Illumina is releasing a new cloud-based, customizable platform that enables tertiary analysis for clinical NGS data, which the company says will streamline interpretation and reporting for a diverse range of application areas. Through application programming interface (API)-based calls, the platform will allow labs to scale up their NGS applications and decrease turnaround times by providing user-defined, automatable workflows and powerful knowledge sources for filtering.
The software, called Connected Insights will be part of the Illumina Connected Software ecosystem and is designed to hasten interpretation by linking users to knowledge sources — including regional guidelines, clinical trial databases, drug labels, and a private repository of data from previous cases within the customer’s lab. The software can accept NGS data from targeted panels, comprehensive genomic profiling (CGP) assays, whole-exome sequencing (WES), whole-genome sequencing (WGS), and transcriptomic data, all from both tissue and liquid samples, and Illumina plans to expand applications into other disease indications as NGS usage continues to expand in clinical testing. The platform will be available in multiple markets outside the US at launch.
The release comes as organizations and health systems increasingly call for NGS testing using CGP panels or WGS, creating a growing need for interpretation of large datasets in a landscape of frequently changing guidelines and drug approvals. Within the oncology field, there has been a growing push in recent years for more comprehensive tumor profiling to better enable diagnosis and therapy response prediction, said Albrecht Stenzinger, director of the Center for Molecular Pathology at the University of Heidelberg. CGP panels, which can cover hundreds of genes, are increasingly used for late-stage cancer patients, and WES and WGS are also seeing growing use, especially for rare and pediatric cancers. Matched normal tissue sequencing to uncover germline variants and transcriptome sequencing for detecting gene fusions add yet more to the pile.
Additionally, earlier cancer detection and recent targeted drug approvals for early-stage disease are enabling a steady shift toward earlier treatment, Stenzinger said, which will eventually require more comprehensive testing for patients in the neoadjuvant and adjuvant settings. A recent Precision Oncology News survey indicates that the number of institutions performing molecular testing on Stage I and Stage II patients is growing. Earlier treatment will mean longer periods of minimal residual disease and resistance monitoring, generating yet more sequencing data. “If you are generating this massive amount of data, you need to interpret this in a meaningful way,” Stenzinger said. “With these thousands or even millions of different variants, even in intergenic regions, it's very hard nowadays to reliably interpret them in a way that is clinically, directly applicable.” In addition to trials generating clinical evidence, new tools to help handle the massive data generated from CGP and WGS and to automate analysis will be critical, he said. “Any lab that is not innovative will die. … So, the pressure of getting this implemented is immense.”
The Rise of WGS
Routine WGS for guiding or monitoring cancer treatment is still early in its implementation, but some institutions are beginning to offer it routinely for certain cancer types and populations. Memorial Sloan Kettering Cancer Center, for example, began offering WGS and transcriptome sequencing to pediatric cancer patients last spring, and Washington University Medical Center in St. Louis has been offering it to all new patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) since 2021. In the UK, WGS is available to patients with pediatric cancer, sarcomas, brain cancers, ovarian cancer, and breast cancer at hospitals throughout the country through seven regional NHS molecular testing hubs. WGS for pediatric cancers is standard of care in some regions, said Patrick Tarpey, lead scientist for solid tumors at the NHS East Genomics Laboratory Hub, and uptake is increasing across the country.
Pediatric cancers, hematologic malignancies, sarcomas, and central nervous system malignancies stand to benefit most from WGS as they are often driven by major structural changes to the genome in addition to single-nucleotide variants, meaning targeted panels may miss important rearrangements and mutational signatures.
Eric Duncavage, professor of pathology and immunology and head of molecular oncology at Washington University, said he expects that WGS will eventually supplant other oncology testing methodologies, at least for hematologic cancers, likening adoption of the technology to buying an electric car. “I haven't reached the point in my decision making where I'm going to go out next week and buy an electric car. But I know, ultimately, it's going to happen,” he said. “I think each laboratory, each health system is going to find its own tipping point when it makes economic and clinical sense to switch. But the writing is on the wall. … It's just a question of time.”
