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Tumor Mutational Burden Can Help Predict Response to Immunotherapy in Many Different Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 01/17/2019
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Very early on in the development of the immunotherapy drugs called checkpoint inhibitors doctors realized that melanoma and lung cancer have something important in common. These cancers were the first shown to respond to checkpoint inhibitors. Both tend to have a lot of DNA mutations. Tumors with an elevated number of mutations are referred to as having a high tumor mutational burden (TMB).

Researchers from Memorial Sloan Kettering have conducted a wide-ranging study to find out if the relationship between high TMB and a positive response to checkpoint inhibitor drugs holds across other cancers. Their findings were recently published in Nature Genetics.

“Based on observations in lung cancer and melanoma, experts in the field have made the assumption that the association between mutation burden and immunotherapy response is true for all cancers,” says surgeon-scientist Luc Morris, one of the three senior authors on the paper. “Until now, however, it hasn’t been well studied. Our study asked if TMB has value as a predictive biomarker across all cancers.”

The investigators confirmed that TMB is predictive across many cancer types. They also noted that people with high-TMB tumors who were treated with immunotherapy lived longer compared with those who had high-TMB tumors and got other kinds of treatment. And importantly, they determined that what is considered a high level of TMB varies depending on the type of tumor. This is a critical question that needed to be answered before using this information when caring for patients.

Bringing Tumors Out of Hiding

The relationship between a high TMB and response to immunotherapy was first demonstrated in two groundbreaking studies from MSK researchers. One, published in 2014 by physician-scientists Timothy Chan and Jedd Wolchok, reported the connection in melanoma. Another study the following year from Dr. Chan and then MSK researcher Naiyer Rizvi reported the same relationship between immunotherapy response and high TMB in non-small cell lung cancer.

The connection made sense. DNA mutations lead to the production of altered proteins that the immune system is able to recognize as foreign. The more mutated proteins a tumor has, the more likely it is that the immune system will attack the cancer, and that drugs that promote an immune response, such as checkpoint inhibitors, will be successful in eliminating it.

For melanoma, the high number of mutations results from exposure to the sun’s damaging UV rays. For some lung cancers, bladder cancers, and head and neck cancers — for which immunotherapy drugs often work well — the high TMB may be due to carcinogens in tobacco.

Using Data to Confirm a Long-Standing Assumption

Other cancers also have high TMBs, but these elevated mutation rates tend to appear with less frequency and at varied levels. “The assumption that TMB is a useful predictor of response to checkpoint inhibitors for all types of cancer has not been proven,” Dr. Morris explains. “Until now, we also haven’t known whether this testing is valuable for people who are treated as part of routine care, as opposed to those who were carefully selected for clinical trials.”

The current study used data from more than 1,600 people who were treated with checkpoint inhibitor drugs at MSK and about 5,300 people who received nonimmune-based treatments. All of the patients had their tumors analyzed with MSK-IMPACT™. The US Food and Drug Administration has authorized this targeted tumor-sequencing assay, which is offered to MSK patients. The test looks for mutations in tumors that can be targeted with drugs and also reports TMB. Results from MSK-IMPACT were anonymously linked with clinical records, allowing researchers to tease out connections between different levels of TMB and drug response.

“The bottom line is that we confirmed that TMB does have predictive value across a range of cancer types,” Dr. Morris says. “We also showed that the predictive value of TMB is dose dependent. This means that the higher the TMB in a person’s cancer, the more likely they are to respond to the drugs.”

But the researchers found that there is not one universal definition for what it means to have a high TMB. For example, having six mutations was considered high in breast cancer and glioblastoma, compared with 31 in melanoma and 52 in colorectal cancer.

A Collaborative Project Focusing on Many Cancer Types

The team was able to conduct such a large, multifaceted project thanks to contributions from 57 researchers from a number of Disease Management Teams. MSK’s Immunogenomics and Precision Oncology Platform (IPOP) and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) helped bring together the collaborators and analyze the data.

To further advance this important and growing field of research, all of the data from the study are being made available to other scientists through MSK’s cBioPortal for Cancer Genomics. This will allow scientists at other institutions to use the data to design future trials.

“We are still optimizing the use of TMB as a way to predict response to therapy,” Dr. Morris notes. “We need more research to determine the optimal number of mutations that we should use for each cancer type. We hope that based on our data, researchers will move forward with more clinical studies that will ultimately result in the ability to select the best treatments for people with cancer and allow them to avoid treatments that are unlikely to help them.”

The first author of the Nature Genetics paper is Robert Samstein, a fellow in radiation oncology at MSK. In addition to Dr. Morris, the other senior authors are Dr. Chan, Director of IPOP, and physician-scientist David Solit, Director of the CMO.

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There’s an App for That: When the Meaning of a BRCA Mutation Isn’t Clear-Cut

Source: Memorial Sloan Kettering - On Cancer
Date: 02/11/2019
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Many people have heard that mutations in the genes BRCA1 and BRCA2 increase the risk of developing certain cancers, especially breast cancer and ovarian cancer. What they may not know is that the connection is not always clear-cut.

