Molecular profiling for precision cancer therapies

Abstract

The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

“…Detection tests should be able to accurately identify cancer-specific mutations that can be targeted through a synthetic lethal approach. Constant technical revolutions in patient stratification techniques such as next generation sequencing are resulting in different test types that can now guide treatment decisions [116]. For example, for PARP inhibitors, techniques identifying HR-deficient patients range from sequencing to functional ex vivo assays of DSB repair on tumor tissue [117].…”

Human Plasma-Derived 3D Cultures Model Breast Cancer Treatment Responses and Predict Clinically Effective Drug Treatment Concentrations

“…However, much work needs to be done, as our understanding of the potential efficacy of targeted treatments remains quite limited but continues to grow. It has become clear that the identification of a particular genomic alteration often does not correlate with clinical efficacy when an agent "targeting" that alteration is utilized [111][112][113]. We will further investigate the efficacy of novel treatment options in a focused fashion utilizing HuP3D cultures, which we hypothesize will be a more accurate representation of in vivo activity of these novel targeted agents.…”

Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities

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