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The Science of Eating Well: MSK Research Focuses on Nutrition after a Stem Cell Transplant

Source: Memorial Sloan Kettering - On Cancer
Date: 03/28/2018
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People who have stem cell and bone marrow transplants face many challenges. One obstacle that is often overlooked is the difficulty that many of them have eating well during and after the transplant process.

Now there is a new focus on nutrition during transplants, especially at Memorial Sloan Kettering. In fact, MSK researchers are leading work showing the role that a healthy diet plays in recovery. They are developing unique ways to help people who are having transplants maintain good nutrition.

We spoke with Marissa Buchan, a research nutritionist who works exclusively with the bone marrow transplant team, about how MSK is using science to ensure that patients have proper nutrition.

Why is it so hard for people undergoing transplants to eat a healthy diet?

There are several reasons why it’s challenging to eat a healthy diet while having a transplant. One is that they generally just don’t feel well, which decreases their appetite. On top of that, they often experience side effects of the treatments they are given, such as nausea, vomiting, diarrhea, or sores in the mouth and throat that can make eating difficult or painful.

Another big problem is that people undergoing transplants often report that their sense of taste has changed. Chemotherapy can affect the taste buds and other cells inside the mouth. This is something that we’ve known about for a while, but no one has ever done research to quantify it or to figure out what to do about it.

Can a change in taste be measured?

We’re starting to look at it. As far as we know, we’re the first ones ever to do so. Sergio Giralt [Chief of MSK’s Adult Bone Marrow Transplant Service], myself, and several others are conducting a study to measure which specific tastes are upset in people undergoing autologous transplants [transplants using their own blood stem cells].

We’re giving patients taste tests and using chemistry techniques to measure which flavors seem to have changed. Certain flavors may be lost. Others may become stronger. These changes can happen right away or down the road. Not only do we not know which specific flavors are involved but no one has ever studied how long it takes for these problems to get better. We also measure other factors related to taste, such as the amount of saliva produced and the bacteria in the mouth.

We don’t have any answers yet, but we’re starting to get good information. Our hope is that we can find new ways to develop a personalized diet for each person based on their individual taste changes and symptoms.

Why is maintaining good nutrition during a transplant so important?

I am currently leading a study to understand how diet affects the microbiota. This is the balance of microbes that live in the intestinal tract. I presented what I’ve found so far at the American Society for Blood and Marrow Transplantation’s annual meeting in February 2018.

Earlier studies done at MSK showed that the makeup of gut bacteria had a huge impact on outcomes after transplant. This included relapse, survival, and the development of graft-versus-host disease (GVHD). GVHD is a potentially fatal side effect in which the new blood cells attack the patient’s tissues. For example, the team found that if people maintain the naturally occurring intestinal bacteria Blautia, they are less likely to develop GVHD. The researchers discovered that Blautia is sensitive to the antibiotics that people are given during the course of treatment. It also declines in those who aren’t eating.

Our latest research is digging deeper into the role of nutrition in the maintenance of a healthy, diverse microbiota. We have found that people who eat fewer calories have decreased diversity in their intestinal flora. This decline happens even if they are not taking antibiotics. Our discovery shows the importance of maintaining a varied diet after a transplant. This practice can keep the gut active and preserve important flora, like Blautia.

What is MSK doing to change the way people who have transplants eat?

Because transplants increase the risk of infection, in the past we’ve recommended a low-microbial diet. This meant very few fruits and vegetables. Everything had to be well cooked. But our nutrition team came to realize that this diet was unnecessarily restrictive. After much review, we changed our official dietary recommendations last summer.

Our transplant patients are now allowed to eat raw fruits and vegetables, as long as they’re washed well. This diet gives them more options to maintain a healthy, varied diet while still emphasizing food safety to minimize the risk of foodborne illnesses.

In addition, nutrition has become an integral part of care at MSK. Everyone on the care team is focused on getting patients to eat, since they realize how important it is. During the transplant process, we tell patients that eating is one of their jobs.

Bone health can be a problem for some survivors. We recommend diets that are high in calcium, vitamin D, and other nutrients.

Other survivors may have changes in their metabolism that lead to diabetes or obesity. Our clinical dietitian-nutritionists and other experts can work with them to help maintain a healthy diet and lifestyle.

What’s your favorite recipe to give someone who is recovering from a stem cell transplant?

Our nutrition service has developed a whole menu of smoothies and other healthy recipes for people having cancer treatment, depending on their symptoms. One smoothie that’s especially good for people with GVHD is the apple pie smoothie.

These smoothie recipes are great for anyone having cancer treatment. In particular, those who may be experiencing nausea or diarrhea as a side effect of chemotherapy may find them helpful.

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Reality Check: Study Examines Metastasis after Breast Cancer Surgery

Source: Memorial Sloan Kettering - On Cancer
Date: 04/13/2018
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Earlier this week, scientists from the Massachusetts Institute of Technology published a study looking at some of the ways in which breast cancer spreads, or metastasizes, in mice. They reported data showing that surgery may trigger an immune response that makes it easier for cancer to spread throughout the body. Additionally, the study pointed to anti-inflammatory drugs like aspirin and ibuprofen as a possible way to decrease cancer’s ability to spread.

The news media reported on the research, which is still in early stages. These headlines may be scary or confusing for people facing a recent diagnosis, as well as for those who have already had surgery.

We spoke with Larry Norton, Memorial Sloan Kettering’s Senior Vice President and Medical Director of the Evelyn H. Lauder Breast Center, about what people should know about the study and why it shouldn’t affect decisions about treatment.