The reason is that there are many possible mutations in these genes, not just one. Not all of these changes, also known as variants, result in the same risk of developing cancer: For about 40% of BRCA mutations, the health effects are unclear. This can be confusing and stressful for the people who carry them.

To address these unknowns, clinical genetics experts from Memorial Sloan Kettering and other institutions around the world have launched the BRCA Exchange. This online database shares data about BRCA mutations and what they actually mean for cancer risk. It is also available as a mobile app. People can search the database for information on BRCA1 and BRCA2 variants and how experts classify the risks of different mutations in real time. The creators hope that opening up the database to others in the field will lead to better classification of the variants that have an unknown risk.

“One of the nice features of the mobile app is that users can elect to receive notifications when classifications change in the future,” says Kenneth Offit, Chief of MSK’s Clinical Genetics Service and a member of BRCA Challenge, the international group that created the BRCA Exchange. The database is open sourced, but as Dr. Offit points out, it is intended primarily for those with genetic training who are interpreting results for people who have been tested.

Coping with the Unknown

When a gene contains a mutation, that means that its instructions for how to make a protein have been altered. But not all genetic mistakes lead to the same outcome. Some may dramatically change the shape of the resulting protein, leading to a severe disruption in how the protein functions. Others may have little or no effect.

There are five categories of gene variants: benign, likely benign, uncertain, likely pathogenic, or pathogenic. Benign mutations are not cancer causing, and pathogenic ones are cancer causing. The problem is the many variants in the uncertain group. These are also called variants of unknown significance.

When a person learns they have a pathogenic BRCA mutation, doctors and genetic counselors usually recommend that they take measures to protect themselves. This often means undergoing more frequent cancer screenings. Many women with these mutations take medication to reduce their cancer risk. They may also choose to have surgery to remove their breasts, ovaries, or both.

But when a person learns they have a BRCA variant of unknown significance, the next steps are less clear. People are advised to turn to experts in cancer genetics for guidance. “Now, through the BRCA Exchange, experts as well as members of the informed public will have increased access to this important information,” says Mark Robson, a clinical geneticist and Chief of MSK’s Breast Cancer Medicine Service.

Concerns about how to classify variants go beyond the BRCA genes. Other genes linked to cancer are at issue as well. Last year, MSK clinical geneticist Michael Walsh led the development of new guidelines for using tumor genetic testing to classify the meaning of variants in hereditary cancer genes.Back to top 

A Growing Popularity and a Growing Need for Research

The BRCA Exchange was established as a resource so doctors can review the classifications and help people understand their risk. A panel of experts in cancer genes developed the classifications. The database also provides information on gene variants to researchers, data scientists, patients, and patient advocacy groups. It already includes more than 20,000 BRCA1 and BRCA2 variants. As genetic testing becomes more widespread, that number will continue to grow.

Additionally, as more people get genetic testing, it is becoming increasingly important to make sure that people understand what the results mean for their own cancer risk, as well as understanding the limits of the tests themselves. To figure out the best way for people to receive this kind of health information, a team of clinical genetics experts recently launched the BRCA Founder Outreach (BFOR) study. The study is being spearheaded by MSK and three other cancer centers.

Dr. Offit is one of the leaders of BFOR. He says it’s important to get genetic testing done by healthcare providers who can help interpret the results rather than a direct-to-consumer test offered by companies like 23 and Me. In the BFOR study, individuals of Ashkenazi Jewish ancestry who are more likely to carry certain BRCA mutations are offered testing for those mutations at no cost. They access the study via a website and can choose to receive their results from their own doctor or another expert.  

“Together, projects like the BRCA Exchange and the BFOR study are using the power and reach of the internet to empower both experts and healthcare providers to make more accurate and more accessible genetic information available,” Dr. Offit concludes.

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Research Uncovers the Genetic Causes of Aggressive Leukemia in Children

Source: Memorial Sloan Kettering - On Cancer
Date: 02/18/2019
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A study exploring the genetic landscape of leukemia in children has discovered that the kinds of mutations behind certain pediatric blood cancers are different from those that trigger leukemia in adults.

The genetic changes the researchers found help explain why some pediatric leukemias are so difficult to treat. They also suggest new approaches for more-accurate diagnosis and better therapies. The multicenter study was co-led by Memorial Sloan Kettering physician-scientist Alex Kentsis and published in the journal Leukemia. The first authors were MSK investigators Nicole McNeer and John Philip.

“The types of mutations that we saw implicate an entirely different set of genetic causes for blood cancer in children compared with adults,” says Dr. Kentsis, a pediatric oncologist who also leads a lab in the Sloan Kettering Institute’s Molecular Pharmacology Program. In adults, he explains, the most common mutations are relatively simple changes in the genetic code, called point mutations. In children, the genetic changes involve much more complicated rearrangements of the DNA.

New Findings about the Causes of Pediatric Leukemia

In the study, the researchers analyzed cancer cells from 28 children who had a form of acute myeloid leukemia (AML) that’s resistant to chemotherapy. About half of children with more-aggressive subtypes of AML eventually die from the disease.

