Simplifying Next-generation Sequencing in the Clinic

Next-generation sequencing (NGS) can play a key role in precision medicine approaches, enabling clinicians to select treatments most likely to benefit patients, based on their genomic profiles. However, due to barriers such as cost and difficulty, most local hospitals have yet to adopt NGS-based testing, and instead continue to rely on single-gene tests, which yield much more limited information for clinicians. As a result, many laboratories resort to outsourcing testing, which can come with its own set of disadvantages. Simplifying genomic testing so that it is readily available in all hospitals could be a game-changer for cancer patients, giving them rapid access to the best treatment approach.

We recently spoke to Luca Quagliata, Ph.D., Global Head of Medical Affairs for Clinical NGS and Oncology at Thermo Fisher Scientific, to discuss some of the barriers preventing full adoption of NGS-based genomic testing in hospitals, and learn more about a solution that can help to address these.

Anna MacDonald (AM): What are some of the barriers preventing local hospitals from adopting NGS-based genomic testing?

Luca Quagliata (LQ): The barriers for full adoption of NGS as part of an integrated, molecular-based routine diagnostic workflow are the same for local and large reference hospitals. The main difference is that local hospitals often lack the resources to overcome those perceived challenges. Based on familiarity with older versions of NGS technology, some providers still perceive NGS as a complex, hard to implement and validate method that requires many samples to be analysed in parallel to be cost efficient. NGS also has a reputation for requiring substantial investments in terms of both instrumentation and highly skilled personnel for sample handling and data analysis. We designed the new Ion Torrent Genexus System to simplify NGS and address these challenges in the future.

AM: In the absence of NGS, what technologies do these hospitals rely on? What are the limitations of these methods and how does this impact patients?

LQ: Usually, a local hospital’s pathology division will rely on classic histo-morphological diagnosis accompanied by some IHC capability and, less frequently, FISH. However, while that morphology is still the basis for an initial diagnosis, the approval of tissue agnostic cancer drugs emphasizes the need for more accurate biomarker tumour profiling. IHC can partially serve this purpose, but it is often necessary to validate a positive result with an orthogonal method, such as NGS, due to the inaccuracy of IHC. One example of IHC’s inaccuracy can be seen in its inability to detect NTRK fusions. The same is true for FISH, a method that has progressively lost its popularity for the detection of some important gene fusions, such as RET or NTRKs, where it has been shown to suffer from a significant false positive and negative rate. This can result in either unnecessary patient drug exposure or the prevention of appropriate therapeutic decisions, respectively. Additionally, both ICH and FISH interpretation has shown to be subjective and highly influenced by the pathologist’s expertise. Altogether, relying on these traditional, less comprehensive, methods can result in reduced diagnostic accuracy that directly impairs downstream patient clinical management.

AM: Why is it disadvantageous for NGS testing to be outsourced?

LQ: Outsourcing NGS comes with a number of issues. The most obvious one is purely logistics, as the receiving reference lab might be many miles away from the collection point and shipment of precious samples can increase costs and prolong time to results. That can be stressful for both the ordering clinician and the patient. Faster turnaround times are critical for effective cancer treatment decisions, particularly for late-stage patients who don’t have time to spare.  Generating data in house is not only faster but, equally important, also helps build productive exchanges between the cancer management team by fostering in-situ interactions to better inform clinical decision-making. For example, the clinical significance of observed variants is often unclear. To accurately evaluate the variants, the treating physician could substantially benefit from the local support of an NGS expert who is familiar with the patient’s medical history, rather than calling or exchanging emails with someone who is far away and has no previous knowledge of the case. In-house testing generates a culture and a know-how around molecular profiling that will be pivotal for precision medicine uptake.

AM: Can you tell us about the Ion Torrent Genexus System and how it can help enable clinicians to access genomic information?

LQ: In a nutshell, the Ion Torrent Genexus System features an automated specimen-to-report workflow that delivers results in a single day. This system holds the potential in the future to truly advance the precision medicine paradigm into the clinic. Its unprecedented turnaround time, as low as 14 hours, will make it possible for labs to get results in far less time; currently, it can take up to four weeks for oncologists to receive outsourced NGS test results. Shortening the turnaround time for results means clinicians can potentially start patients on targeted therapies faster, rather than defaulting to what may be less-effective regimens of chemotherapy or radiation that can have harsh side effects.

The Genexus System also comes with a fully automated workflow, requiring no specialty expertise to run and minimal operator intervention. The machine essentially does everything, including providing a fully annotated report for final interpretation. The system also supports genomic variant interpretation by aggregating data from various curated databases and providing direct links to treatment guidelines, approved FDA drugs and references to on-going clinical trials. This facilitates the clinician’s utilization of generated molecular information. Lastly, the system processes all major sample types with minimal sample input, as low as 10 ng of DNA.

AM: Aside from oncology, what other clinical applications could this technology benefit?

LQ: The first assay Thermo Fisher introduced for the Genexus System is the Oncomine Precision Assay, a first-of-its-kind, pan-cancer panel that enables comprehensive genomic profiling from formalin-fixed, paraffin-embedded (FFPE) tissue and liquid biopsy samples. We are planning to develop assays for other applications that we’ll announce in the future.  

Luca Quagliata was speaking to Anna MacDonald, Science Writer for Technology Networks.