In addition to being better able to detect structural alterations normally detected by cytogenetics, Duncavage said, unlike targeted CGP panels, WGS can detect all variants present in the genome without bias, meaning WGS assays don’t need to be updated or revalidated in response to new biomarker recommendations or drug approvals. “As a lab director, the problem that I have [with targeted panels] is that every time there's a new publication about a gene that's implicated in some disease, I have to go back and revalidate the panel,” he said. “That’s fairly expensive in the clinical environment.”
In research published in the New England Journal of Medicine, Duncavage and colleagues found that whole-genome data would be critical in stratifying patients when biased FISH or NGS panels may not capture regions important to rare alterations, leading to equivocal test results. “Cytogenetics is accurate to maybe five megabases. And FISH … is probably no more accurate than 50 to 100 kilobases. Whereas with whole-genome sequencing, we get single-base resolution, so we know exactly what's happening,” he said. “One advantage of whole genome is the whole genome is the whole genome,” he said. WGS could even help detect HLA type for patients getting bone marrow transplants, blood type, pharmacogenomic information, or cancer predisposition syndromes. “We've only really gotten to the tip of the iceberg,” he said.
WGS data may also be able to provide clearer views of mutational signatures that span the genome, like homologous recombination deficiency, according to Stenzinger. “We have seen that even large panels … are considerably small when it comes to inferring data on complex structural aberrations and signatures present in the tumor’s genome,” he said. “So to reliably obtain such a genomic scar composed of [large-scale transition], [telomeric allelic imbalance], and loss of heterozygosity, you need large panels with a certain coverage backbone that allows you to reliably infer such aberrations across wider parts of the genome.” Additionally, said Tarpey, mutational signatures associated with distinct tumor types can help investigate tumors with unknown primary origins. These signatures are best discerned from whole-genome data, he said, citing recent research by Michael Stratton and colleagues in the Pan-Cancer Analysis of Whole Genomes Consortium. Additionally, alterations in intergenic or non-coding DNA may inform diagnosis, which can only be utilized when going beyond gene panel sequencing.
Hurdles to WGS Access and Use
Traditionally, barriers to WGS adoption and access have been assay complexity, provider knowledge, cost, lack of reimbursement, and complex analysis, said Duncavage. However, he said, WGS tests can be less complex to run than panel tests, and costs are dropping rapidly. “The assumption is it’s complicated, it takes a lot of analysis time, it takes a lot of tech time,” he said. “In reality, the tech time that goes into making a whole-genome sequencing library is very minimal. It's far easier than any other sequencing-based methodology in a laboratory because there's no enrichment step. You just make a library and you put it on a sequencer.”
Duncavage and Tarpey said they expect the cost of WGS to drop below the cost of other assays as sequencing costs drop. Other WGS assays that require more sample prep and quality-control steps have higher labor costs, and, as WGS becomes more common, it will be easier to batch samples to reduce cost and turnaround time.
Greater coverage, however, can come at the cost of lower sensitivity, which can be an especially challenging problem with noisy data from FFPE samples. Better access to high-quality fresh tissue will require a change in mindset and resources in hospitals, both from surgeons and pathologists, Stenzinger said.
Additional test complexity comes from requiring matched normal tissue to help discern cancer-driving genes from inherited variants. However, more extensive and confident mapping of common germline alterations means that the Washington University lab no longer uses matched normal tissue as they can simply compare tumor genomes to large datasets of germline SNPs.
Targeted NGS for hematologic malignancies is fairly well covered by insurance, Duncavage said, as molecular data is required to classify and manage those diseases according to NCCN guidelines. Duncavage also noted that Washington University’s WGS assay is now covered by Medicare for AML and MDS patients. But he expects similar guidelines and, therefore, insurance coverage, for other cancer types in the near future. “I think if you look historically, typically heme runs about five years ahead scientifically of solid tumors,” he said. “And part of the reason, I think, is because heme malignancies are easier to study.”
An additional barrier is provider capacity, said Tarpey. Obtaining patient consent for new tests, pursuing samples, and participating in molecular tumor boards may be challenging for busy oncologists to take on.