The investigators set out to determine why this cancer is so difficult to treat. The ultimate goal is to develop new targeted therapies that will work better than existing treatments and have fewer side effects than chemotherapy.

“Our findings were very much in agreement with the emerging understanding that children develop cancer through an entirely different set of causes than adults do,” Dr. Kentsis says. “We think these findings apply to all leukemias, not just AML subtypes.”

What Happens When a Normal Process Goes Wrong

In adults, the majority of cancer is caused by aging and exposure to environmental factors that disrupt DNA. The causes of cancer in children can be very different, however. Most young people have not had time to accumulate these kinds of mutations or damage from exposures, such as to UV light. (The exception is children who have been exposed to radiation or chemotherapy as treatment for another cancer. This can sometimes cause pediatric AML.)

Instead, the investigators believe that the kinds of large-scale errors seen in these pediatric leukemias result from built-in defects in the DNA’s stability in developing cells. For example, a maturing immune system needs to make antibodies. These proteins help the immune system learn to recognize foreign substances. Rearranging the DNA is an important part of normal antibody production. “But for reasons we don’t yet fully understand, rearrangements that are normally required for immune function can sometimes be abnormally activated in developing blood cells. This can result in the formation of cancer-causing genes and ultimately blood cancers,” Dr. Kentsis says.

“We found that these pediatric leukemias have extensive changes in their DNA that lead to the production of fusion genes, complex deletions, and translocations — where pieces of DNA get moved around,” he adds. Previous research from Dr. Kentsis’s lab looked at the role of similar genome rearrangements in many types of solid tumors in children.

“Based on this research and many other efforts across the world, we at MSK are now incorporating genetic tests to look for these kinds of errors in all our pediatric patients,” Dr. Kentsis concludes. “We’ll use this new information to develop targeted therapies that are tailored to individuals’ specific tumors to ultimately provide therapies that are precise, curative, and safe.”

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Some People Who Need a Bone Marrow Transplant Will Never Find a Donor — and What Can Be Done about It

Source: Memorial Sloan Kettering - On Cancer
Date: 03/27/2019
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For many people who have leukemia, lymphoma, or certain other blood disorders, stem cell or bone marrow transplantation (BMT) offers the best chance of a cure. But only about 25% of people who need an allogeneic transplant — the type of transplant in which donor cells are used — have a sibling who is a suitable genetic match. The remaining 75% usually look to registries of unrelated adult volunteers to find a compatible donor.

A study from investigators at Memorial Sloan Kettering reports that for people of certain racial and ethnic backgrounds, finding an unrelated donor match can be difficult if not impossible. This is despite huge growth in the pool of volunteer donors who have joined these donor registries, to tens of millions in recent years.

“Our research demonstrates that many people will never find a matched volunteer donor from any registry because of their racial and ethnic background,” says lead author Juliet Barker, a hematologic oncologist who specializes in BMT. “For this increasingly large group of the US population, funding for research into alternative donor options such as cord blood transplantation is important. These other options can greatly expand access to transplantation for patients without a matched adult donor.”

Cord blood is collected from the umbilical cord and placenta of healthy newborns and donated by the baby’s parents at birth.

Finding a Matched Donor

The study, published in Blood Advances, followed 1,312 people treated at MSK between 2005 and 2017 who needed a BMT but did not have a suitably matched brother or sister. The patients were categorized by their racial and ethnic backgrounds based on how they identified themselves and their family history. Thirty-four percent had non-European backgrounds. This included patients of Asian, white Hispanic, African, Middle Eastern, and other mixed non-European descents.

“MSK is an ideal center to do this kind of study because our patient population is so diverse,” Dr. Barker says. “And this study is important as the US population is increasingly becoming more diverse: The problem of finding matched donors will impact more and more transplant centers all over the country.”

The researchers also reported that despite the notion that people of European descent can more easily find donors, many patients of southern European ancestry had diverse markers and therefore were not able to find a match. This includes people from places such as southern Italy and Greece.

The Science of HLA Matching

Stem cell donors and bone marrow transplant recipients must be matched for their tissue type. Specifically, the matching process looks at markers, or proteins, known as human leukocyte antigens (HLAs). HLA markers are inherited and allow the immune system to recognize which cells belong and which are foreign. Over hundreds of generations, humans in different parts of the world have acquired many different HLA genes. Some people, such as those from Africa, have very diverse HLA types.

A close HLA match is critical when transplanting blood and bone marrow–forming stem cells from an adult donor to a patient. This makes it difficult for people of certain races or mixed ancestry to find a match.

By contrast, cord blood transplants do not require a strict HLA match. Another important finding from the study was that cord blood was able to extend transplant access to people from a wide variety of racial and ethnic backgrounds.

Benefits of Cord Blood Transplants

Cord blood is a rich source of blood-forming stem cells. Like stem cells from adult donors, cord blood is obtained through donor registries. Dr. Barker is an expert in this type of transplant and leads MSK’s Cord Blood Transplantation Program.

A major advantage of cord blood is that the immune system of a newborn baby is not yet fully developed. This means that the match that’s required between the cord blood cells and the cells of the person receiving them is less strict.

