The Next Frontier of Precision Diagnostics in Cancer Care

It all starts with the right diagnosis.

Finding the right cancer treatment means figuring out the molecular changes that caused the cancer in the first place. It’s the reason it matters so much where patients are treated first.

The precisely matched treatments available to patients today are the result of a big idea and a generous donation a decade ago, which launched the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO). The bold goal: to give every patient who needs drug treatment a personalized therapy, and to do so regardless of what type of cancer they have.

At the CMO’s inception, scientists at Memorial Sloan Kettering Cancer Center (MSK) believed in the possibility of what it could do for future patients. But at the time, patients with only a handful of cancer types and a few gene mutations could benefit.

Today, the application of precision oncology has skyrocketed. People with cancer, especially those with metastatic disease, are routinely screened for hundreds of mutations in their tumors. And dozens of targeted therapies have received approval from the U.S. Food and Drug Administration (FDA).

This quantum leap can be attributed largely to the work of the CMO.

“These approaches have benefited not only patients treated at MSK, but all over the world,” says medical oncologist David Solit, MD, Director of the CMO. “And as the CMO enters its second decade, it’s clear that testing tumors for gene mutations is only the beginning.”

Moreover, data science and artificial intelligence are accelerating progress and guiding the treatments that cancer patients receive at MSK and beyond.

“Increasing the kinds of tests we do will enable us to get a better view of what’s driving cancer and how to stop it,” says pathologist Kojo Elenitoba-Johnson, MD, Chair of the Department of Pathology and Laboratory Medicine. “It’s not at all farfetched to say that this will position us to see things we’ve never been able to see before.”

Test the Tumor, Find the Target, Develop the Drug

The CMO’s first big milestone was the 2017 FDA authorization of MSK-IMPACT^®, a test that now detects mutations in more than 500 cancer-related genes. The test was developed in partnership with MSK’s Molecular Diagnostics Service, which is led by pathologist Marc Ladanyi, MD. It was the first test of its kind to be authorized by the FDA.

Later tests developed by the CMO include MSK-ACCESS^®, which allows doctors to examine DNA from solid tumors using a blood test called a liquid biopsy. This helps to noninvasively detect targetable mutations prior to the start of therapy as well as monitor a patient’s progress without having to extract tissue.

A decade later, there are many drugs that block the activities of specific cancer-driving genes. Several are “tumor agnostic,” meaning that they work regardless of where the cancer started in the body. This innovation has been important especially for patients with rare cancers, because it is often impossible to enroll enough patients in a clinical trial who share a specific tumor type.

Molecular testing can also guide the use of treatments that harness a patient’s own immune system, by identifying certain kinds of genomic signatures that make patients more likely to respond to immunotherapy drugs called checkpoint inhibitors.

Going Beyond Tumor DNA: A New RNA Sequencing Test

Unfortunately, despite all this progress, it’s clear that new types of testing are needed. Not all patients are able to be matched with treatments using current molecular diagnostic tests.

“DNA sequencing only tells us so much,” Dr. Solit says. “We need to be able to collect additional complementary information about the biology of an individual patient’s tumors that cannot be obtained from our current tests. This includes looking at gene expression — which genes are actually being made into proteins — and what these proteins are doing.” That’s because changes in protein function are what ultimately affect how cells behave — and what causes them to become cancerous.

One exciting new advance is a test designed to measure RNA rather than DNA. This is called gene expression. (The difference between DNA and RNA is that DNA stores genetic information, while RNA converts that information into instructions for creating proteins.) RNA sequencing provides deeper insights into tumor cells. It can also reveal changes in a patient’s immune system related to disease. This new diagnostic test, called MSK-TARGET™, will enter into clinical use in 2025.

“Studying RNA will lead to the discovery of new kinds of changes that can’t be detected with our current tests and enable the development of new drugs based on our understanding of those changes,” says molecular geneticist Michael Berger, PhD, Co-Director of the CMO.

“This test will also allow us to learn more about the tumor microenvironment — the cells that surround the cancer,” Dr. Solit adds. “This is important for finding ways to boost the effectiveness of novel immune and cellular therapies.”

Another next-generation test is “whole-genome sequencing.” It scales up the hunt for cancer-causing mutations far beyond the 505 genes currently analyzed by MSK-IMPACT. Whole-genome sequencing looks for mutations in any of the 23,000 genes found in the human genome. It’s already used on a limited basis for patients treated at MSK Kids, the pediatric cancer program at MSK, because cancer drivers in children can be different from those found in adults.

Germline Testing: A Deeper Dive Into Inherited Cancer Genes

One of the most revolutionary aspects of MSK-IMPACT is that, from the start, it was able to detect cancer-causing mutations not only in tumors, but also in a patient’s normal DNA. Testing the normal DNA — called “germline testing” — reveals whether patients have mutations that are inherited. That knowledge may affect their treatment.

