A sequencing study performed on a recurrent HCC after surgical resection showed 10 different alterations and distinct cell populations across the primary tumor and the recurrence.16, 17 Authors were able to identify molecular aberrations BMS-777607 molecular weight that favored clonal outgrowth and conferred a more aggressive phenotype. Overall, these studies raise several concerns about the validity of single tumor-biopsy to infer genomic information

applicable in patient decision-making. In other words, is the whole model of personalized oncology jeopardized until tools are available to accurately assess intra-individual tumor heterogeneity? Certainly, the presence of molecular heterogeneity introduces a new variable in the personalized oncology approach. Intra-individual heterogeneity probably explains why, despite effective blockade of oncogenic addiction loops, we are

still unable to attain a 100% complete response rate and cure the disease. It may also justify why targeted therapies in solid tumors are less effective compared with hematological malignancies. Nonetheless, there PI3K inhibitor are still many unanswered questions, such as the accurate distribution of the different mutational variants present in a given tumor and their predominance in tumor progression. Liver biopsy results are subject to sample variability and require a careful interpretation. In HCC, noninvasive criteria are accepted for the diagnosis of this neoplasm,18, 19 but recent guidelines recommend collecting tissue samples in a systematic

manner in the context of clinical trials and research studies.19 Study investigators testing molecular heterogeneity using next-generation sequencing are encouraged to determine whether additional mutations identified in different tumor sites or in multiple tumors have any functional impact on progression, resistance Pregnenolone to therapy, and dissemination of this cancer. Our studies exploring transcriptomic heterogeneity within single early HCC tumors showed quite homologous molecular subclasses in samples obtained from the same nodule, albeit no next-generation testing was conducted.20 In conclusion, solid evidence indicates that blocking oncogenic addiction loops improves survival in cancer patients (Table 1), even when drivers are evaluated in a single tumor biopsy. These examples reflect what Gerlinger et al. state at the end of their Discussion: “larger series will probably identify genes that can be targeted in the trunks of the phylogenetic tree for each tumor type.” Hence, despite its limitations, working with single biopsies for exploring common oncogenic drivers improves outcome in patients with cancer. This does not diminish the need for new readouts of tumor biology and heterogeneity (e.g., tumor circulating cells and functional imaging21).