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Subspecialties Oncology, Omics, Precision medicine, Genetics and epigenetics

Comprehensive Genomic Profiling – A New Look

sponsored by Illumina

Increased understanding of the molecular drivers of disease allows us to offer targeted therapy to patients with disease- associated molecular variants. But for personalized cancer care to reach its full potential – in terms of both global reach and individual patient impact – we need genomic profiling technology that can detect key variants and improve outcomes by directing management. It’s this need that underlies Illumina’s CE-marked IVD TruSight Oncology Comprehensive (TSO Comprehensive) test for solid tumor profiling. We spoke with Phil Febbo, Chief Medical Officer at Illumina, about how this unique technology will maximize information for pathologists – and help drive better patient outcomes.

Advantages of CGP over iterative single-biomarker and small panel tests


  • Reduces turnaround time
  • Spares biopsy material
  • Improves operational efficiency
  • Provides more actionable information to guide therapy


  • More likely to receive genomically matched or targeted therapy
  • Potential improvement in outcomes

Optimal clinical content

The advantages of the comprehensive genomic profiling (CGP) approach (Box 1) are clear. First, pathologists no longer need to constantly update gene panels or collate results from various individual gene tests – simplifying planning and saving time. Second, CGP generates a comprehensive profile from a single specimen, using less tissue than alternative options that require more tissue for each sequential assay or panel (1,2). “Almost 30 percent of advanced lung cancer patients lack sufficient tissue for serial molecular tests,” says Febbo, emphasizing the importance of tissue preservation. Furthermore, the CGP approach improves efficiency, because laboratory personnel and validation procedures focus on a single platform. Finally, comprehensive biomarker coverage for both DNA and RNA variants increases the probability of generating actionable findings (3,4). These attributes clearly optimize disease management.

Informing therapeutic choices

Patients often do best when their therapy targets genetic variants matched with their individual tumor. That’s why it’s critical to employ CGP technology that can detect relevant variants – not just tumor-specific markers, but also tumor- agnostic markers such as microsatellite instability (MSI), tumor mutational burden (TMB), and NTRK fusions (5,6).

TSO Comprehensive has been designed with these requirements in mind. This future-proofed, sample-to- answer CGP solution covers predictive markers specified by NCCN guidelines. Using Illumina’s highly sensitive hybrid capture-based technology, it can interrogate both DNA and RNA variants associated with over 500 genes, detecting insertions, deletions, single nucleotide variants, amplifications, fusions, and splice variants. “This helps maximize detection of actionable alterations, including low-prevalence variants that are peripheral to or outside protein coding regions,” says Febbo. Importantly, TSO Comprehensive allows detection of TMB and MSI – important pan-cancer biomarkers for immunotherapy so patients who might benefit from these transformative therapies can be identified. In addition, its RNA capabilities allow TSO Comprehensive to identify more fusions than methods that interrogate only DNA. Febbo adds, “Given the impressive responses seen when we target NTRK and similar fusions, I would demand a technology that can reliably detect these variants. Just as we do not want to miss any patient who can benefit from immunotherapy, we cannot miss any patient who has a targetable fusion such as NTRK, given the remarkable outcomes experienced.” To ensure that more and more patients can potentially benefit from these promising therapies, the knowledge base for TSO Comprehensive is continuously updated as new biomarkers are identified, assuring pathologists of continued state-of-the-art coverage.

Finally, the TSO Comprehensive roadmap begins to address economic challenges associated with CGP: namely, larger test panels are not fully reimbursed and healthcare institutions consequently have to subsidize genomic analysis for the good of their patients. By working with pharmaceutical partners to validate TSO Comprehensive for the addition of future companion diagnostic claims to the test, Illumina is establishing broad clinical utility for the technology. “This de-risks reimbursement,” says Febbo.

On-site testing delivers more advantages than just speed

TSO Comprehensive is a kit-based IVD test and thus permits in-house implementation of CGP, so the test can be performed closer to the clinicians who will make therapy decisions. Tissue samples don’t need to leave the pathology department, reducing turnaround times (7) and facilitating follow-on assays. This, in turn, enables rapid development of treatment recommendations – essential for late-stage patients.