Can you tell us how this study was conducted?

This was a study done in the lab using a mouse model. The mice had been injected with cancer cells and then underwent simulated surgeries. Those mice later developed tumors. However, when the mice were given an anti-inflammatory drug at the time of the surgical procedure, the tumors were smaller.

I want to emphasize that this is an excellent lab experiment, and it fits in with much of the lab research we’re doing here at MSK. But it’s far from ready to influence clinical care.

What is the take-home message from the findings?

There is nothing in this study that should lead to any changes in the way we treat breast cancer. I don’t want anyone to read the media coverage of this study and think that they shouldn’t have surgery. That would be a disaster.

From studies conducted in London way back in the 1800s, we know that before doctors started doing surgery for breast cancer, everyone with breast cancer died. Some died soon after diagnosis, within months or a few years, and some lived for many years. But everyone eventually developed metastases and died from them. Surgery is still the mainstay of treatment for breast cancer and is the most important way to prevent metastases.

We have come a long way in the diagnosis and treatment of breast cancer since those early days, and today most people do very well. It’s true that some people still develop metastases, even if their cancer is caught early. Therefore, it’s clear that some tumors seed metastases very early in their development, long before they are ever detected and surgically removed. So it is not the surgery that causes the metastases.

What about taking anti-inflammatory drugs like aspirin or ibuprofen to reduce any potential risk?

I think a lot of people will hear about the study and grab onto this notion of taking these drugs at the time of surgery. But just because these drugs are available over the counter, it doesn’t mean they’re completely without risk. We know they can increase bleeding, and that may turn out to be more harmful than the response to inflammation.

It’s important to note that today many people with breast cancer get drug therapy before or immediately after their surgery. This includes chemotherapy and steroids. The steroids we give are much more potent than aspirin as far as their anti-inflammatory abilities. So there’s no reason to automatically assume that a small additional boost from aspirin or ibuprofen would make a difference. It’s an interesting question and it merits further research, but it’s something that needs to be studied with controlled clinical trials in patients.

What is MSK’s role in studying cancer metastasis?

MSK is conducting a great deal of research on the question of metastases. For example, Sloan Kettering Institute Director Joan Massagué is a world leader in studying how cancer metastasizes. Many of his studies also have looked the role of the immune system in suppressing cancer cells that have broken off from a tumor. He’s conducted research on how these cells later wake up and start to cause trouble. The biology is complex, and there are still a lot of things we don’t know. But everyone agrees this is a very important area of research, and one we will continue to study.

Is there anything else you’d like to say about the research?

This study was an interesting piece of well-conducted science. It’s certainly adding to our knowledge and giving us some ideas for new things to look at in the lab and in the clinic. But while it would be terrific if stopping metastasis were as easy as taking an over-the-counter anti-inflammatory drug, everyone studying metastasis knows that it’s not.

However, this work and much of the other work on this topic is pointing us in a good direction, with the ultimate aim of stopping cancer cells from spreading from the very beginning, or even before the beginning — as in cancer prevention. I do believe that the future is bright in this regard, although there is much work still to do to make it a reality.

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Immunotherapy Combination Is Better than Chemotherapy for Non-Small Cell Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 04/16/2018
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A treatment that combines two specific immunotherapy drugs has already had success in some people with advanced melanoma and kidney cancer. A phase III study has now shown that the same combination was also effective for people with lung cancer. The international research team that conducted the trial was led by Memorial Sloan Kettering medical oncologist Matthew Hellmann. The findings are being presented at the 2018 American Association for Cancer Research (AACR) annual meeting. They are being published online in the New England Journal of Medicine as well.

The clinical trial was called CheckMate -227. It looked at combining nivolumab (Opdivo®) and ipilimumab (Yervoy®) to treat people with advanced non-small cell lung cancer, the most common type of lung cancer. The analysis being presented focused on people with a molecular marker indicating that there were many mutations in their tumors. Previous studies from MSK have suggested that tumors with many mutations are likely to respond to immunotherapy. After a minimum follow-up of nearly a year, those whose tumors had many mutations who received the immunotherapy combination were 42% less likely to have their cancer progress compared with those in the control group, who got standard-of-care chemotherapy.

“This trial had two important findings,” says Dr. Hellmann, who is a member of the Parker Institute for Cancer Immunotherapy at MSK. “First, it showed us that the combination of these immunotherapies together control lung cancer better than chemotherapy. Second, it showed that molecular markers are effective in helping to predict which people will benefit from immunotherapy.

“The results of this study highlight the importance of molecular profiling to identify the best treatment options for each patient,” he adds. “We are already doing this type of testing routinely for people with lung cancer, for example, with MSK-IMPACT™.”

Leading the Way in Clinical Trials

Ipilimumab and nivolumab are both in the class of drugs called immune checkpoint inhibitors. These drugs help control cancer by taking the brakes off the immune system. This allows the white blood cells called T cells to attack tumors. MSK physician-scientist Jedd Wolchok led the clinical research that resulted in the approval of ipilimumab in 2011 by the US Food and Drug Administration for the treatment of advanced melanoma.

Dr. Wolchok also led the pivotal clinical trial that resulted in FDA approval for the combination of ipilimumab and nivolumab in melanoma in 2015. Because that combination has worked well for melanoma, researchers decided to evaluate it for other cancers as well, including non-small cell lung cancer. Nivolumab on its own is already approved for this type of lung cancer, as well as for a number of other cancers.

