogeneity can be broadly divided into genomic instability and non-mutational processes, including stochastic variations in cellular responses, modulation by tumor microenvironment and or phenotypic/ functional plasticity relating to cancer stem cells. We believe that these biological mechanisms are not mutually exclusive and emphasize the need for more suitable methodologies to exploit the spatiotemporal patterns of intratumoral heterogeneity using novel approaches such as quantitative tissue-based biomarker assessment and systemic fluid analytics. Generating a comprehensive patient-centric phenotypic disease profile should generate a ‘codex’ which can be employed to change the current treatment decision process.

Keywords::

• biomarker
• exosomes
• next-gen sequencing
• system pathology
• tumor heterogeneity

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Intratumoral heterogeneity will negatively impact the success of targeted therapies in standard clinical trials unless steps are introduced to reduce sampling bias, improve specimen quality/preservation and develop molecular analytic techniques amenable for small-volume specimen characterization.

• Identifying and understanding the observed molecular (DNA/RNA) diversity present within tumor specimens (primary diagnostic, post-treatment or metastasis) will be critical for developing an effective treatment plan, which may include the use of combinatorial drug regimens in a clinical trial setting.

• Biologic–biochemical information contained in the intact tumor specimen must be interrogated and extracted using novel biomarker assessment tools integrated with clinical models as described in the systems/precise pathology platform.

• Employing fluid-based approaches such as exosomes and cell-free DNA represents the future of dynamic disease management from diagnosis through treatment response.