But the benefits of this approach are not limited to speed. First, in addition to a final clinical report, all other data files containing variant and genomic information about the sample, are made available to the hospital, supporting additional studies and empowering generation of databases that can be used to help inform the care of other patients. Similarly, performing CGP on-site enables stronger stewardship of patient samples, which enables efficient case triage and compliance with requests for additional tissue. Finally, in-house CGP fosters strong links between pathologists and clinicians. “Increasingly, molecular pathologists are part of the care team in cancer,” Febbo reports. “When that happens, more patients who have a targetable variant identified get a genomically matched therapy.” Indeed, hospitals now commonly form multidisciplinary tumor boards in which oncologists, pathologists, and staff collaborate to discuss treatment options for each patient. Here, oncologists learn about the impact of gene mutations on prognosis or therapy and pathologists become more involved in disease management.

Overall, in-house CGP brings testing closer to the patient, encourages closer integration between molecular pathologists and oncologists (Box 2), and uses genomic profiling results to inform therapy choice. In this way, solutions such as TSO Comprehensive contribute to the ongoing major transformation in oncology: the broad adoption of genomic tests – exemplified by the incorporation of molecular markers into the American Joint Committee on Cancer classification system.

How TSO Comprehensive supports pathologists

  • Provides insights to help inform therapy decisions according to clinical guidelines
  • Detects full spectrum of genomic variant types in a single test, avoiding delays associated with serial testing, to accelerate clinical decisions
  • Consolidates the pathology workflow into a single, comprehensive test and single report
  • Brings CGP on site, giving pathologists control over the entire workflow from sample receipt to report delivery
  • Enables pathologists to become more involved in patient care and treatment decisions

Looking ahead

Illumina believes that genomic profiling tests will become increasingly integral to patient healthcare. TSO Comprehensive is a key component of this vision because it permits in-house testing of a broad range of cancer- relevant markers and genomic signatures to inform treatment decisions in patient care, which may lead to better clinical outcomes. The comprehensive biomarker content of the test has also attracted interest from multiple pharma companies, such as Bayer AG and Eli Lilly that offer groundbreaking cancer therapies. Illumina has established partnerships to add Companion Diagnostic claims to the test over time.

The impact of cancer genomics is not limited to guiding treatment. “It will contribute to a massive shift of clinical focus towards early-stage disease,” Febbo asserts. “Multi cancer early detection (MCED) tests, based on cell- free DNA, can identify patients in the first stages of cancer; when detected, detailed assessment of tumor genomics will suggest optimal disease management strategies.” Finally, post-treatment monitoring for minimal residual disease or recurrence is already leveraging genomics and the number of cancers for which these tests improve management will increase dramatically over the next few years. “It is our hope that blood- based tests detecting residual disease or progressing disease will be ordered in conjunction with radiology in this setting. Instead of a paradigm of ‘scan, then use a genomic test,’ the paradigm will be ‘test, then scan.’”

Performing CGP will allow realization of the promise of personalized cancer care. Adopting TSO Comprehensive in routine diagnostic workflows will allow pathologists to rapidly generate more complete, actionable results that can help improve patient outcomes. The approach is part of a larger organizational shift that will see molecular pathologists becoming increasingly essential to the care team. This will benefit all team members – with the patients being the biggest winners.

For in vitro diagnostic use. Not available in all Countries or Geographies.

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  1. TM Yu et al., “Multiple biomarker testing tissue consumption and completion rates with single-gene tests and investigational use of Oncomine Dx target test for advanced non-small-cell lung cancer: a single-center analysis,” Clin Lung Cancer, 20, 20 (2019). PMID: 30243889.
  2. A Drilon et al., “Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches,” Clin Cancer Res, 21, 3631 (2015). PMID: 25567908.
  3. A Zehir et al., “Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients,” Nat Med, 23, 703 (2017). PMID: 28481359.
  4. S Kopetz et al., “Use of a targeted exome next-generation sequencing panel offers therapeutic opportunity and clinical benefit in a subset of patients with advanced cancers,” JCO Precis Oncol, 3, PO.18.00213 (2019). PMID: 32914008.
  5. V Pestinger et al., “Use of an integrated pan-cancer oncology enrichment next-generation sequencing assay to measure tumour mutational burden and detect clinically actionable variants,” Mol Diagn Ther, 24, 339 (2020). PMID: 32306292.
  6. A Vanderwalde et al., “Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients,” Cancer Med, 7, 746 (2018). PMID: 29436178.
  7. S Heeke et al., “In-house implementation of tumor mutational burden testing to predict durable clinical benefit in non-small cell lung cancer and melanoma patients,” Cancers (Basel), 11, 1271 (2019). PMID: 31470674.
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