Dr. Barker explains that for patients in need of a donor transplant who don’t have a matched sibling, MSK doctors can determine very quickly, based on the patients’ HLA markers, whether they are likely to find a match in unrelated volunteer donor registries.

She says this allows doctors to move very efficiently to alternative donor options for the transplant. “Timing is especially important,” she says. “Many patients will be too sick to have any kind of transplant if they wait too long.”

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When a Cancer Therapy Stops Working: Experimental Drug Addresses Resistance

Source: Memorial Sloan Kettering - On Cancer
Date: 04/01/2019
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In November 2018, the US Food and Drug Administration approved the targeted therapy larotrectinib (Vitrakvi®, also called LOXO-101) for cancers caused by a molecular change called a TRK (pronounced “track”) fusion. About 75% of people with this type of mutation initially benefit from the drug. Unfortunately, some of these people eventually stop responding to the drug, and their tumors start to grow again.

On April 1, 2019, at the annual meeting of the American Association for Cancer Research, an international team of researchers led by Memorial Sloan Kettering’s David Hyman presented results from the first phase I clinical trial of a related drug, LOXO-195 (also called BAY 2731954). LOXO-195 was developed specifically to treat people whose tumors have developed resistance to existing TRK inhibitors, like larotrectinib. Nearly half (nine of 20) of the people treated with LOXO-195 who had developed resistance to prior TRK inhibitors because they had acquired new TRK mutations responded. In another six, the tumors didn’t shrink but also didn’t grow.

“Responses to drugs that target TRK fusions, like larotrectinib, can be dramatic. But we know that acquired resistance can develop later, meaning that these patients will need new treatment options,” says Dr. Hyman, Chief of MSK’s Early Drug Development Service.

Blocking Cell Growth Driven by Gene Mutations

TRK fusions occur when a TRK gene and an unrelated gene become abnormally linked together. The result is uncontrolled cell growth. Although TRK fusions are rare, collectively they affect thousands of people who are diagnosed with cancer each year.

Precision oncology is based on the concept that drugs can be designed to target specific gene mutations that drive cancer growth. With this approach, the same drug may work against many tumor types. Larotrectinib was approved for any type of cancer that has a TRK fusion, in both adults and children. LOXO-195 appears to work on many kinds of TRK fusion-positive cancers as well: People with 15 different tumor types were treated in the trial.

LOXO-195 was designed by the company Loxo Oncology based, in part, on research from Dr. Hyman and his colleagues. This prior research found that in people who initially responded to drugs targeting TRK but who later stopped responding, two kinds of changes led to this acquired resistance. For some people, new mutations in the TRK fusion gene had developed, causing these tumors to be insensitive to prior TRK inhibitors. For others, the tumors found a way to grow without the continued need for the TRK fusion. LOXO-195 is designed to work with tumors that develop new mutations in the TRK fusion gene.

Longer-Lasting Results for Some People

In addition to the 20 people who were treated as part of the trial, another 11 received the drug through the FDA’s Expanded Access Program, which allows people who don’t have other treatment options and who cannot participate in clinical trials to receive experimental drugs. In total, 24 adults and seven children received the drug.

None of the people who had developed resistance to a prior TRK inhibitor and who didn’t have the additional mutations in the TRK fusion gene that LOXO-195 targets responded. “These findings were generally consistent with what we expected based on our biological understanding of how the drug works,” Dr. Hyman says. “While it is too early to say for sure whether LOXO-195 could be a meaningful treatment option for patients whose tumors don’t develop these new TRK mutations, these very early data suggest that more research is needed to determine the optimal treatment approach for these people.”

The most common side effects observed in the trial were dizziness, nausea, anemia, muscle and abdominal pain, fatigue, and a reduced number of lymphocytes (a type of white blood cell). Most side effects seemed to vary with the amount of drug given, with LOXO-195 being very well tolerated at lower to moderate doses. The side effects were reversible.

“This research shows the value of continuing to focus on precision oncology,” Dr. Hyman adds. “By studying patients after they develop resistance, we’ve been able to quickly develop additional drugs to extend the total benefit of this approach.”

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Scientists Develop a Tool to Watch a Single Gene Being Transcribed in a Living Cell

Source: Memorial Sloan Kettering - On Cancer
Date: 07/05/2020
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A picture is worth a thousand words, or so the saying goes. But it can be quite a challenge to capture a picture of something that’s so tiny it’s on the scale of individual molecules.

The field of structural biology is dedicated to constructing images of very, very small things. But most of the techniques used by structural biologists to take these pictures require that the molecules are frozen in one position. This makes it difficult to watch the dynamic, shifting processes that are essential to life.

For the first time, researchers from the Sloan Kettering Institute have found a way to peer inside living cells and observe gene transcription. This is the process by which DNA is copied into messenger RNA (mRNA), which then specifies how a protein is made.

“Gene transcription is one of the most fundamental processes in all of biology,” says SKI structural biologist Alexandros Pertsinidis, senior author of the study, which was published in Cell. “We know that it’s highly regulated and uses complicated molecular machinery. Being able to watch this process as it happens is an important step forward in understanding what goes on inside cells.”

