Next-Generation Sequencing: The Next Microscope

Pathology is one of the oldest fields in medicine, with practices such as autopsy and anatomy dating back to ancient civilizations. The adoption of the microscope in the 19^th century truly refined the trade, allowing practitioners to assess disease at the cellular level. Though there was initial resistance to this new technology, it is now a mainstay of laboratory medicine. We are currently embracing a new technology that is enabling the routine evaluation of diseases at a subcellular level – next-generation sequencing (NGS).

NGS uses similar principles to Sanger sequencing at a high throughput, or massively parallel, level. Traditional setups of the technique relied on a lengthy workflow including nucleic acid extraction, library preparation, and bioinformatic analysis. As such, NGS was first adopted by large, subspecialized laboratories that could offer the space, equipment, and personnel to perform these tasks. Novel NGS technology has since become available that condenses the entire workflow to a single instrument that can be operated by a single user, with results in a single day. Though the core technology is unchanged, this streamlined delivery has now brought NGS within reach for community-based practices like the William Osler Health System (Osler).

NGS allows for the simultaneous interrogation of multiple genetic biomarkers. As the number of targeted therapies and actionable biomarkers grows, NGS is an increasingly necessary standard of care in modern oncology. Despite this, there are multiple barriers to NGS access. In particular, the technology is not available in-house at many cancer treatment centers – especially community hospitals. This leads to long delays in obtaining biomarker results – or worse, treatments prescribed based on incomplete testing. With this in mind, we recently installed a new automated NGS platform and validated it for clinical use. Our new system integrates several elements of the NGS workflow, including library preparation and bioinformatic analysis. This simplified setup allows our histotechnologists to operate the instrument – so NGS can be integrated with morphology and immunohistochemistry (IHC) in a single report.

Before investing in comprehensive genomic testing, Osler had already shifted from an outsourced testing model to in-house single biomarker testing. This gave us much faster test results, but we found that, for some cancers, we were running upwards of seven different single-gene tests and still had an incomplete picture. That’s why we started to explore comprehensive testing, which offers a more economical alternative in scenarios where multiple single-gene tests are needed.

When insourcing single-gene testing, we established a median turnaround time for lung cancer biomarkers of four days. In turn, 94 percent of patients had complete biomarkers available at the time they first met with an oncologist, compared to 17 percent when testing was sent to an outside center. Modern lung cancer treatment is simply not possible without biomarker data. Having these available at first consult provides dramatic cost savings while simultaneously improving patient outcomes and experiences.

Switching to comprehensive NGS markedly expanded the number of actionable markers for which we were testing. MET exon 14 skipping alterations are a prime example. There is no good single-gene test for these events, so they were not being routinely tested even though well-tolerated oral therapy is available. Since implementing NGS testing, we have identified a large number of these events, enabling improved outcomes and quality of life for these patients with highly effective pill-based therapies.

The transition to comprehensive profiling has carried tremendous benefit for our cancer patients – and our median turnaround time has remained unchanged at four days. This rapid delivery will once again enable patients to meet with their oncologist for the first time and have biomarker data available for discussion – only now, it’s comprehensive.

But precision medicine is not without its barriers – particularly in a publicly funded healthcare system. Despite its immense promise and clinical benefit, many institutions cannot overcome the fiscal hurdle of NGS. Insourcing costs include capital expenditure, reagents, maintenance, storage, supplies, and more. The true cost of delivering NGS data for clinical care is poorly understood, but one thing we do know is that technologists are the most expensive component. Using a fully automated gene sequencing system paired with a minimum number of technologists was the key for us in moving past the financial barriers – and, from there, the additional savings on shipping, accessioning, and stenography bolstered our argument.

Gene sequencing has been around for over half a century, and we are now a decade past the advent of NGS. Now, with fully automated workflows, the technology is reaching its true potential in the healthcare setting. Combining all the necessary steps into a single instrument means the technology can be placed in a clinical pathology lab – enabling comprehensive biomarker testing in a clinically relevant timeframe and with ongoing cost savings.

The pathologist’s role is always changing. It’s our job to use all available laboratory data to guide patient care to the best of our ability. As pathologists, we have the opportunity – and, I would argue, the duty – to bring the benefits of precision medicine to more patients by leading the adoption of comprehensive molecular profiling in our own facilities and communities. The technology is here; it’s up to us to bring it to our patients.