LA TENDENCIA GENERAL AL FORMALISMO
LA SUBSTANCIA SOCIAL DE LA RACIONALIDAD OPERACIONAL
The National Institute of Health Biomarkers Definitions Working group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or a pharmacologic process response to a therapeutic intervention” (Atkinson, Colburn et al. 2001). An ideal biomarker for early detection of cancer would be one secreted by tumour but not normal tissue therefore highly specific and be easily and cheaply detected in a body fluid so it can be detected non- invasively (Pepe, Etzioni et al. 2001). The issue of specificity is important when considering biomarkers for screening programmes as even a small false positive rate when multiplied
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on a population scale will be a large financial burden and potentially cause psychological stress to individuals (Pepe, Etzioni et al. 2001).The improvement of morbidity and mortality is a primary aim of clinical research and as such are clinical endpoints (Strimbu, Tavel 2010). Biomarkers become surrogate endpoints when they have been proved to have well evaluated clinical relevance (Atkinson, Colburn et al. 2001); there must be robust scientific evidence that clinical outcome is consistently and accurately predicted by a biomarker (Strimbu, Tavel 2010). The process of developing a clinical biomarker is therefore necessarily rigorous and must undergo several phases (Pepe, Etzioni et al. 2001) from discovery to clinical trials before they become part of routine patient management. At present there are no molecular biomarkers routinely used for the diagnosis or prognostication of oral cancer.
1.2.1 Diagnostic biomarkers
In a disease that often presents late with associated poor prognosis, has identifiable high risk groups and limitations on detection from clinical examination, a biomarker with satisfactory accuracy for identifying OSCC early would be valuable. Clinical examination is the mainstay of oral cancer diagnosis at present but disease can be occult and evade the naked eye. The pressing need for improved diagnostics is because of the marked differential in survival rates between early and advanced stage cancer. There is a trend for late presentation which is likely multifactorial (Noonan 2014) but could be due to the fact that OSCC is largely an asymptomatic condition, especially in the early stages. Another reason could be that aggressive tumours progress rapidly. The sensitivity of visual inspection for the detection of oral cancer in primary care settings can be variable (Walsh, Liu et al. 2013) with limitations of non-specialists to recognise cancerous oral lesions (Carter, Ogden 2007). To date studies of opportunistic oral screening studies based on visual inspection in unstratified populations have not made significant improvement in mortality through early detection (Brocklehurst, Kujan et al. 2013). Added to this, risk stratification based on age and lifestyle factors associated with OSCC may not be sufficient; as a subgroup of young patients are developing OSCC with little or no exposure to the common risk factors (Llewellyn, Linklater et al. 2003).
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1.2.2 Prognostic biomarkers
Prognostic biomarkers predict how the malignancy will progress and the patients’ overall outcome without therapy (Oldenhuis, Oosting et al. 2008). HPV in oropharyngeal SCC is an example of a prognostic molecular marker that successfully stratifies patients into predicted outcomes and informs treatment strategy (Rios Velazquez, Hoebers et al. 2014). Currently, OSCC prognostication is informed by the American Joint Committee on Cancer and the Union for International Cancer Control TNM staging criteria which is an anatomical classification. In a comprehensive review Takes and colleagues (Takes, Rinaldo et al. 2010) discuss the limitations of this system in the context of prognosis and patient management. A key criticism is that the TNM stages are too broad and as a result there is a wide range of survival and treatment response within any given stage. They propose this is contributory to continued poor survival rates and morbidity as a result of over or under treatment. They also raise the lack of consideration for the biological nature of the tumour and highlight the fact that a T1N2C tumour would receive the same ‘stage’ as a T4N0 when they are biologically, very different. Clinical markers of tumour biology which are known prognostic indicators, such as depth of invasion and nodal extracapsular spread, are notably missing from the staging method (Takes, Rinaldo et al. 2010).
Another need for prognostic biomarkers in OSCC is frequent recurrence and second primary tumours (Koo, Lim et al. 2006, Rogers, Brown et al. 2009) which have poor survival. The main theory for this propensity is field change in which tumours develop within areas of histologically atypia (Slaughter, Southwick et al. 1953) and molecular aberrations (Tabor, Brakenhoff et al. 2002, Braakhuis, Tabor et al. 2002). Molecular biomarkers may be able to identify those patients at risk of second field tumours at diagnosis of the primary disease and filter these patients into more intense post-operative disease surveillance follow-up, new chemotherapy treatments or future gene therapies (Braakhuis, Tabor et al. 2003).
1.2.3 Predictive biomarkers
Predictive biomarkers suggest how a cancer will respond to a therapeutic intervention (Oldenhuis, Oosting et al. 2008). Some cases of OSCC are preceded by a visible oral lesion (Napier, Speight 2008) and histopathological diagnosis is used to predict the risk of malignant change (Warnakulasuriya S, Reibel J et al. 2008) but severity of dysplasia does not always predict transformation (Holmstrup, Vedtofte et al. 2006). Surgical incisional biopsy can under diagnose cancerous oral lesions (Holmstrup, Vedtofte et al. 2007) and the