Following the Recipe

If you think of the genetic code as a universal cookbook, containing all of the instructions needed to make every part of a living organism, you can think of the various cell types as different restaurants, Dr. Pertsinidis explains. “French restaurants follow French recipes to make French dishes, and Italian restaurants follow Italian recipes to make Italian dishes,” he says. “In the same way, brain cells make the proteins that brain cells need to function, and liver cells make the proteins for liver function.”

A family of enzymes called RNA polymerases and a large set of factors that are associated with them regulate the transcription of individual genes and control the characteristics that cells exhibit. “The interplay between RNA polymerases and regulatory factors helps determine which genes are turned on and off in specific cells,” he says. “They also control how cells respond to outside signals, which can influence their activities.”

Until now, the function of RNA polymerases and associated regulatory factors has been studied indirectly, through biochemical reactions: Cells are broken open in a test tube and purified into individual parts. By adding or removing components and measuring the outcomes, scientists have been able to figure out certain molecular activities. How the machine as a whole works inside cells, however, has remained obscure.

“For 50 years, hundreds of researchers all over the world have studied these reactions,” Dr. Pertsinidis says. “But the problem has been that nobody has been able to directly observe how gene transcription happens inside a live cell.”

Zooming In on a Single Gene

In the study, the investigators used a highly specialized optical microscope to look at the activity of one RNA polymerase, called RNA polymerase II, as it interacted with genes and synthesized mRNA. The new method, developed by Dr. Pertsinidis’s lab, is called single-molecule nanoscopy.

To be able to look at the individual parts of cells, researchers label molecules with a fluorescent tag that makes them glow under the microscope. “But a cell is very crowded, and there are many reactions happening at the same time,” Dr. Pertsinidis says. “If you label all the polymerases in a cell, the whole nucleus is just a big glow.

“What’s new about this technology is the ultrasensitive, integrated system that lets us zoom in on a single tagged gene even when the cell nucleus is moving around and the specific chromosomal location is jiggling due to random microscopic motion,” he says. “At the same time, the system suppresses the signals from the other reactions that are happening, casting them into the background. This enables us to extract the signal for only the gene of interest and zoom in on it.”

The organization and dynamics of RNA polymerase II in the nucleus have been a topic of intense study over the past few decades. “Here, we directly observed the activity of this molecule and how it functions in the nucleus of live cells,” Dr. Pertsinidis says. “Being able to see how it interacts with other regulatory factors has unveiled the intricate hierarchies and interdependencies of these various factors. These insights enable us to reach a more detailed and comprehensive picture of transcription in live cells.”

Expanding to Other Cellular Processes

The researchers hope that their tool will be widely used to study complicated reactions inside living cells.

“There are enough details in our paper that other labs will be able to pick up and implement the technology,” Dr. Pertsinidis says. “We also have labs both inside and outside MSK that are interested in collaborating with us on specific projects.”

He adds that although he is focused on understanding gene transcription, the tools his team has developed could be used to study the details of other vital biological processes, such as DNA repair and protein synthesis.

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What Causes Leukemia after Breast Cancer? Research Shows That a Mutation May Be Present All Along

Source: Memorial Sloan Kettering - On Cancer
Date: 09/09/2019
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Doctors have known for a long time that cancer survivors may be at risk of a rare aftershock: developing a secondary leukemia years or even decades later. Because some chemotherapy drugs can damage the DNA in the bone marrow, where leukemia forms, experts have assumed that the drugs trigger the formation of cancerous blood cells that lead to leukemia.

A new study of people with breast cancer treated at Memorial Sloan Kettering is turning that idea on its head. The findings suggest that in some people, leukemia-causing gene mutations may be present in blood cells from the time that breast cancer is originally diagnosed, before chemotherapy is ever given. Although this discovery is important, the study looked at only a small group of patients, so larger studies are needed to confirm the findings.

“In the past, we’ve never been able to predict which breast cancer patients may be at risk for developing leukemia in the future,” says medical oncologist Elizabeth Comen, first author of the study published August 27 in the Journal of the National Cancer Institute (JNCI). “Our findings provide new clues about how and when these leukemias may originate. They also suggest that we may be able to identify who is at risk of developing leukemia, paving the way to prevent secondary leukemias.”

About 70% of secondary leukemias occur in people who have been treated for breast cancer. (The rest are in people treated for other types of cancer, mostly other solid tumors.) Around 0.5% of people treated for breast cancer eventually develop a secondary leukemia.

Searching for a Change in the Blood

The investigators focused on seven women treated for breast cancer at MSK who later developed a specific type of leukemia called acute myeloid leukemia. They studied the original tumor tissue that was removed at the time of surgery to look for signs of cancer in the blood. They focused on white blood cells, a component of the immune system, which are often present in the environment surrounding tumor cells.

“In four of the seven women who went on to develop leukemia, we could detect cancer-causing mutations in the immune cells that were removed with their original tumors,” says physician-scientist Ross Levine, senior author of the study. “Previous studies have reported cases in which leukemia mutations were observed years before people with solid tumors developed therapy-related leukemia. We were able to show that in many cases, secondary leukemia arises because preexisting altered blood cells are already there at the time of the first cancer.”

