With the first TKI therapy Imatinib (Gleevec) targeting the fusion BCR-ABL1, approved by FDA in 2001, we have witnessed the birth of modern targeted therapy and personalized medicine. Powered by next generation sequencing (NGS) technologies, innovative sequencing investigations in large patient cohorts have paved the way for highly promising personalized treatment strategies based on each individual’s molecular characteristics of a personalized genome blueprint. There are more than 1000 ongoing cancer therapeutic trials linked to a gene-based molecular biomarker. By testing for the characterization of patients at the genomic level, precision oncology ensures that each patient gets the right treatment at the right time.
Historically, the approach to testing for the presence of targetable mutations or genomic signatures has required multiple single-analyte immunohistochemistry, FISH (fluorescence in-situ hybridization) or polymerase chain reaction (PCR) assays which often only test for one alteration at a time. As guidelines recommend testing for more than ten alterations for non-small cell lung cancer patients, the available tumor tissues are often exhausted before actionable targets are identified. With an ever-growing number of actionable gene alterations and pan-cancer biomarkers testing has trended towards a single multiplex testing platform that is comprehensive and efficient. Comprehensive genomic profiling (CGP)1 is a next-generation sequencing (NGS) approach that uses a single assay to assess hundreds of genes simultaneously covering relevant cancer biomarkers for therapy guidance and clinical trials. Compared with traditional single gene tests, comprehensive genomic profiling (CGP) provides a broad picture of the genetic alterations and independent pathways that characterize a patient’s cancer. CGP detects the four main classes of genomic aberrations: single nucleotide variations (SNVs), insertions and deletions (InDels), copy number variants (CNVs), and rearrangements or fusions and gene signatures such as tumor mutation burden (TMB) and microsatellite instability (MSI). Identification of somatic sequence variants is the foundation for calculation of TMB as well as for detecting clinically actionable tumor alterations. TMB and MSI are becoming more important biomarkers to predict patients that are more likely to benefit from immune checkpoint inhibitors. Pembrolizumab already has a pan-cancer or tumor type-agnostic approval for use in MSI-high cancers. TMB is emerging as another potential pan-cancer biomarker, and it is measured by assessing the total number of mutations across a large expanse of coding genome. Cancer cells with a high TMB are believed to express more neoantigens which are recognized by immune cells, giving a better response to immune-oncology (IO) therapies. It is essential to include robust detection of RNA based gene fusions and splice variants as part of a CGP assay as well. Detecting both known and unknown (novel) fusion partners is important because they all can be actionable. NTRK fusions2, for example, are rare gene mutations that are responsible for certain rare types of salivary gland tumors and sarcomas, and are also a cause of a subset of lung and thyroid cancers. Comprehensive genomic profiling by NGS can enable a more comprehensive molecular test, CGP can enable better-informed treatment decisions on patient management and fully utilize the precious patient samples. The information and insights will provide the foundation for the development of novel therapeutic drugs that will ultimately benefit cancer patients.
Targeted therapies, such as tyrosine kinase inhibitors, monoclonal antibodies and modern immunotherapeutic approaches are well-established as monotherapy and combination therapy for many hematological and oncological malignancies. A plethora of innovative therapies targeting various components of intracellular signaling cascades and effective mechanisms against oncogenes as well as the availability of NGS technologies enable personalized cancer treatment based on the molecular profiles of individual tumors and genetic stratification. CGP NGS would lead to significantly more eligibility to clinical trials and more utilization of targeted therapies, which would ultimately help reduce adverse events and costs associated with non-targeted therapies. Therefore, benefits highlight the potential for CGP testing to be a truly transformative advance for precision medicine.
NeoGenomics pharma services works in partnership with biotech and pharmaceutical companies to develop new drugs for personalized biological therapy. We offer the most informative and state-of-the-art molecular technology platforms for NGS, ctDNA, CTC and, qPCR assays. We have currently validated 300+ gene panels for both solid tumors and hematologic neoplasms to support our pharma clients’ clinical trials and biomarker discovery. With the continuous CGP trend, our NeoGenomics La Jolla laboratory is currently developing, validating, and automating Illumina TruSight Oncology 500 high throughput (TSO500 HT)3 CGP testing and plans to launch soon. TSO 500 HT tissue test, which comprises a 2.2 Mb targeted 500+ gene panel, simultaneously analyzes both DNA and RNA in one integrated workflow with an accompanying Dragen bioinformatics analysis platform to enable comprehensive genomic profiling of sequence and structural variants, as well as genomic signatures such as TMB and MSI in patients, across pan-solid tumors.
In summary, harnessing the promise of molecular information, developing new strategies with partners to evolve the practice of personalized cancer care, and expanding access to comprehensive genomic profiling are significantly advancing cancer care for patients. We are extremely excited in the new era of personalized medicine. A vision for the future of precision medicine will integrate comprehensive multi-omic tumor characterization and dynamic monitoring of liquid biopsy samples for early tumor detection and prevention.
- Emiliano et al NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018 Dec;15(12):731-747. doi: 10.1038/s41571-018-0113-0.
- Alvarez et al. Comparison of comprehensive genomic profiling (CGP) and hotspot next generation sequencing (NGS) assays in identifying treatment options for care of patients with metastatic cancer in in the community setting. Meeting Abstract, 2016 ASCO annual meeting
- Illumina website support https://support.illumina.com/content/dam/illumina-support/documents/doc…