Importance of Mutational Burden

Despite the striking success of checkpoint inhibitors at stopping cancer growth and even eliminating tumors in some people, these drugs don’t work for everyone. Research at MSK has focused on why that’s the case and looked for ways to predict beforehand who is most likely to benefit.

One important discovery that’s been made in many types of cancer is that tumors with a greater number of mutations tend to respond better to checkpoint inhibitor drugs than those with fewer mutations. This characteristic is called a high tumor mutation burden (TMB). In a related study, published online April 12, 2018, in the journal Cancer Cell, Dr. Hellmann and colleagues at MSK and elsewhere focused on the role of TMB in people with non-small cell lung cancer who were treated with nivolumab plus ipilimumab. The goal of study was to examine was to link the molecular features of the tumors to the patients’ outcomes after treatment with nivolumab plus ipilimumab in a phase I trial called CheckMate-012.

Based on their analysis, the researchers found that a high TMB was a good way to predict the effectiveness of combination immunotherapy in people with non-small cell lung cancer. The findings were used to guide the testing that was later done in the CheckMate -227 trial. TMB is already part of the results obtained from the MSK-IMPACT test.

A New Treatment Option for Non-Small Cell Lung Cancer

In CheckMate -227, among people whose tumors had a high TMB, the response rate was much better for those who got immunotherapy rather than chemotherapy. After getting the combination, 45% had their tumors shrink compared with 27% of those who got chemotherapy. And responses were distinctly durable with immunotherapy, where 68% were still responding to the immunotherapy combination one year after treatment started compared with only one-quarter of those who got chemotherapy.

The researchers say that immunotherapy is an important addition to the roster of treatment options for people with advanced non-small cell lung cancer. “This drug combination shows that some people can be spared treatment with chemotherapy,” Dr. Hellmann says. “And if a person stops responding to immunotherapy, they can still be given chemotherapy for additional benefit.”

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Testing for BRCA: What Is the Best Way to Screen for Cancer Genes?

Source: Memorial Sloan Kettering - On Cancer
Date: 04/25/2018
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In March 2018, the US Food and Drug Administration approved an at-home, mail-in kit that tests for some of the inherited mutations in the genes BRCA1 and BRCA2. These mutations are linked to an increased risk of breast cancer, ovarian cancer, and prostate cancer, and possibly others.

Storefront centers that conduct cholesterol checks, do thyroid panels, and screen for sexually transmitted diseases have made people more comfortable initiating their own medical tests. But many experts say that some types of testing — including for cancer genes — should continue to be done under a healthcare provider’s guidance.

“The developers of at-home genetic tests have said they should be as easy and available as a pregnancy test, which any woman can take at home alone in her bathroom,” says Kenneth Offit, Chief of MSK’s Clinical Genetics Service. “But that’s exactly what we’re worried about. For men and women, finding out that you’ve inherited a cancer gene can raise a lot of issues. We want to make sure that people who receive these results are getting the support that they need.”

To answer some of the questions about the best way for people to get this kind of health information, a team of clinical genetics experts has launched the BRCA Founder Outreach (BFOR) study. The study is being led by Memorial Sloan Kettering and three other cancer centers.

A Contrast to Recreational Genomics

“Thanks to new avenues of communication and education, we can enhance genetic counseling and widely share the knowledge of top experts when screening for cancer genes,” explains Mark Robson, Chief of the Breast Medicine Service and a co-principal investigator of the study. “BFOR is designed to help us do that.”

The purpose of the BFOR study is to evaluate how to best combine the convenience of direct-to-consumer genetic tests with guidance from a medical care provider. It will allow 4,000 women and men with Jewish ancestry to enroll in screening for the three most common BRCA mutations linked to increased cancer risk. These mutations are quite rare in the general population, but one in 40 people of Ashkenazi (Eastern European) Jewish descent carries at least one of them.

“This is not recreational genomics, which is what most home-testing kits have traditionally been,” says Dr. Offit, who is one of the principal investigators and head of the executive committee running the BFOR study. “The stakes for these kinds of cancer genetic tests are much higher than just looking at your ancestry.”

People who are age 25 and older and have one or more Ashkenazi Jewish grandparent can go to the BFOR website and fill out a questionnaire to determine whether they are eligible. Once they complete the online educational and consent process, they can go to a local Quest Diagnostics center to get a blood test. Quest is providing testing at no charge to the study participants.

Explaining Potentially Life-Changing Genetic Test Results

Under the BFOR model, participants receive the results from someone who can explain what the findings mean, rather than getting them in the mail. They can choose whether to get their results from a clinical genetics expert or their own doctor. Some of the issues raised by learning of an increased cancer risk include whether to consider risk-reducing surgery and how to inform other family members who may also carry the mutation.

Currently, the study is limited to people living in metropolitan areas that have participating centers, so they have access to genetics experts. In addition to MSK in New York City, the other sites involved are Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center in Boston, the University of Pennsylvania in Philadelphia, and Cedars-Sinai Medical Center in Los Angeles.

Another important note is that with both the BFOR study and the commercial genetic-testing service, only the three most common BRCA mutations are included. These three mutations account for about 95% of BRCA1 and BRCA2 mutations in Ashkenazi Jews. BRCA mutations overall explain only about a quarter of inherited breast cancers.

“Just because you test negative for these three BRCA mutations doesn’t mean you’re in the clear, especially if you have a strong family history. You may need to decide if you want to undergo additional testing,” explains Kelly Morgan, a genetic counselor dedicated to this study. “This is just another illustration of why working with a trained healthcare provider is so important.”