The changes observed in the immune cells are due to a phenomenon called clonal hematopoiesis (CH), which Dr. Levine studies. People with CH have an increased number of white blood cells that carry mutations that are also found in blood cancers. Some people with CH will go on to develop leukemia, although most do not.

“CH mutations are part of aging,” Dr. Comen says. “You can think of them like gray hairs or wrinkles but in the immune system.” Studies have suggested that between 10 and 20% of people over age 70 have signs of CH in their blood.

A Unique Collaboration

The JNCI study came about because of a unique collaboration among members of MSK’s Breast Medicine Service, Leukemia Service, and Department of Pathology. Physician-scientist Jorge Reis-Filho, Chief of the Experimental Pathology Service and an expert in uncovering detailed molecular information from archival tumor samples, was another co-author on the study.

Dr. Reis-Filho used a lab technique called laser capture microdissection (LCM) to separate immune cells from tumor cells within the tumor tissue. “This technology has been around for more than a decade,” he explains, “but this was the first time that we used this method to ask such an important clinical question and to define the clinical impact of mutations affecting immune cells.”

Although the mutations are present much earlier than previously known, the investigators don’t completely dismiss the role of chemotherapy in the development of leukemia. They believe that these drugs may make the environment for leukemia more hospitable and may help it grow and spread more effectively.

Next Steps for a Surprising Finding

Much more research needs to be done to validate these findings in a larger number of people. The investigators also plan to expand this work to look for the presence of immune cells with CH mutations in other types of solid tumors. Drs. Comen and Reis-Filho are currently developing new ways to look for these mutations that are less labor-intensive than LCM.

According to Dr. Levine, there are several long-term goals of this research. “Once we know who is at risk of developing leukemia, we can monitor them so we can catch the disease early. It’s also possible that these findings could influence the treatment that patients get for their initial cancer,” he says. “Ultimately, we hope this research will lead to ways to prevent or reverse the progression from CH to leukemia.”

These efforts are all part of a larger push in CH research across MSK under the Precision Interception and Prevention Program, which is led by Luis Diaz, Head of the Division of Solid Tumor Oncology.

“This study — of breakthrough potential — is a great example of the kind of science that can only be accomplished by a dedicated multidisciplinary team melding laboratory expertise and clinical insight,” says co-author Larry Norton, Senior Vice President in the Office of the President of MSK and Medical Director of the Evelyn H. Lauder Breast Center. 

“While this study provides key insight into how we may better predict who is at risk for a future leukemia, it is not cause for alarm. The risk of leukemia still remains exceptionally small for people with breast cancer,” Dr. Comen says. “Those who have specific concerns should speak to their doctors.”

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How an Altered Gatekeeping Protein Can Cause Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/16/2020
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Cancer is caused by gene mutations, but sometimes it’s hard to figure out which mutations actually drive tumor growth and which are just along for the ride. One way to determine this is to look for so-called mutational hot spots. These areas of the genome are mutated in tumors more frequently than would be expected by chance. The frequency suggests that they may play an active role in cancer.

MSK-IMPACTTM, Memorial Sloan Kettering’s diagnostic test that looks for genetic changes in more than 400 genes in patients’ tumors, has proven quite useful in the discovery of new hots pots. Researchers in the Human Oncology and Pathogenesis Program (HOPP) have used the identification of one particular hot spot to explain why a gene called XPO1 causes cancer. The findings were published online July 8 in Cancer Discovery.

“Researchers already knew that XPO1 regulates which proteins are located in a cell’s nucleus and which get moved to the cytoplasm. This is a basic function for any cell,” says senior author Omar Abdel-Wahab, a physician-scientist in HOPP. “But until now, nobody has ever shown how the alteration of the XPO1 protein could cause cancer. This study shows how this happens.”

Decoding the Function of an Important Protein

XPO1 is often mutated in blood cancers — especially many types of lymphoma. XPO1 mutations are also found in some solid tumors. A drug that targets these mutations, called selinexor (Xpovio®), was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma. It is being tested in clinical trials for other cancers at several institutions, including MSK. But researchers weren’t sure which patients were most likely to respond to the drug.

An analysis of MSK-IMPACT data led by study co-author Barry Taylor, a computational oncologist and Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, suggested that a specific mutation in XPO1, called E571, was common in cancer. To study the function of that particular mutation, Dr. Abdel-Wahab’s team put a version of the gene with the E571 mutation into mice. The mice developed cancer at a high rate. The researchers then did additional studies in the mice and in human cancer cells to find out how the mutation causes cancer.

“We found that the mutant form of XPO1 promoted excessive cell growth,” says first author Justin Taylor, an MSK medical oncologist and member of Dr. Abdel-Wahab’s lab. “Further analysis showed that this occurs because of XPO1’s role as a gatekeeper that regulates which proteins can exit the nucleus.” The researchers found that mutations affect the function of this gate, changing which proteins stay in the nucleus and which leave and go to the cytoplasm.

