Longitudinal ctDNA profiling in precision oncology and immunο-oncology.

Serial analysis of circulating tumor DNA (ctDNA) over the disease course is emerging as a prognostic, predictive and patient-monitoring biomarker. In the metastatic setting, several multigene ctDNA assays have been approved or recommended by regulatory organizations for personalized targeted therapy, especially for lung cancer. By contrast, in nonmetastatic disease, detection of ctDNA resulting from minimal residual disease (MRD) following multimodal treatment with curative intent presents major technical challenges.

Proof-of-Concept Pilot Study on Comprehensive Spatiotemporal Intra-Patient Heterogeneity for Colorectal Cancer With Liver Metastasis.

Introduction: The mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood.

Objective: We evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability.

Methods: A total of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients were analyzed targeted next-generation sequencing (NGS).

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.

Comprehensive intra-individual genomic and transcriptional heterogeneity: Evidence-based Colorectal Cancer Precision Medicine.

Despite advances in translating conventional research into multi-modal treatment for colorectal cancer (CRC), therapeutic resistance and relapse remain unresolved in advanced resectable and, particularly, non-resectable disease. Genome and transcriptome sequencing and editing technologies, coupled with interaction mapping and machine learning, are transforming biomedical research, representing the most rational hope to overcome unmet research and clinical challenges. Rapid progress in both bulk and single-cell next-generation sequencing (NGS) analyses in the identification of primary and metastatic intratumor genomic and transcriptional heterogeneity (ITH) and the detection of circulating cell-free DNA (cfDNA) alterations is providing critical insight into the origins and spatiotemporal evolution of genomic clones responsible for early and late therapeutic resistance and relapse.

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.

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.

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.

Primary liver cancer genome sequencing: translational implications and challenges.

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.