How a Cutting-Edge Liquid Biopsy for Cancer Was Created at MSK

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Group photo of researchers Michael Berger, Marc Ladanyi, Dana Tsui, Rose Brannon, Ryma Benayed, Ahmet Zehir, and David Klimstra.

Members of the team that developed MSK-ACCESS. From left to right: Michael Berger, Marc Ladanyi, Dana Tsui, Rose Brannon, Ryma Benayed, Ahmet Zehir, and David Klimstra. Photo from February 2020.

One of the most exciting recent developments in cancer care has been the increased use of liquid biopsies to analyze tumors. These tests, which are noninvasive and only require blood for testing, enable doctors to determine the genetic mutations driving the growth of a patient’s tumor and — in many cases — match the patient with drugs targeting those particular mutations.

Just over two years ago, in June 2019, Memorial Sloan Kettering received approval from the New York State Department of Health for MSK-ACCESS, its in-house liquid biopsy test. MSK-ACCESS allows doctors to detect the presence of genetic mutations in 129 cancer-associated genes originating from solid tumors anywhere in the patient’s body. On June 18, 2021, in the journal Nature Communications, the team that developed MSK-ACCESS published a paper describing how the test was designed and validated. The study also reported findings from the first 617 patients who had their tumors analyzed with MSK-ACCESS.

“Since it was approved, MSK-ACCESS has become our standard liquid biopsy clinical test,” says geneticist Michael Berger, Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO), who co-led the creation of the test, along with scientists in the CMO Technology Innovation Laboratory and MSK’s Molecular Diagnostics Service (MDS) in the Department of Pathology. “We have now sequenced more than 3,500 samples from more than 2,800 patients.”

Tracking Genetic Changes and Cancer Relapse

More than 2,800 patients have had their tumors analyzed with MSK-ACCESS

A simple blood draw can yield a wealth of lifesaving information. “ACCESS” in the test’s name stands for “analysis of circulating cfDNA to evaluate somatic status.” (The term cfDNA refers to cell-free DNA, which is released into the bloodstream when cells — including tumor cells — break down.) MSK-ACCESS was developed as a companion to MSK-IMPACTTM (integrated mutation profiling of actionable cancer targets), a test that detects cancer-related mutations in solid tumor tissue.

One main difference between MSK-ACCESS and MSK-IMPACT lies in how the material is collected from patients. MSK-IMPACT, which looks for changes in more than 500 cancer-related genes, has been used to diagnose patients since early 2014. It requires a tissue sample to be collected surgically or with a long needle, something that may be difficult depending on where in the body the tumor is located.

Because MSK-ACCESS allows the analysis of tumors with a simple blood draw, it’s much less demanding for patients. Additionally, about 9% of the samples collected for MSK-IMPACT analysis are found to be inadequate for testing because of low tumor content in the tissue. MSK-ACCESS offers those patients a second chance for comprehensive genomic profiling.

Although MSK-ACCESS is important, it doesn’t completely replace MSK-IMPACT for diagnosis. The MSK-ACCESS study published in Nature Communications has shown that mutations detected in the tissue can be missed in the plasma. This is mostly due to low tumor shedding and a very low fraction of cfDNA in the plasma actually coming from the tumor.

Additionally, MSK-IMPACT looks at many more genes than the liquid biopsy test does. It also allows for a more robust identification of more complex mutation signatures that can predict responses to certain types of immunotherapies.

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Answering Important Questions about Cancer

“MSK-ACCESS allows us to answer more questions than MSK-IMPACT does,” says molecular geneticist Ryma Benayed, Director of the Clinical Next Generation Sequencing Lab in the MDS and co-corresponding author of the Nature Communications paper. “It’s useful for the early detection of relapse, as well as for monitoring to determine whether a patient is beginning to develop resistance to a targeted drug.” Because it can detect tumor DNA originating from everywhere in the body, MSK-ACCESS also allows doctors to learn about genetic changes in multiple tumors at the same time.

[MSK-ACCESS is] useful for the early detection of relapse, as well as for monitoring to determine whether a patient is beginning to develop resistance to a targeted drug.
Ryma Benayed Director, Clinical Next Generation Sequencing Laboratory

In the paper, the investigators explained how they used data from more than 25,000 tumors analyzed with MSK-IMPACT to design MSK-ACCESS. They described how sequencing data from solid tumors was applied to the liquid biopsy in order to validate the test and highlighted some of the genes that were most commonly mutated in the patient samples, including ALK, BRAF, EGFR, and KRAS. Many of these genes are mutated in lung cancers, which made up the majority of patients in the first group that was analyzed.

Overall, of the first 617 patients who had their tumors evaluated with MSK-ACCESS, 73% had detectable cancer mutations. More than one-third of patients had mutations that were considered clinically actionable, meaning they could be targeted with specific drugs. These findings demonstrate the usefulness of the test in matching patients with the right personalized therapy.

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Identifying the Most Important Mutations

One important capability of MSK-ACCESS is being able to unearth the molecular “needles” linked to cancer within a whole haystack of genes.

MSK-ACCESS is not the only liquid biopsy available for analyzing DNA released into the blood by solid tumors. But because of the way it’s designed, it’s able to provide more information than similar tests. That’s because it also looks at changes in the DNA from noncancerous cells for comparison. This enables the researchers to screen out DNA alterations that were inherited and likely playing no role in causing the cancer.

“Unlike most commercial tests that are available, MSK-ACCESS also sequences the DNA from patients’ white blood cells for comparison,” explains bioinformatician Ahmet Zehir, Director of Clinical Bioinformatics in the MDS, the study’s other co-corresponding author. “This allows us to remove any mutations that are not coming from the tumor.” This extra step is particularly important in patients who have clonal hematopoiesis (CH), a blood condition related to aging that can also cause mutations.

Being able to drill down to the genetic changes originating from cancer cells is key — of all the cfDNA that’s found in blood plasma, only a very small fraction comes from tumor tissue. Most comes from white blood cells, where CH is found; the rest comes from other noncancerous cells. One important capability of MSK-ACCESS is being able to unearth the molecular “needles” linked to cancer within a whole haystack of genes.

Dr. Berger notes that the development of MSK-ACCESS was a huge effort involving researchers and doctors from across the institution, including experts in molecular genetics, pathology, computational biology, and a number of different types of cancer. The paper’s two first authors were A. Rose Brannon and Gowtham Jayakumaran, both in the MDS.

 

Key Takeaways
  • Liquid biopsies help match patients with the right targeted therapies and allow for the early detection of relapse or resistance to therapy. 
  • MSK’s liquid biopsy, called MSK-ACCESS, has been used for more than two years.
  • The test offers more accurate information than similar tests that have been developed elsewhere.
  • MSK-ACCESS enables the detection of very small amounts of tumor DNA in the bloodstream.
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The study was supported by National Institutes of Health grants P30 CA08748, P50 CA221745, P01 CA228696, and R01 CA234361. It was also supported by Cycle for Survival, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Wien Initiative in Liver Cancer Research, and The Society of MSKCC.

Dr. Berger has received consulting fees from Roche and grant support from Illumina and Grail and is a co-inventor on a provisional patent application for systems and methods for detecting cancer via cfDNA screening. Dr. Benayed has received a grant and travel credit from ArcherDx, honoraria for advisory board participation from Loxo Oncology, and speaking fees from Illumina. Dr. Zehir has received speaking fees from Illumina.