What is the role of Next-Generation Sequencing (NGS) in cancer diagnosis and treatment?

From the Guidelines

Next-generation sequencing (NGS) should be used to guide cancer diagnosis and treatment by identifying actionable mutations and predicting response to targeted therapies, as recommended by the ESMO precision medicine working group in 2024 1.

Key Points

• NGS technology allows for the simultaneous analysis of hundreds to thousands of genes, detecting mutations, copy number variations, gene fusions, and other genomic alterations that drive cancer growth.
• In clinical practice, NGS panels like Foundation One CDx, Guardant360, Caris Molecular Intelligence, and MSK-IMPACT are commonly used to identify actionable mutations that can guide targeted therapy selection.
• NGS can detect specific mutations, such as EGFR mutations in lung cancer, BRAF V600E mutations in melanoma, or HER2 amplifications in breast cancer, which can inform treatment decisions.
• The technology also measures tumor mutational burden (TMB) and microsatellite instability (MSI) status, which help predict response to immunotherapy agents like pembrolizumab.
• NGS has enabled precision oncology by matching patients to targeted therapies based on their specific molecular profiles, improving outcomes compared to conventional approaches and sparing patients from ineffective treatments with potential toxicities.

Recommendations

• ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer, as well as in patients with advanced breast cancer and rare tumours 1.
• NGS should be carried out in clinical research centres and under specific circumstances discussed with patients.
• The technology supports liquid biopsy approaches using circulating tumor DNA, allowing for non-invasive monitoring of treatment response and early detection of resistance mechanisms.

Evidence

• A 2024 report from the ESMO precision medicine working group provides updated recommendations for the use of NGS in patients with advanced cancer 1.
• A 2024 study in the British Journal of Cancer provides recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer 1.
• While earlier studies, such as a 2019 study in the Journal of Internal Medicine, highlight the potential of NGS in diagnosis, classification, prognostication, disease surveillance, and identification of patients suitable for targeted treatment, the most recent and highest quality study should be prioritized 1.

From the Research

Role of Next-Generation Sequencing (NGS) in Cancer Diagnosis

• NGS has dramatically increased sequencing data output and transformed biomedical investigations, enabling the generation of genetic data specific to patients from tumor tissue samples 2.
• This allows for targeted therapies to be used, and the obtained data enables the prioritization of effective therapies based on the tumor-specific genotype 2.
• NGS has the capacity to ameliorate genetic screening in families with previous histories of high occurrence of various cancer-associated genes, including TP53, APC, BRCA2, and BRCA1 2.

Clinical Applications of NGS in Cancer Diagnosis

• NGS is utilized to detect novel diagnostic and rare cancer mutations, detection of translocations, inversions, insertions, and deletions, detection of copy number variants, and detect familial cancer mutation carriers 3.
• NGS provides the molecular rationale for appropriate targeted, therapeutic, and prognostic approaches 3.
• NGS holds many advantages, such as the ability to fully sequence all types of mutations for a large number of genes and the sensitivity, speed, and relatively low cost compared to other sequencing modalities 3.

NGS Approaches in Cancer Research

• NGS technologies have allowed for an "omics" approach to cancer, revealing genomic, transcriptomic, and epigenomic landscapes of individual malignancies 4.
• Integrative multi-platform analyses are increasingly used in large-scale projects to fully characterize individual tumors as well as general cancer types and subtypes 4.
• NGS technologies have contributed to "omics" approaches in cancer research, allowing for large-scale integrative analyses that consider hundreds of tumor samples 4.

Future of NGS in Cancer Diagnosis and Treatment

• The field of precision cancer therapy is continuously growing, and NGS is likely to significantly expand as the technology advances 2.
• NGS has the potential to improve the management and treatment of numerous cancers, with therapies being less toxic and more efficient compared to conventional chemotherapies 2.
• The integration of NGS in the study and treatment of cancer is expected to mature, with a move toward more complete 100% genome sequencing, including non-coding regions 5.