Founders in the Field of Cancer Mutations

The three mutations included in the study — two in BRCA1 and one in BRCA2 — are called founder mutations. A founder mutation is a genetic change that appears with high frequency in a small group of people who were geographically or socially isolated for a long time and had ancestors who carried that specific gene mutation. Because Ashkenazi Jewish populations were culturally separated for hundreds of years, these BRCA mutations, which initially occurred by chance, became more common in that group.

In 1996, Dr. Offit and his team discovered the most common BRCA2 mutation linked to breast and ovarian cancers. The mutation has since been linked to other cancers, including prostate cancer and pancreatic cancer. Around the same time, other research groups identified the two BRCA1 founder mutations.

Teaming Up with the Community

Dr. Offit emphasizes that as a National Cancer Institute–funded cancer center, MSK counts treating the community in which it’s located as one of its primary roles. About two million people of Jewish descent live in the New York City metropolitan area, most of them Ashkenazi, and 20% of people treated at MSK have Jewish ancestry, making this focus especially fitting.

However, he notes, the information gained from focusing solely on this group in the BFOR study can later be applied to the wider population, just as other BRCA-related findings have been more broadly applied in the past.

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Genomic Marker Is Associated with Lynch Syndrome, a Hereditary Cancer Condition, Across Many Different Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 06/02/2018
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Memorial Sloan Kettering researchers have found that the genetic condition Lynch syndrome may be associated with more cancers than earlier thought. Lynch syndrome runs in families. It was previously known to increase the risk mainly of colon cancer, rectal cancer, and endometrial (uterine) cancer. The MSK team has now linked Lynch syndrome to cancers that are rarely or not already associated with the syndrome. These include pancreatic cancer, prostate cancer, adrenocortical tumor, sarcoma, and many others. Results of the study were reported today at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study looked at people with advanced cancer whose tumors carried a genomic biomarker called high microsatellite instability (MSI). The data showed that these patients had a one in six chance of having Lynch syndrome — regardless of what type of cancer they had. Lynch syndrome is currently believed to occur in about 1 in 300 people in the general population.

The findings have wide-ranging implications. They suggest that people whose tumors demonstrate high MSI should be tested for Lynch syndrome mutations. Those who are found to have Lynch can undergo more frequent screening for certain cancers. Family members can also be tested to see if they have the condition.

“Our findings suggest that anyone with an advanced solid tumor who is found to have high MSI should be tested for Lynch mutations, regardless of the location of the tumor or family cancer history,” says medical oncologist and clinical geneticist Zsofia Stadler, who led the study. The research was presented at the ASCO meeting by medical genetics fellow Alicia Latham Schwark.

“We expect that genetic testing of all people with high-MSI tumors will help identify additional individuals and families with Lynch syndrome,” Dr. Stadler adds.

Expanding Tumor Testing

The study focused on more than 15,000 people with many different types of cancer who were tested at MSK for MSI in their tumors. MSI is a genetic defect that occurs in about 5% of advanced cancers. It leads to the accumulation of hundreds or even thousands of mutations in a single tumor. In the past, testing for this biomarker has been limited. But thanks to the US Food and Drug Administration’s approval of pembrolizumab (Keytruda®) in May 2017 for any cancer that has a high level of MSI, many more people are now having their tumors analyzed for this defect.

In addition to tests for MSI, the people included in the study also had genomic testing with MSK-IMPACTTM. This tool looks for mutations in 468 cancer-associated mutations in tumors as well as a number of cancer-linked hereditary mutations found in normal tissues. These inherited mutations include those linked to Lynch syndrome.

“At MSK, because we sequence the tumors of so many people, we have a unique opportunity to make these kinds of discoveries,” says Dr. Stadler, who is clinic director of MSK’s Clinical Genetics Service and a member of the Robert and Kate Niehaus Center for Inherited Cancer Genomics. “This kind of research helps people with cancer and, in this case, also helps us provide predictive genetic testing for at-risk family members, who may then benefit from increased cancer surveillance and cancer prevention measures.”

A Cancer Syndrome That Runs in Families

Lynch syndrome is an inherited condition caused by a mutation in one of five genes known as mismatch repair (MMR) genes. When one of the MMR genes is mutated, cells are unable to repair errors that can occur when they divide — resulting in MSI.

Lynch syndrome has been known about for decades, but in the past, it has been largely associated with just a few cancers. MSK’s Clinical Genetics Service offers testing for Lynch syndrome to people who have multiple relatives with related cancers. However, the findings from this study suggest that many cases of Lynch syndrome could be going undetected.

Consequences for Future Research, and for Families

Knowing whether a cancer is due to Lynch syndrome has important implications for families. Lynch mutations are autosomal dominant, which means a person with Lynch has a 50% chance of passing it down to a child. MSK’s genetic counselors recommend that when someone is found to have Lynch syndrome, their parents, siblings, and children get tested too.

Experts also recommend more frequent screening for certain cancers if a Lynch-associated mutation is found. In particular, people with Lynch mutations should get regular colonoscopies to look for colon and rectal cancer.

Focusing on families with inherited cancer genes is a major part of the Precision Interception and Prevention (PIP) initiative. This MSK effort concentrates not only on catching cancer very early but also on preventing it from developing in the first place.

PIP is led by Luis Diaz, Head of MSK’s Division of Solid Tumor Oncology, and MSK Physician-in-Chief José Baselga. It was created to take advantage of all of the findings coming out of MSK-IMPACT.