Addressing Bottlenecks in Analysis, Reporting, and Informed Treatment
As hurdles to performing WGS and even large panel tests are addressed, the bottlenecks in interpreting, reporting, and acting on results in a clinically meaningful way remain. Automating and standardizing parts of interpretation, particularly as part of a clinical-grade genomic test, will be critical to ensuring access and benefit, Stenzinger said. “Variant interpretation is still heavily based on human resources and manual curation. But we need to come to a point where more and more of this part can be automated to some extent,” he said. “And then still you need the human brain to verify that whatever tool you are using is predicting [correctly].”
Making the volume of data manageable for pathologists and providers will be critical, said Jing Gao, vice president of clinical software at Illumina. “While CGP panels and WGS provide greater clinical value with comprehensive genetic information, people are comfortable with conventional testing methodologies because of the small data size they generate,” she said. The large volumes of data, the complex interpretation, and even the tech support needs for large genomic tests are major hurdles for many hospitals and health systems, she said. Gao said the company is working toward a future where a single whole-genome sequence can be queried to test for a variety of markers or conditions, a concept Illumina refers to as genome-as-a-platform. “Today, laboratories often employ and support an array of multi-generation testing methodologies. Illumina’s long-term vision of providing the genome as a platform for clinical testing will standardize the NGS workflow to a simple high-performance setup.”
Gao said that improving access to NGS testing is increasingly a priority for Illumina, as many cancer patients are treated in community hospitals where NGS can be less accessible. She said that Connected Insights is designed to reduce and standardize training requirements and to enable data sharing among users in a health system. A feature called “My Knowledge Base” allows labs to curate data about past cases to inform future reports. Thus, interpretation becomes easier across the community the longer the system is used.
The software is also designed to standardize interpretation and reporting across NGS test types, whereas, currently, different assays have different analysis pipelines that make standardizing results and comparing data challenging.
Gao said that standardizing analysis tools and connecting data across the genomics workflow are commitments that Illumina is doubling down on with the creation of their modular software ecosystem that fits together as Illumina Connected Software. For cloud-based solutions such as Connected Insights, data is hosted on Amazon Web Services (AWS) in a secure environment that Gao said enables rapid and economical genomic analysis for Illumina customers. Over the years, Illumina’s DRAGEN software for secondary analysis and implementation of integrated workflows has become a standard across applications.
“I used to always tell our trainees, there’s not a Microsoft Office for genome analysis. You have to run all these different tools and it’s complicated,” Duncavage said. “I think what Illumina has done [with DRAGEN and their other platforms] is that they’ve made genome analysis a step closer to a Microsoft Office-like suite where it'll do everything."
With Connected Insights, Illumina hopes to genericize analysis across assays further, Gao said. “As the medical field advances, panels will inevitably become larger,” she said. “Illumina aims to provide a future-proof product. We want a generic, highly scalable platform where NGS data is generated, analyzed, annotated, and interpreted consistently. Data sharing, comparison, and collaboration can happen easily across institutes and sample cohorts, insight accumulation, and AI will help advance the science.”
Gao, who said she has seen generations of assay technologies come and go, added that the Illumina Connected Software ecosystem is designed to be robust to changes in molecular testing technologies. “With DRAGEN and Connected Insights, we will provide a fully-featured genome for comprehensive molecular evaluation,” she said. “We always keep an eye to the future so that when the customer is ready to go with a new test or application, integration of genomic data into clinical practice is ready to go .”
Connected Insights comes as Illumina takes an accelerated approach to its transition from focusing on NGS technology innovation to pushing for broader adoption and access to genomics, Gao said. This push has included the launch of the NovaSeq X series of sequencers to lower sequencing costs and a focus on customer utility of the Connected Software Portfolio, including the DRAGEN bioinformatics suite and the Connected Analytics infrastructure for managing and querying genomic data for research.
Gao said the urgency Illumina is placing on the adoption of NGS has been brought on by the maturation of high-throughput sequencing technology and its clinical applications. In addition, the COVID-19 pandemic put molecular testing at the front of mind for the general public, increasing demand for molecular tests in other diseases, she said. “We are, in many ways, at an inflection point right now. For Illumina, 2023 is all about deployment and supporting the missions of our global user community. More precise, more standardized, more accessible cancer care is on the horizon, and we will not stop innovating in partnership with our customers until we get there.”