Precision oncology based on omics data: The NCT Heidelberg experience

Abstract

Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on increasingly accurate, high-resolution molecular diagnostics as well as the functional and mechanistic understanding of individual tumors. While molecular stratification of patients can be achieved through different means, a promising approach is next-generation sequencing of tumor DNA and RNA, which can reveal genomic alterations that have immediate clinical implications. Furthermore, certain genetic alterations are shared across multiple histologic entities, raising the fundamental question of whether tumors should be treated by molecular profile and not tissue of origin. We here describe MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a clinically applicable platform for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors. We illustrate how a standardized workflow for selection and consenting of patients, sample processing, whole-exome/genome and RNA sequencing, bioinformatic analysis, rigorous validation of potentially actionable findings, and data evaluation by a dedicated molecular tumor board enables categorization of patients into different intervention baskets and formulation of evidence-based recommendations for clinical management. Critical next steps will be to increase the number of patients that can be offered comprehensive molecular analysis through collaborations and partnering, to explore ways in which additional technologies can aid in patient stratification and individualization of treatment, to stimulate clinically guided exploratory research projects, and to gradually move away from assessing the therapeutic activity of targeted interventions on a case-by-case basis toward controlled clinical trials of genomics-guided treatments.

Data Literacy in der Medizin

“…In der Onkologie erhofft man sich durch gezielten Einsatz der technischen Mög-lichkeiten hinsichtlich Sequenzierung und bioinformatischer Analyse sowie der anschließenden fächerübergreifen-den Ergebnisauswertung neue, besser an den individuellen Patienten angepasste Behandlungskonzepte [1]. In einer Initiative des Bundesministeriums für Bildung und Forschung (BMBF) wird das Ziel einer individualisierten Medizin fächer-übergreifend als grundlegende Strategie verfolgt [2].…”

Modern Information Technology for Cancer Research: What’s in IT for Me? An Overview of Technologies and Approaches

“…Hence, Molecular Tumor Boards are established for biologists, pathologists and oncologists to collaborate in finding targeted therapies for patients, who do not benefit from standard treatment [50]. For the Molecular Tumor Boards at the National Center for Tumor Diseases [51] in Germany bioinformatics pipelines analyze patient and cancer cell transcriptome and exome, search for modifications and filter for those known to be susceptible for medication [52]. Using this information, physicians gather known publications, past or present trials, known gene relations and further knowledge on specific variations or mutated genes.…”

Variant classification in precision oncology

“…During the last few years, the use of diagnostic genetic analyses of tumor samples has markedly expanded, facilitating the growth of precision oncology through the identification of a continuously increasing number of therapeutic targets and molecularly defined stratification of patients . Panel‐based next‐generation sequencing (NGS) for the detection of tumor‐specific somatic mutations is already widely available in routine clinical use and a number of bioinformatics tools have been developed for their assessment, including data quality, which is paramount for all subsequent steps (for summaries of these tools see Refs.…”

“…). While most current targeted NGS approaches interrogate a few kilobases of the tumor exome to identify specific targets for which approved drugs exist, more comprehensive sequencing efforts ranging from larger gene panels detecting aberrations on both the DNA and RNA level to whole‐exome and‐genome sequencing (WES/WGS) as well as transcriptome sequencing are entering routine diagnostics . As a direct consequence, an increasing number of genetic alterations beyond drug‐approved entity‐specific targets and combinations thereof are identified in a broad range of tumor entities, offering potential access to off‐label treatments and molecularly stratified clinical trials.…”