“Dr. Baselga’s initiative of genomic analysis of a very large number of patients through MSK-IMPACT has been instrumental to this project,” Dr. Stadler concludes. “This test has been vital in making sure that people get the best treatments for their cancer and enabled us to do these kinds of important studies that can ultimately benefit whole families.”

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Gene Mutations in the Blood Can Complicate Findings from Tumor Sequencing

Source: Memorial Sloan Kettering - On Cancer
Date: 06/05/2018
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MSK-IMPACTTM is a diagnostic test that looks for mutations in more than 450 cancer-causing genes in people’s tumors. It has led to major advances in precision medicine. Based on the mutations that are found, people with cancer may receive treatment with an approved targeted therapy or immunotherapy that’s matched to their cancer. Some people may enroll in a clinical trial based on the results.

When Memorial Sloan Kettering experts — including pathologist Marc Ladanyi and geneticist Michael Berger — built the test, they also included the analysis of an individual’s blood sample in addition to the tumor sample. This component is not part of most other tumor-sequencing tests. That’s what makes it possible to determine which mutations are part of a tumor and likely to be driving the cancer and which may be present in other parts of the body.

Today at the American Society of Clinical Oncology (ASCO) annual meeting, a new study illustrates a major benefit of that approach. The findings show if data about the blood are not part of test results, mutations specific to the blood may be misread as mutations in the tumor. This can potentially affect the therapy that someone gets.

“These findings add another layer of complexity to precision medicine,” says MSK bioinformatician Ahmet Zehir, who presented the study at the ASCO meeting. “They show us that there’s lots to consider when matching patients to the right treatment.”

The Consequences of a Blood Condition

Cancer mutations may be present in a person’s blood, even if they don’t have blood cancer, due to a condition called clonal hematopoiesis (CH). Hematopoietic stem cells give rise to all types of blood cells. In CH, those stem cells form a group of cells that is genetically distinct from the rest of the blood stem cells. MSK physician-scientist Ross Levine was part of the research team that first identified the genetic basis of CH and its connection to blood cancer.

CH is most commonly found in older people, especially those who have a history of smoking. Having CH doesn’t mean that someone has or will get blood cancer. In fact, most people with CH will not: Experts estimate that between 0.1% and 4% of people with CH will develop cancer within ten years of diagnosis, depending on their medical history. MSK recently opened a clinic for people with CH, to study the condition and monitor them for the development of blood cancer as well as heart disease, which is also linked to CH.

The reason CH-related mutations show up in tumor analysis is simple. Tumors have a blood supply, so some DNA from the blood is mixed with the tumor DNA.

A Potential to Influence Treatment Decisions

“We already have some examples of how this situation could directly affect patient care,” Dr. Zehir says. In one case, a person was found to have a mutation in BRCA2, suggesting that he could benefit from a class of drugs called poly (ADP-ribose) polymerase (PARP) inhibitors. But that BRCA2 mutation was due to CH, not genetic changes that were driving tumor growth, so a PARP inhibitor would not have been effective.

This study, which is being published today in JAMA Oncology, outlines this case and others. “The findings show that you also need to analyze a blood sample if you want to be 100% confident in choosing the right therapy,” Dr. Zehir says. He adds that misinterpreted sequencing results could alter the outcomes of clinical trials for new drugs if patients are assigned to a trial for a drug targeting a mutation their tumor doesn’t have. The study’s first author was MSK bioinformatician Ryan Ptashkin.

“Our findings show that this phenomenon could affect up to 5% of people with advanced cancer,” Dr. Zehir concludes. “That may not sound like a high percentage, but it’s still a large number of people. I hope that after doctors at other hospitals learn about our findings, they will be more aware of this issue when they’re interpreting tumor-only sequencing results and deciding which treatments to give patients.”

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Meet Chronic Lymphocytic Leukemia Expert Anthony Mato

Source: Memorial Sloan Kettering - On Cancer
Date: 06/12/2018
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Hematologic oncologist Anthony Mato recently joined Memorial Sloan Kettering from the University of Pennsylvania. At MSK, he directs the chronic lymphocytic leukemia (CLL) program. He sees patients in Manhattan and at MSK Basking Ridge, in New Jersey.

We recently spoke with Dr. Mato, an internationally recognized leader in CLL, about the disease and MSK’s expertise in treating it.

What is CLL and how is it different from other types of leukemia?

CLL is the most common type of leukemia. About 20,000 people in the United States are diagnosed every year, almost all of them older adults. CLL occurs when the body begins to make too many B cells, a type of white blood cell. The cancer can spread throughout the blood and bone marrow. It can also affect certain organs, most commonly the lymph nodes and spleen.

Many people don’t have symptoms and have no idea that anything is wrong at the time they’re diagnosed. The disease is usually detected when someone gets a blood test as part of a regular checkup and they are found to have an elevated white blood cell count. CLL is most common in the elderly, but younger people can be diagnosed with it too.

Some leukemias, such as acute lymphocytic leukemia and acute myeloid leukemia, need to be treated urgently, but CLL is treated only after it causes symptoms. About a third of people who are diagnosed will never have symptoms and therefore won’t ever need treatment. But the rest ultimately will. CLL is not a curable disease. As its name suggests, it is a chronic disease. But experts in the field have a number of different ways to keep it under control.

What are the symptoms of CLL?

