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Question 12.1: How would you define molecular pathology testing in solid tumours in routine practice?
What type of information to expect for patient’s management? What types of samples? What types of targets within tumour cells?
Molecular testing as a supplementary test to histology assessment can provide information on the diagnosis (for example specific translocations in sarcomas and lymphomas or B and T cell clonality testing in atypical lymphoid proliferations), the prognosis (Mismatch Repair Proteins loss of expression in colorectal cancer, 1p and 19q loss of heterozygosity in Glial tumours), the prediction to targeted therapy (EGFR mutation in lung cancer, BRAF mutation in melanoma, etc).
Tests should be set up to be suitable for the real life specimens, mainly formalin fixed paraffin embedded biopsies; tests should therefore be validated on small, heterogeneous and degraded fragments.
Molecular testing in solid tumours can target gene mutations (EGFR1, RAS, BRAF, etc) translocations (ALK, EWSR1, SS18, etc), gene amplification (HER2, MET etc), gene deletion (1p, 19q), but also protein over expression (Her2, PDL1), loss of expression (DNA Mismatch Repair System) or nuclear translocation (beta catenin). A tumour will need to be assessed for several alterations requiring various types of technology. Multiplex assessment is not synonymous to assessment of many gene mutations but implies the assessment of various targets (genes, chromosomes and proteins) guided by clinical relevance
Question 12.2: What are the constraints to validate a molecular test in routine practice, both clinically and technically?
Molecular testing in solid tumour in routine practice is guided by clinical relevance. The value of a test has been demonstrated through clinical studies or drug trials. None of the tests has 100% accuracy; studies have shown that the presence of a specific molecular alteration in a specific situation for a type of tumour conveys an advantage which is statistically significant enough to be used in routine.
In practice, the presence of a specific molecular alteration does not have the same clinical value in all types of tumours; for example, not all BRAF mutated malignant tumours have been shown to respond to BRAF targeted therapy. Currently, BRAF targeted therapy has only been licensed in BRAF mutated melanomas (so far it has not been demonstrated that BRAF mutated lung or colorectal carcinomas do respond to this therapy).
Molecular tests need to be highly sensitive and specific and to work in any type of real life samples. Technical validation follows strict guidance to fulfil accreditation requirements. Each test needs to be accredited separately.