Germline testing has revealed a surprise: Inherited cancer mutations are much more common than previously thought.

One landmark study from MSK researchers found that nearly 18% of patients with advanced cancers were born with mutations in genes that increase the risk of developing specific cancer types. Depending on the cancer, that’s double or triple the previously expected rate of patients with an inherited mutation.

Once a patient learns they have a germline change that predisposes them to developing cancer, MSK’s genetic counselors work with them to test family members. It’s called “cascade testing” and is especially important for the patient’s close relatives — parents, siblings, and children.

Genetic Testing To Improve Cancer Prevention

“Genetic testing of at-risk family members allows us to move from our focus on cancer treatment to cancer prevention and interception,” says gastrointestinal oncologist and clinical geneticist Zsofia Stadler, MD. “Through MSK-IMPACT, we have been able to help improve outcomes not just in cancer patients but in entire families.”

The ultimate objective is to prevent cancers from ever developing in the first place.

Through MSK’s specialty clinics and patient registries, scientists are amassing data on genetic warning signals that may be detectable before a cancer ever arises.

For example, MSK-IMPACT tests are being used to study precancerous conditions like Barrett’s esophagus (a precursor to esophageal cancer), colon polyps, and cervical dysplasia (the irregular cells sometimes detected with a Pap smear). The hope is to find new details about the genetic changes that lead up to cells’ transformation from normal into cancer.

“So far, targeted therapies have mostly been used to treat patients with late-stage disease, which we know is always going to be more difficult,” says physician-scientist Yonina Murciano-Goroff, MD, MSc, DPhil, who works at the intersection of clinical genetics and early drug development. “We want to take what we’ve learned from patients with advanced disease and develop approaches to intercept processes inside abnormal cells before they ever become cancer.”

Philanthropic Support Is Crucial for Advancing New Cancer Diagnostics

In the early years of the CMO, molecular testing was considered experimental and was not covered by insurance. Philanthropy enabled MSK patients to have access to these tests and allowed researchers to learn from them. Today, MSK-IMPACT and MSK-ACCESS are usually covered by insurance.

Once again, the future of diagnosing cancer with greater speed and accuracy depends on philanthropy.

“New tests that use RNA sequencing and whole-genome analysis will be critical for developing a new generation of cancer therapies urgently needed for patients for whom current targeted and immune therapies are ineffective,” Dr. Solit says. “I expect that the availability of this next generation of tests will be another key reason patients will come to MSK for their cancer care.” 

How One Patient With a Rare Cancer Benefited From Precision Diagnostics

You could consider renowned composer and jazz pianist Michael Wolff’s story to be one of the greatest hits of precision diagnostics at MSK. Molecular testing saved his life, by identifying the rare cancer that was causing his inexplicable high fevers, violent shaking, and severe weakness, even after he’d been treated for lymphoma at another hospital.

His wife insisted he get a second opinion at MSK. The initial test results were grim. MSK’s pathologists determined lymphoma was not the cause of Michael’s symptoms. He had histiocytic sarcoma, a blood cancer so rare it affects only 300 people in the United States every year. It had spread throughout his body.

But there was hope. It was 2017, and MSK-IMPACT was being offered to all patients with advanced cancer treated at MSK. Michael’s doctor, sarcoma medical oncologist and early drug development specialist Mrinal Gounder, MD, told Michael the results from the test just might point to a new therapy they could use.

The test revealed a mutation in a gene called MAP2K1. Recent studies had revealed the role of MAP2K1 mutations in driving certain cancers. Even more fortunate, a drug called trametinib (Mekinist^®) had been approved to treat melanomas with a vulnerability in a related gene. 

Michael became the first person in the world to take trametinib for histiocytic sarcoma. “We were improvising on the fly,” Dr. Gounder says. “His whole treatment was very much like jazz music.”

And it worked. “After only two days, all my symptoms went away,” Michael says.

At his next appointment, Michael told Dr. Gounder his symptoms had vanished, except for some skin problems caused by the trametinib. A PET scan performed 10 days after Michael started taking the drug confirmed what he was feeling: His tumors had already shrunk by 80%.

“I had chills when I saw the results,” Dr. Gounder says. “It was clear we were on to something big.”

Indeed they were. Three years later, after several scans had shown Michael was free of disease, Dr. Gounder said he could stop taking the drug. Michael’s treatment response was later published as a case study in the New England Journal of Medicine to alert other physicians worldwide about this new treatment option. And after MSK research on other diseases related to histiocytic sarcoma, there are now effective treatments for a whole class of patients who previously had no good options.

Michael says he’s proud to be a textbook example of how correcting just one wrong note in the genetic code can return a patient to good health.  For Michael, his wife, and two sons, everything is now in tune.