From precision medicine to imprecision medicine through limited diagnostic ability to detect low allelic frequency mutations

The Rosetta Stone of the new era of biomedicine includes five essential ideas to understand the real concept of precision medicine (PM): preventive, predictive, personalized, participatory (1), and pertinent. The application of these five “Ps” is currently the Holy Grail of the clinical routine and particularly important for cancer are the concepts of prediction and personalization. It is especially significant in those diseases characterized by higher biological heterogeneity, as it is the case of lung cancer. Obviously, an improvement of biological knowledge must be accompanied by technological breakthroughs. In the last years, new molecular analysis technologies characterized by high specificity and sensitivity rates are being developed, allowing detection of rare clonal sub-types with low allelic frequency. However, the specificity and sensitivity present high variability among platforms, what is of particular importance for the detection of very low allelic frequency mutations. In fact, it has been accepted that variants with a low allele frequency affect the accuracy of mutation detection methodologies (2). Moreover, the variability in the limits of detection (LoD) is especially important for a correct treatment choice as well as an efficient stratification of patients susceptible to be treated with a particular therapy. Therefore, selection of methodologies with ability to discriminate between high and low allelic frequencies is essential for a correct application of PM. In the case of lung cancer, there are several mutation-targeting strategies for personalized treatments among which, tyrosine kinase inhibitors (TKI) are a widely used anti-cancer strategy. The key target of these drugs is the EGFR gene that, when overexpressed, activates cell survival and proliferation pathways. The success or failure of TKI treatments usually relies on presence or absence of sensitizing mutations respectively but together with them also treatment-resistant mutations might play a role (3). The most common resistance mutation is EGFR T790M so screening for this mutation offers information on whether the patient is candidate or not for TKI treatments