The symptoms of CLL include persistent fevers, fatigue, night sweats, abdominal fullness, and weight loss. As the disease advances, people may be more prone to infections and bleeding because their bone marrow isn’t working properly.

Rarely, CLL can turn into a more aggressive type of lymphoma. This is called Richter’s transformation. It’s usually a life-threatening condition that requires urgent treatment.

What would you tell someone who’s just been diagnosed with CLL and doesn’t have any symptoms?

Even if you are asymptomatic and your doctor says you don’t need treatment, it’s important to see an expert in CLL soon after you are diagnosed. MSK offers state-of-the-art diagnostic and prognostic testing. This enables doctors here to devise a strategy for each patient from the very beginning. Our patients are updated on the standard of care, as well as on what new therapies are on the horizon and any clinical trials that may impact them.

MSK has a great deal of experience in determining how closely someone needs to be monitored if they don’t have symptoms. Being monitored doesn’t necessarily mean that no action is needed. For example, people with CLL still need to receive comprehensive care, like vaccinations to prevent infections and screenings for other health conditions.

People aren’t expected to give up longstanding relationships with their regular doctors when they come to MSK for CLL care. We partner with doctors in the community to make sure that people with CLL get excellent care in all areas related to their health.

For those who develop symptoms, what are the treatments for CLL?

We try to prescribe chemotherapy only when absolutely necessary. Targeted chemotherapy-free approaches are available as an alternative to traditional chemotherapy. Three targeted therapies have already been approved for CLL: ibrutinib  (Imbruvica®), venetoclax (Venclexta®), and idelalisib (Zydelig®). Several more drugs are on the way. All of these drugs are taken as pills and target molecular changes that are specific to CLL.

MSK is also a leader in chimeric antigen receptor (CAR) T therapy for CLL. This is when someone’s immune cells are engineered to recognize and attack cancer. Other types of immunotherapy may be effective as well, and that’s something we plan to study.

Why did you decide to come to MSK?

The Leukemia Service and the whole Division of Hematologic Oncology have an incredible commitment to both research and patient care, and that was really a driving force for me. I’m excited to have the opportunity to do the kind of research that I’ve always wanted to do.

MSK’s team approach to care is fundamental to the way we treat CLL. We’ve formed a CLL working group that meets monthly to coordinate all of our efforts. The program has skilled nurses, pathologists, and pharmacists who are involved in patient care every step of the way.

The incredible collection of scientists, clinicians, and research staff, not only at MSK but also at nearby Weill Cornell Medicine and The Rockefeller University, makes this the perfect place to address important questions in the area of CLL.

Now that you’re here and getting settled in, what are your plans?

My colleagues and I plan to start a number of trials to look for better treatments. These trials will incorporate novel drugs and other therapies, as well as studies on how people who have been treated with the standard of care fare in the long term. Because younger people do have the disease, it’s important for us to develop different strategies. Our hope is to produce extended remissions, so that people can live a long time without treatment and with an excellent quality of life.

I’m also really happy that I’m able to see patients at MSK Basking Ridge. The care offered there allows people with CLL to participate in the most cutting-edge clinical trials without ever having to come into the city, and they can receive the best follow-up care as well.

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Findings from Two Patients Shed New Light on Drug Resistance in AML

Source: Memorial Sloan Kettering - On Cancer
Date: 06/27/2018
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Last summer, the US Food and Drug Administration approved enasidenib (Idhifa®) for the treatment of acute myeloid leukemia (AML). Enasidenib works differently than most cancer drugs. Rather than killing leukemia cells, it turns them into normal blood cells. Memorial Sloan Kettering hematologist-oncologist Eytan Stein led the pivotal clinical trial that resulted in the drug’s approval.

Now, a collaborative team of researchers is reporting that people who take enasidenib can develop resistance to it — and in a way never seen before. The findings are being reported in Nature.

“Everyone who studies precision medicine spends a lot of time thinking about why some people respond to certain drugs and why some stop responding or never respond at all,” says physician-scientist Ross Levine, who was one of the paper’s senior authors, along with Dr. Stein. “MSK has been one of the leaders in figuring this out.”

The discovery was made by a team of doctors, laboratory researchers, and pharmaceutical company scientists. They used cells from people who were being treated with enasidenib to uncover why the drug sometimes stops working. 

Targeting a Mutation Found in Several Different Cancer Types

Enasidenib is approved for people with AML that is driven by a mutation in a gene called IDH2. About 15% of people with AML have this mutation. IDH2 mutations and mutations in the related gene IDH1 are found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile-duct cancer.

The proteins made from mutated IDH genes can drive cells to become cancerous. MSK President and CEO Craig Thompson conducted much of the fundamental research on IDH mutations and their relationship to cancer. He is one of the co-authors of the Nature paper.

Researchers had previously shown that only one of the two copies of the IDH2 gene needs to be mutated to drive cancer. The other one is usually normal. In the new paper, the investigators report that when cells developed resistance to enasidenib, the additional mutations that allowed the cells to resist the drug occurred on the normal copy of IDH2.

This stands in contrast to how resistance develops against most targeted cancer therapies. In those cases, an already mutated gene develops an additional mutation that allows the cancer cell to fend off the drug’s effects. “The finding about IDH2 suggests that genetic resistance is more complicated than we thought,” says Dr. Levine, who is a member of MSK’s Human Oncology and Pathogenesis Program (HOPP).

Just two patients were in the study, but the investigators learned a great deal. Experiments with laboratory models allowed them to study how the mutations work. The findings suggest that some people may develop resistance to IDH inhibitors due to a mutation on the same copy of the gene that carries the cancer-causing mutation.

