A new race against lung cancer

J Vis Surg 2017;3:110 jovs.amegroups. com In 2017 lung cancer is still worldwide the huge nightmare among cancers with a tribute in terms of incidence and deaths ceiling 1.8 and 1.6 millions of patients respectively (1,2). The main reasons are l inked to t ime lead bias phenomenon reducing the magnitude of benefit of screening programs in high risk populations. The high incidence and deaths of this tumor in non-smokers patients or with scarce recognized risk factors and the modest efficacy of old fashion chemotherapeutic agents makes this tumor a challenge. Two major axes regarding targeted agents and immunotherapies seem to improve the prognosis of lung cancer patients but resistance mechanisms and immunoescape are the main weakness of these breakthrough agents. However, new therapeutic approaches leading to becoming chronic in some cases lung cancer have improved the number of the so called 5 years long-term survival (3,4). The real reason of failure of all treatments in lung cancer is due to the Darwinian principle of species evolution: cancers are composed by heterogeneous tumor cells and their evolution is not linear but branching evolutionary trajectories that are the main ways leading to uncontrolled growth and metastatic spreading of this tumor. Recently, Cancer Research UK is supporting an ambitious program investing £14 million in studying the evolutionary genetic landscape in non-small cell lung cancer (NSCLC). Swanton and colleagues have reported preliminary results of the whole-exome sequencing of 100 early-stage NSCLC in order to correlate the heterogeneity towards the study of clonal and subclonal events to meaningful clinical outcome named recurrence-free survival (5). Tracking Non-small Cell lung cancer Evolution through Therapy (TRACERx) trail started its activity in April 2014 and more than 800 tumors from completely surgical resected patients affected by NSCLC stage IA through IIIA have been collected in order to deeply fathom heterogeneity through whole exome sequencing. In summary, the authors have found that a few driver mutations like EGFR, MET, BRAF were almost exclusively clonal whereas PIK3CA, NF1, KRAS, TP53 and NOTCH family members were represented as subclonal mutations. Also gene amplification seemed to follow the same pattern of variability with little allelic imbalance being clonal (TERT, 8p loss, 5p gain, FGFR1) while the majority were subclonal. Clonal mutations were sometimes histotypeoriented while subclonal lost that dependency being expression of heterogeneity per se. This aspect has an immediate effect in clinical practice: subclonal driver alterations may appear as clonal in a small biopsy leading to a therapeutic choice that could be unsatisfactory giving an underperformance than expected. On the contrary, we risk to consider a passenger mutation as driver. Another aspect that clearly emerges from this trial regards the importance to intervene earlier with target agents. In fact, true driver mutations are present at the beginning of clonal evolution in the so called “trunk” of clonal evolution and the probability to purge neoplastic cells is higher when we target mutation in the trunk instead of blocking a subclonal mutation in a side branch of this evolutionary clone. During the evolution of the trunk there is a point of no return in which the genome doubling phenomenon accelerates the clonal diversification sprouting many branches with many other subclonal mutat ions/ amplifications. Regarding the clinical aspect the TRACERx trial demonstrated that elevated subclonal heterogeneity was associated with worse outcomes with a meaningful higher Editorial on Thoracic Surgery