Novel Methylome Enrichment Platform Shows Promise Detecting Early-Stage and Low DNA-Shedding Solid Tumors

An early-development study of a liquid biopsy-based multicancer early detection (MCED) test using a novel methylome enrichment platform detected 12 types of cancers, including low DNA-shedding and early-stage cancers. However, prospective validation in asymptomatic populations will be necessary before the test can be successfully implemented as an early screening tool in clinical practice, according to Michael Shusterman, MD.

“Most of us hope that [early detection] means we'll be able to act on the cancer [sooner, which could] lead to better outcomes. The next step is to [assess this platform in] large-scale population studies,” said Shusterman, who is a clinical assistant professor in the Department of Medicine at New York University (NYU) Long Island School of Medicine, and a medical oncologist at Perlmutter Cancer Center at NYU Langone Hospital—Long Island in New York.

Unlike other liquid biopsy tests which sequence the entire genome, the novel genome-wide methylation enrichment platform enables sequencing of the whole methylome through the detection of cell-free DNA (cfDNA) in the bloodstream. This option is not only more cost-effective but can prevent the degradation of cfDNA.

The genome-wide MCED assay was evaluated in a retrospective case-control study, and initial analysis of a subset of 1,903 sampleswas presented at the 2023 AACR Annual Meeting. The assay’s ability to accurately differentiate cancer from non-cancer was measured according to its area under the curve (AUC), with a score of 1 indicating perfect performance. The test had an AUC of 0.94 for all cancer types and stages, and an AUC ranging from 0.89 to 0.99 for individual cancer types. Performance was also high in distinguishing stage I and II cancers from controls, as well as detecting low-shedding cancers such as bladder, breast, renal, prostate, and endometrial cancer. Associated AUC scores were 0.92 and 0.95, and 0.91 for stage I and II cancers, and low-shedding tumors, respectively.

In an interview with OncLive^®, Shusterman expanded on the need for accurate early detection methods in solid tumors for which there aren’t proper surveillance tests, advantages of the unique methylation sequencing technique harnessed by this novel assay, and the importance of investigating the assay’s validation, sensitivity, and utility in additional prospective studies.

OncLive: What was the rationale for investigating the feasibility of a genome-wide methylome enrichment platform for the early detection of multiple solid tumors? What unmet needs could this new platform address?

Shusterman: Multicancer early detection assays are an interesting area of exploration in oncology. [This study] is an extrapolation of the work that's being done with liquid biopsies and circulating tumor DNA [ctDNA] in the cancer space. The question is: can you detect malignancy in individuals for whom there may not be good surveillance tests available in the broader population? We currently have colonoscopy and mammography for colon and breast cancer, [as well as] pap smears for cervical cancer, but there are many other types of cancers for which we don't have a way of detecting them early. Bladder cancer, endometrial cancer, pancreatic cancer, [and] anal cancer are some examples that come to mind. This technology is essentially trying to identify and detect early evidence of these cancers in the blood so that they can be investigated by other means that might not be conventionally applied.

What techniques are used by this assay, and how do they differ from traditional liquid biopsy sequencing platforms?

[The test] uses a new form of sequencing technology [known as] bisulfite sequencing, which looks at something a bit different than most of us in oncology are used to. We typically think of next-generation sequencing [NGS] platforms as looking at and sequencing the gene itself. For example, you know that there's a KRAS gene [present in a given tumor] and you're detecting [its expression at] a certain frequency in the blood. [However], a lot of these assays are not looking at that anymore. They're using this technology to detect methylation patterns, [or] epigenomics.

We know that cancer cells, just like all other cells, activate and deactivate various transcriptional regions in the genome using these methylation patterns, [which] have unique signatures. This test is using a variation of proprietary signatures and saying that we [may be able to] detect this set of sequences using this technology in bladder cancer. If we detect a certain proportion [of a methylation] sequence, [the biopsy] is positive for that tumor within the parameters of the test. It's not saying that you're detecting a specific gene. [DNA methylation detection] technology is [becoming] increasingly more available, and there are even commercialized assays that are using this in a similar way.

What next steps should be taken for the investigation of methylation assays?

The best way to think about this type of technology is that [it is a] validation set. Essentially, the assay is validating itself in a population with known cancers [and non-cancers] to demonstrate that it's able to pick up the types of tumors that we're looking for. What we're interested in, and what we know from other assays that have been available, is the sensitivity of [this test] within specific stages of different tumors. For example, what percentage of these methylation patterns are we picking up in stage I, II and III tumors? It's always important to consider [that question], because [these samples are] being drawn from multiple biobanks. It's [also] a selected population in which you know somebody has cancer at a certain stage, and [are comparing them with] non-cancer controls.

Eventually this [assay] will have to be validated in a larger prospective data set of asymptomatic individuals. We really want to know the [test’s] validation in the people who don't have cancer, because the numbers in the prospective dataset of asymptomatic patients are always likely to be [lower]. In a sense, [the test will] have to survive trial by real-world data.

What other questions remain regarding the efficacy and utility of this methylation assay in advanced solid tumors?

It's always great to see that there's a better version of these assays available. We know that [these assays] can detect evidence of cancer in a patient with cancer. If you take 10,000 individuals who don't have malignancy and screen them with this broad assay that's looking at [multiple] methylation patterns, you have to know the sensitivity with which [the assay is] going to pick up [those markers. How likely [is it] to pick up tumors? What is [its] false positivity rate? How often [is this test] detecting something that [it identifies as] a cancer in that population, but may not necessarily be a true cancer? [That] has many implications. If you are truly picking up these tumors, you also want to know that [you] can detect them using validated techniques. If you're picking up colon cancer, for example, will we detect that colon cancer with a colonoscopy?

The most important [question] is: are we improving the quality and longevity of our patients' lives by being able to detect these tumors early? Those are the steps that are being taken [with] several assays that are already available, and this assay will probably move into that space as well.

What main message would you like to impart to colleagues based on this research?

This technology is now available and is being perfected. The methylation sequencing assays are able, with relatively good specificity, to detect tumors in early stages. We have to cautiously think about them. If they do become commercially available, there needs to be a discussion with patients about whether to [use] them. Most importantly, we should all be participating in clinical studies to offer these assays to our patients. That's going to help us [understand] the utility of this test. We don't want to put the cart before the horse.

Overall, what was the significance of this year’s AACR Meeting?

[AACR] is a great meeting. It generates a lot of preclinical and early clinical data, and it drives the excitement that we have about applying the drugs and the tools [to our practice]. The [current question] that we have is: how are we going to move that forward into clinical studies? That's really what we want to do.​​

Reference

A Liquid biopsy-based multicancer early detection test may detect early-stage disease and low DNA-shedding cancers. News release. American Association for Cancer Research. April 16, 2023. Accessed June 1, 2023. https://www.aacr.org/about-the-aacr/newsroom/news-releases/a-liquid-biopsy-based-multicancer-early-detection-test-may-detect-early-stage-disease-and-low-dna-shedding-cancers/#:~:text=%E2%80%93%20A%20liquid%20biopsy%2Dbased%20multicancer,%2C%20held%20April%2014%2D19.