Dr. Levine says that this prediction was confirmed when the researchers identified a third patient being treated with a similar drug that targets a mutation in IDH1. The IDH inhibitor stopped working in this person when a resistance mutation appeared on the copy of the IDH1 gene with the cancer-causing mutation. This suggests that the process may be universal to all IDH-blocking drugs. “It’s a small number of people, but we’re quite confident that we’ll see this same mechanism in others moving forward,” he adds.

Targeting IDH mutations is a growing area of cancer drug development. Earlier this month, Dr. Stein was a co-first author of a paper published in the New England Journal of Medicinethat looked at another drug that targets the IDH1 mutation in people with AML. The multicenter phase I trial reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with the drug, ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected in people with this stage of AML and severe side effects were rare. The researchers plan to continue studying the drug in larger, placebo-controlled trials.

A New Biomarker for Drug Resistance

After the people in the study developed resistance, their tumors started growing again. Doctors were able to switch them to other drugs that worked in a different way, however, so they were not affected by the additional mutation. There are a number of other treatment options for people with AML. These include both FDA-approved therapies and experimental drugs being tested in clinical trials. Many people with AML ultimately receive stem cell or bone marrow transplants, which offer the opportunity for a cure. However, many people are not able to undergo transplants, which makes developing new drugs an important focus.

“Now that we know resistance to enasidenib can develop, we can start to monitor people for it by conducting blood tests,” says first author Andrew Intlekofer, who is also a physician-scientist in HOPP. “Over the course of therapy, we can use the protein as a biomarker for the formation of resistance. Then we’ll know we need to offer a different treatment.”

Far-Reaching Implications for Other Cancers

Understanding how resistance to enasidenib develops could lead to the development of additional drugs. Although, Dr. Intlekofer adds, more research is needed before new drugs can be identified. He also notes that the new discoveries about enasidenib could apply to other drugs that work in a similar way. Treatment of other cancers that are characterized by IDH1 and IDH2 mutations could be affected as well.

Dr. Levine highlights the importance of collaboration when conducting this kind of research. Working closely with scientists from Agios, the company that makes enasidenib, was of particular importance, he says. “To do this kind of work, it requires a great team. Everyone who worked on this study made important contributions. This work was one of the most satisfying research experiences I’ve ever had.”

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One by One: Single-Cell Analysis Helps Map the Cancer Landscape

Source: Memorial Sloan Kettering - On Cancer
Date: 06/28/2018
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The composition of malignant tumors is incredibly complex. They contain not only cancer cells but also dozens of other cell types, such as supportive tissues, fat, and many kinds of immune cells. These other cells interact with the cancer cells and one another to influence how tumors behave.

To get to the bottom of what drives a tumor’s growth and to find ways to stop it, scientists need to be able to figure out what all these types of cells are and figure out how they work together. Two new studies from Sloan Kettering Institute investigators published today in Cell represent important steps in that direction. One classified the different kinds of immune cells found in breast cancer tumors. It was the largest study of its kind so far. The other took a more fundamental tack. It established a new mathematical framework for extracting as much information as possible from a tumor’s makeup.

“These studies are focused on efforts to look at tumors at the level of each individual cell,” says Dana Pe’er, Chair of SKI’s Computational and Systems Biology Program and senior author of both papers. “Without going down to the level of single cells, we aren’t fully able to understand what’s going on and what is driving a particular cancer.”

A Growing Field Seeks to Map Cancer

The field of single-cell analysis has expanded greatly in recent years. This is due in large part to rapid technological advances. Mathematical and computational techniques now make it possible to sort the huge quantities of data that are generated by these analyses.  

The Human Cell Atlas brings together investigators from all over the world to create a comprehensive reference map of all human cells. Dr. Pe’er, who co-chairs one of this project’s analysis working groups, says the effort has the potential to impact the understanding of many diseases, not just cancer. Collaborative endeavors like this, she notes, can answer fundamental questions about human development.

One of the primary tools in this field is a genomic analysis technique called single-cell ribonucleic acid sequencing (RNA-seq). This system looks at RNA rather than DNA. It enables investigators to determine which genes are expressed, or “turned on,” in particular cells, rather than just which genes are present in the DNA. Because every cell in the body contains the same DNA, RNA analysis provides much-needed detail about cell function and activity.

Characterizing the Immune Landscape of Breast Cancer

One of the new papers is a collaboration among SKI computational biologists and immunologists as well as Memorial Sloan Kettering’s breast cancer team. The study looked at cells taken from human breast tumors. The team also considered normal breast tissue, blood, and lymph node tissue. The investigators analyzed 45,000 immune cells taken from eight tumors and 27,000 additional immune cells.

Identifying such a large number of immune cells could explain why immunotherapy doesn’t always work the same way in each person. Immunotherapy harnesses the power of the body’s natural immune response to fight cancer. Some types of immune cells attack cancer, while others protect tumor cells from harm.

“One of our major findings was that there was a much greater diversity in the states of immune cells found in tumors compared with what we found in normal tissues,” says Alexander Rudensky, Chair of SKI’s Immunology Program and co-senior author of the breast cancer study. A cell’s state is based on not only what type of cell it is but also other factors, such as its location, size, and structure.

“We were surprised to find that, rather than distinct differences between tumor and nontumor tissue, there was a gradient in the levels of different immune cell states,” he says.