Dr. Taylor adds that the research also revealed why the drug is effective. “The mutation changes the electrical charge of the XPO1 protein, which makes selinexor bind to it more strongly. This makes the cancer cells more prone to die.”

Developing a More Personalized Approach

Clinical trials for selinexor are ongoing. Currently, MSK is participating in a trial for people with liposarcoma. The results of a trial for people with myelodysplastic syndrome were presented at a recent meeting of the American Society of Hematology.

Dr. Abdel-Wahab says that the E571K mutation may prove to be an effective way to determine who is likely to benefit from selinexor. This could influence future clinical trials of the drug and lead to a more personalized approach to who gets the drug.

The researchers also plan to study the role of other XPO1 defects in cancer, including cases where the gene is overexpressed but not necessarily mutated.

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MSK’s Expanded Genomics Program Takes a Deep Dive into the Causes of Childhood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2019
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MSK-IMPACT™ detects changes in more than 400 cancer-associated genes. The test has made a meaningful difference for many adults treated at Memorial Sloan Kettering. By identifying the mutations driving a tumor’s growth, test results may indicate which targeted therapy or immunotherapy is likely to work against a tumor. Results can also be used to find an appropriate clinical trial.

But the picture is quite different for children with cancer. About half of their tumors do not have a significant mutation that can be identified with MSK-IMPACT or any other standard clinical test. For these kids, developing new forms of molecular diagnosis is essential.

“As a whole, pediatric cancers are a collection of very diverse and very rare tumor types,” says MSK molecular geneticist and data scientist Elli Papaemmanuil. “Their genomes are very different from the genomes of most cancers seen in adults. We still have so much to learn about them.”

This is the motivation behind the establishment of MSK’s Expanded Genomics Program. The program, led by Dr. Papaemmanuil, was launched in September 2018 to develop a way to comprehensively map the unique changes driving each individual tumor. The ultimate goal is to understand and eventually identify personalized treatment approaches for every child treated for cancer at MSK Kids.

Going Beyond the Standard Approach

In the lab, the Expanded Genomics team has already performed an in-depth examination of tumors from more than 120 children treated at MSK. This analysis includes looking at the gene mutations detected by MSK-IMPACT, sequencing the rest of the tumor genome, and measuring levels of RNA. Changes in RNA can help indicate which genes are affected.

“We hope to be in a position where we can identify the novel genetic events that define each tumor and explain what’s driving the cancer,” Dr. Papaemmanuil says. “By learning more about these disease-defining changes, we aim not only to pinpoint which drugs are likely to be effective but also to develop diagnostic and prognostic markers.” These markers would help doctors determine which cancers may be more aggressive and require more treatment, and which tumors can successfully be cured with less-aggressive therapies, enabling patients to avoid side effects.

Finding New Clues about Cancer’s Origins

Another important aspect of genomic research in pediatric cancer is that it can identify which tumors may be caused by inherited mutations. Current literature, as well as work by MSK geneticist and pediatric oncologist Michael Walsh, suggests that about 10 to 15% of children with cancer have germline (hereditary) mutations.

Knowing when a cancer is caused by a hereditary mutation can benefit whole families because relatives can get tested for the same mutation. If they have it, they may be able to enroll in screening programs to catch cancer at an earlier stage or have preventive care.

A large proportion of cancer susceptibility genes affect repairing DNA damage under normal conditions. Expanded genomic analysis can readily pinpoint the evidence of damaged DNA in people with impaired DNA repair genes. This provides another way to identify people with inherited gene mutations.

Additionally, the presence of these mutations can suggest who may benefit from treatment with immunotherapy drugs, such as checkpoint inhibitors. These drugs work better against tumors that have a lot of mutations. Traditionally, they have not been used to treat pediatric cancers because tumors in younger people tend to have fewer mutations.

Taking Lab Findings into the Clinic

As promising as this research is, more work needs to be done before these types of analyses can be used to make decisions about patient care. “One of our big aims right now is to evaluate whether these comprehensive sequencing approaches are informative enough to be clinically helpful,” Dr. Papaemmanuil says. “We are still in the early stages of this research. Yet in our early findings, we showcase that with comprehensive sequencing techniques, we can identify diagnostic-, prognostic-, and therapy-informing markers that would have not been picked up by standard clinical sequencing tests.”

Her team is working with pediatric oncologists to validate their laboratory findings. They want to determine the best way to match each genetic signature to existing or investigational drugs. As an integral part of the MSK Kids Pediatric Translational Medicine Program, the Expanded Genomics team collaborates with doctors who can use the results from this wide-ranging genomic testing to find targeted therapies for childhood cancers.

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Machine Learning May Help Classify Cancers of Unknown Primary

Source: Memorial Sloan Kettering - On Cancer
Date: 11/14/2019
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Experts estimate that between 2 and 5% of all cancers are classified as cancer of unknown primary (CUP), also called occult primary cancer. This means that the place in the body where the cancer began cannot be determined. Despite many advances in diagnostic technologies, the original site of some cancers will never be found. However, characteristic patterns of genetic changes occur in cancers of each primary site, and these patterns can be used to infer the origin of individual cases of CUP.

