Dynamic genome and transcriptional network-based biomarkers and drugs: precision in breast cancer therapy.

Despite remarkable progress in medium-term overall survival benefit in the adjuvant, neoadjuvant and metastatic settings, with multiple recent targeted drug approvals, acquired resistance, late relapse, and cancer-related death rates remain challenging. Integrated technological systems have been developed to overcome these unmet needs. The characterization of structural and functional noncoding genome elements through next-generation sequencing (NGS) systems, Hi-C and CRISPR/Cas9, as well as computational models, allows for whole genome and transcriptome analysis. Rapid progress in large-scale single-biopsy genome analysis has identified several novel breast cancer driver genes and oncotargets. The exploration of spatiotemporal tumor evolution has returned exciting while inconclusive data on dynamic intratumor heterogeneity (ITH) through multiregional NGS and single-cell DNA/RNA sequencing and circulating genomic subclones (cGSs) by serial circulating cell-free DNA NGS to predict and overcome intrinsic and acquired therapeutic resistance. This review discusses reliable breast cancer genome analysis data and focuses on two major crucial perspectives. The validation of ITH, cGSs, and intrapatient genetic/genomic heterogeneity as predictive biomarkers, as well as the valid discovery of novel oncotargets within patient-centric genomic trials, encouraging early drug development, could optimize primary and secondary therapeutic decision-making. A longer-term goal is to identify the individualized landscape of both coding and noncoding key mutations. This progress will enable the understanding of molecular mechanisms perturbating regulatory networks, shaping the pharmaceutical controllability of deregulated transcriptional biocircuits.

From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers.

Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

Research and clinical applications of cancer genome sequencing.

PURPOSE OF REVIEW: To highlight the recent advances in cancer genome research and its clinical applications made possible by next-generation sequencing (NGS), with particular emphasis on gynecological and breast cancers is the purpose of the review. RECENT FINDINGS: Through advances in NGS technologies, whole-exome sequencing and whole-genome sequencing (WGS) have been performed on various cancers, identifying in the process numerous recurrent mutations and highly mutated genes. These cancers include uterine serous carcinomas, high-grade serous ovarian adenocarcinomas and breast cancer. In contrast to identifying somatic mutations in sporadic cancers, a far smaller number of studies using NGS have been conducted to identify new causal mutations or genes for hereditary cancer syndromes. In addition to research discovery, diagnostic applications of NGS have also become increasingly evident. Thus, WGS has been applied in a diagnostic context to identify a complex chromosomal rearrangement in a patient with acute myeloid leukemia of unclear subtype. Similarly, the targeted sequencing of panels of known cancer genes using NGS has demonstrated its robustness in the context of identifying known pathological mutations. SUMMARY: The research and clinical applications of cancer genome sequencing have progressed at an unprecedented pace over the last few years, and this promises to be accelerated with new developments of high-throughput NGS technologies and robust analytical tools.

Drug resistance: origins, evolution and characterization of genomic clones and the tumor ecosystem to optimize precise individualized therapy.

Progress in understanding and overcoming fatal intrinsic and acquired resistance is slow, with only a few exceptions. Despite advances in modern genome and transcriptome analysis, the controversy of the three different theories on drug resistance and tumor progression, namely dynamic intratumor heterogeneity, pre-existing minor genomic clones and tumor ecosystem, is unresolved. Moreover, evidence on transcriptional heterogeneity suggests the necessity of a drug bank for individualized, precise drug-sensitivity prediction. We propose a cancer type- and stage-specific clinicogenomic and tumor ecosystemic concept toward cancer precision medicine, focusing on early therapeutic resistance and relapse.

Bulk and Single-Cell Next-Generation Sequencing: Individualizing Treatment for Colorectal Cancer.

The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice to the innovative development of screening, predictive and therapeutic tools. Explosive integration of next-generation sequencing (NGS) systems into basic, translational and, more recently, basket trials is transforming biomedical and cancer research, aiming for substantial clinical implementation as well. Shifting from inter-patient tumor variability to the precise characterization of intra-tumor genetic, genomic and transcriptional heterogeneity (ITH) via multi-regional bulk tissue NGS and emerging single-cell transcriptomics, coupled with NGS of circulating cell-free DNA (cfDNA), unravels novel strategies for therapeutic response prediction and drug development. Remarkably, underway and future genomic/transcriptomic studies and trials exploring spatiotemporal clonal evolution represent most rational expectations to discover novel prognostic, predictive and therapeutic tools. This review describes latest advancements and future perspectives of integrated sequencing systems for genome and transcriptome exploration to overcome unmet research and clinical challenges towards Precision Oncology.

Discovering novel valid biomarkers and drugs in patient-centric genomic trials: the new epoch of precision surgical oncology.

Despite standardization of multimodal treatment and approval of several targeted drugs for resectable, non-metastatic cancer (M0 patients), intrinsic and acquired resistance and relapse rates remain high, even in early-stage aggressive tumors. Genome analysis could overcome these unmet needs. Our comprehensive review underlines the controversy on stable or spatiotemporally evolving clones as well as promising yet inconclusive data on genome-based biomarkers and drug development. We propose clinicogenomic trials in M0 patients for the validation of intratumor heterogeneity (ITH), circulating genomic subclones (cGSs) and intra-patient genomic heterogeneity (IPGH) as biomarkers and simultaneous discovery of novel oncotargets. This evidence-based strategy highlights the coming of precision surgical oncology with a future perspective of understanding and disrupting deregulated transcriptional networks.

Primary liver cancer genome sequencing: translational implications and challenges.

INTRODUCTION: The prognosis of primary liver cancer (PLC) remains poor and is explained by the slow progress in understanding the molecular pathways driving tumorigenesis, therapeutic resistance and relapse. For early PLCs, complete surgical resection is the only effective treatment, with sorafenib and, more recently, regorafenib prolonging overall survival by a few months. Areas covered: Application of next-generation sequencing (NGS), including targeted NGS (tNGS), whole-exome sequencing (WES), whole-genome sequencing (WGS) and RNA sequencing (RNAseq), on clinical samples from patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) could aid in comprehending tumorigenesis, genetic and genomic heterogeneity, as well as developing molecular classifications for specialized targeted therapy. Expert commentary: Despite the many overenthusiastic original and opinion reports, we have critically reviewed available NGS studies, with focus on the challenges to achieve clinical implications. Based on the recommendations for valid identification of clinically crucial genomic alterations (GAs) by NGS, we propose NGS integration into appropriately designed clinical trials. Furthermore, valid detection of genomic heterogeneity enables the conduction of clinical trials investigating the efficacy both of GAs as prognostic and predictive tools, as well as the discovery of novel oncotargets, on the basis of an early drug development strategy.