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MSK Starts Offering Pediatric Cancer Patients Whole-Genome, Transcriptome Sequencing

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Memorial Sloan Kettering

NEW YORK – Memorial Sloan Kettering Cancer Center said this week that it has started making whole-genome and transcriptome sequencing available to help guide treatment decisions for pediatric cancer patients. The lead investigators have also spun out a company, Isabl, that aims to make the approach available to the broader community, while pediatric patients at MSK can access it through an expansion of their initial study.

On Wednesday, the group published a paper in Nature Communications on the performance of the platform, which they believe overcomes challenges that have prevented this type of testing from being clinically implemented in the past.

Led by MSK scientists Andrew Kung and Elli Papaemmanuil, the researchers showed that they could provide clinically relevant information to clinicians in about a week's time, including findings that the cancer center's clinical panel sequencing test MSK-IMPACT would not have detected.

Kung said in a statement that the goal is to offer pediatric patients and patients with rare cancer types, who often don't benefit from panel testing, a more comprehensive alternative.

Cancer gene sequencing panels, including large assays like MSK-IMPACT, have moved further and further into the standard of care in recent years as tools to guide treatment for adults. But the same tests have not proven as useful for children and young adults, whose rarer tumors often arise through different molecular pathways than those of older people.

For example, adult cancers are typically caused by the lifelong accumulation of point mutations, or single-nucleotide variants. Childhood tumors, on the other hand, are more likely to be driven by larger structural changes in chromosomes, including shifts that take place outside of the coding region of the genome.

Numerous efforts have emerged to develop sequencing approaches that provide better detection of cancer-driving or therapeutically important changes in pediatric cancers, either by sequencing the genome more broadly or by adding analysis of RNA, or both.

Most haven't gone so far, though, as to turn to both whole-genome and whole-transcriptome sequencing, which is what MSK's new service incorporates, and, according to Papaemmanuil, teams at other institutions haven't yet published defined, optimized clinical protocols.

A relatively high price tag and long turnaround times have thus far prevented broad implementation of whole-genome sequencing in cancer care. The struggle to analyze results in ways that properly isolate informative findings from what can be a huge background of data have also posed a practical challenge.

But Kung and Papaemmanuil believe that costs have dropped enough in recent years — according to a statement from MSK, it will soon be under $1,000 — that the time was right to prepare to bring this to the clinic. In their new study, they proved that their method could also report clinically useful findings within a practical timeline.

The team's central achievement, according to Papaemmanuil, is in the method's analytical workflows.

"Whereas in the past, annotation of putative variants of functional or clinical relevance relied entirely on annotation databases, Isabl analytics integrate findings from [the tumor whole genome, germline, and transcriptome] to validate and, importantly, prioritize variants of clinical relevance," she wrote in an email.

"Importantly, this analysis is achieved in a matter of hours," she added, reiterating that the ability to analyze and deliver results within clinically relevant time frames has been a critical obstacle for implementation.

In their study applying the method in the clinic at MSK, Kung, Papaemmanuil, and their colleagues analyzed samples from 114 pediatric, adolescent, and young adult patients with solid tumors, comparing their findings to MSK-IMPACT results for the same subjects.

"There are no previously established standards in terms of the technical specifications required to conduct WGS and RNA-seq, and our study helps define those standards for the detection of clinical variants by comparison to a 'gold standard' test," Papaemmanuil said.

"Historically, sensitivity has been a major concern for WGS. Our data demonstrate that at a threshold of 100X coverage, we were able to see 100 percent of the findings of [the MSK-IMPACT] panel-based assay, which assuages [these] concerns."

Besides capturing variants equivalently with panel sequencing, the whole genome/transcriptome method also picked up a significant number of relevant findings that MSK-IMPACT could not.

Specifically, the approach identified at least one additional cancer-associated variant in 54 percent of patients (62 out of 114). Of these, 33 patients had one or more findings that were of direct clinical relevance.

Papaemmanuil noted that many of the clinically relevant findings from their whole-genome approach would also not have been identified if they had used exome sequencing instead.

"Prior studies, including our own work, have shown very limited added value of exome over panel sequencing. This is in part because panels have been designed to capture the most important information from the exome," she said. "In our study, we show that most of the added value comes from the identification of structural variants, genomic rearrangements, or genome-wide signatures that can only be picked up by WGS."

Illustrating the potential for clinical benefit, the authors highlighted one case in the cohort, a 13-year-old patient whose findings led his physician to put him on an immunotherapy drug that caused his refractory adrenal cortical carcinoma to go into complete remission.

In a statement, Alex Kentsis, a pediatric tumor expert at MSK who was not involved in the study, said the group's comprehensive approach improved the accuracy of diagnoses significantly and enabled the detection of genetic rearrangements that cause many cancers in children and young adults.

Papaemmanuil noted that the test could also potentially be translated to noninvasive blood-based sampling, at least for patients with a significant amount of cancer in their body.

Although this could help capture even more variants by overcoming the issue of tumor tissue heterogeneity, a liquid biopsy test would likely not be ready for clinical implementation anytime soon, she said. Although the group provided proof of concept in the study that the entire cancer genome can be profiled from blood, the sequencing depth required is prohibitive, both financially and technically.

Papaemmanuil said her and Kung's spinout Isabl participated in the Y Combinator accelerator program and received an undisclosed amount of seed funding from Two Sigma Ventures in July 2020.

The firm's assay, licensed from MSK and now dubbed Isabl GxT, also recently received breakthrough designation from the US Food and Drug Administration, granting the company increased access to the FDA and the possibility of an accelerated timeline to approval.

Papaemmanuil said Isabl is working now on establishing partnerships with cancer centers and pharmaceutical companies to support prospective clinical research programs and new WGS-based biomarker validation in areas like immuno-oncology and DNA damage response.

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