In a study published November 14, a team from Memorial Sloan Kettering reports that they have harnessed data from MSK-IMPACT™ to develop a machine-learning algorithm to help determine where a tumor originates. MSK-IMPACT is a test to detect mutations and other critical changes in the genes of tumors. When combined with other pathology tests, the algorithm may be a valuable addition to the tool kit used to make more-accurate diagnoses. The findings were reported in JAMA Oncology.

“This tool will provide additional support for our pathologists to diagnose tumor types,” says geneticist Michael Berger, one of the senior authors of the new study. “We’ve learned through clinical experience that it’s still important to identify a tumor’s origin, even when conducting basket trials involving therapies targeting genes that are mutated across many cancers.”

Basket trials are designed to take advantage of targeted treatments by assigning drugs to people based on the mutations found in their tumors rather than where in the body the cancer originated. Yet doctors who prescribe these treatments have learned that, in many cases, the tissue or organ in which the tumor started is still an important factor in how well targeted therapies work. Vemurafenib (Zelboraf®) is one drug where this is the case. It is effective at treating melanoma with a certain mutation but doesn’t provide the same benefit in colon cancer, even when it’s driven by the same mutation.Cancer of Unknown Primary Origin

If it is unclear where in the body a cancer started, it is called cancer of unknown primary (CUP) or occult primary cancer.

Harnessing Valuable Data

Since MSK-IMPACT launched in 2014, more than 40,000 people have had their tumors tested. The test is now offered to all people treated for advanced cancer at MSK.

In addition to providing detailed information about thousands of patients’ tumors, the test has led to a wealth of genomic data about cancers. It has become a major research tool for learning more about cancer’s origins.

The primary way that pathologists diagnose tumors is to look through a microscope at tissue samples. They also examine the specific proteins expressed by cancers, which can help predict a cancer’s origin. But these tests do not always allow a definitive conclusion.

“However, there are occasionally cases where we think we know the diagnosis based on the conventional pathology analysis, but the molecular pattern we observe with MSK-IMPACT suggests that the tumor is something different,” Dr. Berger explains. “This new tool is a way to computationally formalize the process that our molecular pathologists have been performing based on their experience and knowledge of genomics. Going forward, it can help them confirm these diagnoses.”

“Because cancers that have spread usually retain the same pattern of genetic alterations as the primary tumor, we can leverage the specific genetic changes to suggest a cancer site that was not apparent by imaging or conventional pathologic testing,” says co-author David Klimstra, Chair of MSK’s Department of Pathology.

“Usually the first question from patients and doctors alike is: ‘Where did this cancer start?’ ” says study co-author Anna Varghese, a medical oncologist who treats many people with CUP. “Although even with MSK-IMPACT we can’t always determine where the cancer originated, the MSK-IMPACT results can point us in a certain direction with respect to further diagnostic tests to conduct or targeted therapies or immunotherapies to use.”

Collecting Data on Common Cancers

In the current study, the investigators used data from nearly 7,800 tumors representing 22 cancer types to train the algorithm. The researchers excluded rare cancers, for which not enough data were available at the time. But all the most common types are represented, including lung cancer, breast cancer, prostate cancer, and colorectal cancer.

The analysis incorporated not only individual gene mutations but more complex genomic changes. These included chromosomal gains and losses, changes in gene copy numbers, structural rearrangements, and broader mutational signatures.

“The type of machine learning we use in this study requires a lot of data to train it to perform accurately,” says computational oncologist Barry Taylor, the study’s other senior author. “It would not have been possible without the large data set that we have already generated and continue to generate with MSK-IMPACT.”

Both Drs. Berger and Taylor emphasize that this is still early research that will need to be validated with further studies. In addition, since the method was developed specifically using test results from MSK-IMPACT, it may not be as accurate for genomic tests made by companies or other institutions.

Improving Diagnosis for Cancer of Unknown Primary

MSK’s pathologists and other experts hope this tool will be particularly valuable in diagnosing tumors in people who have CUP. Up to 50,000 people in the United States are diagnosed with CUP every year. If validated for this purpose, MSK-IMPACT could make it easier to select the best therapies and to enroll people in clinical trials.

“This study emphasizes that the diagnosis and treatment of cancer is truly a multidisciplinary effort,” Dr. Taylor says. “We want to get all the data we can from each patient’s tumor so we can inform the diagnosis and select the best therapy for each person.”

This work was funded in part by Illumina, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Cycle for Survival, National Institutes of Health grants (P30-CA008748, R01 CA204749, and R01 CA227534), an American Cancer Society grant (RSG-15-067-01-TBG), the Sontag Foundation, the Prostate Cancer Foundation, and the Robertson Foundation.

Dr. Varghese has received institutional research support from Eli Lilly and Company, Bristol-Myers Squibb, Verastem Oncology, BioMed Valley Discoveries, and Silenseed. Dr. Klimstra reports equity in Paige.AI, consulting activities with Paige.AI and Merck, and publication royalties from UpToDate and the American Registry of Pathology. Dr. Berger reports research funding from Illumina and advisory board activities with Roche. All stated activities were outside of the work described in this study.