In other words, they found a range of differences in the immune makeup of these tissues, not a clear line between the immune cells present in cancer and normal tissue. “This helps explain why tumors have a range of behaviors — not all tumors respond in the same way to immunotherapy,” adds Dr. Rudensky, who is also a Howard Hughes Medical Institute investigator. “But at the same time, we saw common features among the breast cancer samples that were not seen in the normal tissues. From this work, we can start to think about how to develop immunotherapy that’s custom-built for people based on their individual tumor microenvironment.”

Dr. Rudensky explains that the focus on breast cancer was only a starting point to see if the approach would work. The researchers have plans to expand this research to many other types of cancer. “Until very recently, analyzing the data from thousands of cells at the same time would have been a major undertaking,” he says. “But thanks to the transformative work that’s been done by Dr. Pe’er’s team, we can start to grow this area of immunology research.”

Uncovering Hidden Data with MAGIC

The other Cell paper concentrates on identifying the differences among cancer cells themselves, rather than looking at immune cells in their midst. A culmination of five years of work from Dr. Pe’er, the study focuses on cutting-edge ways to reduce the high levels of noise and highlight the biological trends that come from such large quantities of data.

Dr. Pe’er compares the challenge to a common event on crime shows like CSI, in which an image from a photograph is too blurry to make out. “The detectives bring in an expert who has created a computer algorithm to analyze the pixels, allowing them to clearly read the letters and numbers on a license plate,” she says. “In the same way, we have developed a way to reduce the fuzziness in our data and see clear patterns.”

Dr. Pe’er’s collaborators included Smita Krishnaswamy, a former postdoctoral fellow in her lab who now leads her own lab at Yale University. The team dubbed the technique MAGIC for Markov affinity-based graph imputation of cells. The algorithm can recover gene expression data that may be missing from an individual cell if not all of the RNA has been captured.

“Cancer cells have a range of activities. The ones that have the ability to outsmart drugs or to spread to another part of the body are actually quite rare,” she concludes. “Only by looking at the tumor with single-cell resolution are we able to identify them and study them, enabling us to get to the bottom of what gives them these capabilities.”

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Splicing May Be an Effective Target in the Fight against Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/18/2018
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Cancer is a disease of the genes. But genes don’t directly cause the uncontrolled cell growth that characterizes the disease — proteins produced by those genes do. Consequently, most precision cancer drugs target these malfunctioning proteins and block their activity.

Some investigators are looking to stop cancer by blocking steps on the path from gene to protein. One of these tactics focuses on a process called splicing. It has yielded a drug, called H3B-8800, which is now being evaluated in an early-stage clinical trial for myelodysplastic syndrome (MDS) and two types of leukemia.

“This drug works differently than other targeted drugs that block proteins,” says Memorial Sloan Kettering physician-scientist Omar Abdel-Wahab. “But we think it’s a very good approach because between 60 and 80% of people with MDS have the defect in splicing that this drug targets.”

A Promising New Focus for Cancer Drugs

Genes get translated into proteins through an intermediate molecule called messenger RNA (mRNA). If genes are the written instructions for how to make a protein, and the protein itself is the final product, then mRNA is the go-between that brings the plans to the construction crew. Splicing is one part of the manufacturing process. It determines which part of the genetic sequence gets used, and which part is cut out and thrown away. When splicing goes wrong, it can lead to defective proteins that drive cancer growth.

Dr. Abdel-Wahab studies the splicing process in his lab in the Human Oncology and Pathogenesis Program. Based on a recent discovery that genetic changes in the splicing process are very common in leukemias, he found that cells carrying these genetic changes are especially sensitive to drugs.

Research on splicing and mRNA is part of the broader field called epigenetics. Epigenetics is the study of changes in cell behavior that are not due to changes in the DNA sequence. It’s an increasingly important focus in cancer research. Dr. Abdel-Wahab is also a member of MSK’s Center for Epigenetics Research, which focuses on studies into how epigenetic changes can cause cancer.

Finding a Way to Correct Genetic Splicing Errors

H3B-8800, which is being developed by a company called H3 Biomedicine, is a version of a natural substance that was first found in soil bacteria. It was chemically modified to work better as a drug. Earlier this year, Dr. Abdel-Wahab, along with MSK MDS expert Virginia Klimek, was part of an international team that reported on the function and efficacy of H3B-8800 in a dish and in mouse models of leukemia. The study, published in Nature Medicine, found that H3B-8800 can induce cell death in cancer cells that are dependent on splicing.

“Mutations in splicing genes are very common in MDS, so we fully expect that these mutations are linked to the bone marrow dysfunction and low blood counts seen in MDS,” Dr. Klimek explains. “The development of this new targeted drug is exciting because it has the potential to help many people with MDS. We’re grateful for those who donated the blood and bone marrow samples that were used to make these discoveries, and which led to the development of H3B-8800.”

The drug is now being tested in a phase I clinical trial at MSK and several other hospitals to determine the highest dose that can be given safely and to look for side effects. At MSK, the trial is being led by Dr. Klimek. 

“This effort really highlights the importance of collaboration between doctors and scientists,” she adds. “Such collaborations enable us to take observations from patients into the research lab, where breakthrough discoveries can be made and turned into new treatments. Our collaborative approach and our tremendous research program are some of MSK’s greatest strengths.”

“Research in the lab has taught us a lot about how errors in splicing can impact the products of genes,” Dr. Abdel-Wahab notes. “We think these functions are particularly important for different kinds of blood cells, but it’s possible this approach may work for some solid tumors as well.”