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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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Patient-Reported Side Effects: A Crucial Part of Cancer Clinical Trials

Source: Memorial Sloan Kettering - On Cancer
Date: 02/26/2019
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Memorial Sloan Kettering researchers oversee hundreds of clinical trials every year. Some of the most exciting and potentially revolutionary studies look at brand-new drugs that are being given to people with cancer for the very first time.

Clinical trials investigate both the safety and efficacy of new treatments. One component of safety relates to side effects that impact the quality of life of the person getting the treatment. Symptom-based side effects — like fatigue, insomnia, and pain — often can’t be measured with a scan or a blood test yet are still significant.

Patient-reported outcomes are unfiltered reports directly from patients. They reflect the symptoms and experiences of people enrolled in clinical trials, and are considered the gold standard for documenting these side effects. Increasingly, the experiences of people in trials are helping shape how a new treatment is used and even whether it ultimately gets approved by the US Food and Drug Administration.

“People who participate in clinical trials are truly our partners in cancer research,” says Thomas Atkinson, of MSK’s Patient-Reported Outcomes, Community-Engagement, and Language Core. “It’s our duty to allow them to provide input into clinical decision-making processes.”

Collecting data on patient-reported side effects is a key part of clinical trials, explains clinical trials nurse Asia McCoy, who helps oversee the studies at MSK related to bladder cancer. “We stress to patients who are participating in clinical trials that they need to contact us if they’re experiencing any new symptoms, even if they seem insignificant or unrelated,” she says.

An Increased Focus on Patient-Reported Symptoms

Dr. Atkinson was part of a team funded by the National Cancer Institute (NCI) that developed a new system to make it easier for patients to report their treatment-related symptoms during clinical trials. In 2014, the team released an electronic platform called the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). It collects information about these symptomatic experiences. PRO-CTCAE is now used in the majority of NCI-funded trials.

“There’s been a shift toward capturing information about side effects directly from patients,” he explains. “It’s no longer considered acceptable for a clinician to assess how a patient is feeling without including input from the patient.”

Dr. Atkinson says the increased emphasis on survivorship is a big reason for this change. The primary focus of cancer treatment was once treating the disease almost at any cost, he notes. But as people are living longer with cancer and many are being cured of their disease, the short- and long-term side effects of therapy have become ever more important.

With Side Effects, Expect the Unexpected

With the boom in the development of cancer therapies, including newer treatments like immunotherapy and targeted therapy, the number of clinical trials conducted every year has grown. Every clinical trial must be approved and monitored by a hospital’s Institutional Review Board. This team of experts is responsible for protecting the rights and welfare of trial participants.

Until a new drug is given to a patient for the first time, however, researchers can’t always anticipate every side effect. Some symptoms may not be predictable even when researchers know which kinds of cells and tissues will be affected by the drug. Other side effects are not easy to measure in animal studies.

“The first time I meet with a patient, I review all of the possible side effects that we already know about,” says Lauren Kaplanis, a clinical trials nurse who helps manage many of the trials conducted by MSK’s Early Drug Development Service. “When it’s a new drug, we’re honest about the fact that we don’t always know what all the side effects will be.”

“Data about symptoms is important information for us to have,” Ms. McCoy adds. “It can propel a drug into the next stages of development, or it can shut down a protocol.”

An Emphasis on Open Communication in Cancer Trials

Dr. Atkinson, Ms. McCoy, and Ms. Kaplanis all worry that people enrolled in trials may be afraid to report side effects.

“They’re concerned they may have to make an extra trip to come see us,” Ms. McCoy says. “Or they think we’ll view them as complaining too much.”

Fear of being removed from a study may also be a factor, especially if the patient considers it their last chance for successful treatment.

“It’s human nature to worry that if you’re constantly reporting things like severe pain or nausea, you may get taken off a trial,” Dr. Atkinson says. “But trial participants need to understand that they have to report these things. If the drug eventually gets FDA approved, the doctors who are prescribing it need to know which side effects may occur, so they can help future patients.”

If a patient is experiencing a lot of symptoms when receiving a new drug, they may be able to continue receiving it, at a lower dose, for example, or they may take a temporary break, Ms. Kaplanis explains. “We want people to know about these opportunities for treatment, and we stress the idea of having an open dialogue,” she says. “We’re all on the same team.”

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8 Questions with Philip Kantoff, An MSK Leader and Prostate Cancer Expert

Source: Memorial Sloan Kettering - On Cancer
Date: 03/07/2019
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Philip Kantoff is Chair of Memorial Sloan Kettering’s Department of Medicine. He came to MSK in November 2015 from the Dana-Farber Cancer Institute and Harvard Medical School.

As Chair of the Department of Medicine, what do you do?

I oversee the medical treatment of people with cancer — treatments like chemotherapy, targeted therapies, and immunotherapies. My department also leads the development of new approaches to drug treatments. Heading a department of medicine at a cancer center is very different from doing that job at a regular hospital. Although we have specialists in fields beyond oncology, the focus of everyone here is cancer.

What is your focus at MSK?

A main emphasis for me is mentorship. One of the first things I did when I started was move the office for the medical oncology fellows next to mine. These fellows, who are getting specialized training in cancer care, are the future of oncology. Now it’s easier for all the fellows to come seek my guidance, whether it’s about patient care or career advice. I take pride in helping others succeed.

Another focus has been fostering better partnerships among different members of the healthcare team, medical staff, and administration, as well as building bridges between laboratory scientists and clinical investigators.

What cancers do you specialize in?

My focus is genitourinary cancers, especially prostate cancer and testicular cancer. Although the treatment for men with early-stage prostate cancer is usually surgery or radiation rather than drugs, which is my main area of expertise, about half of the patients I see have early-stage disease. They’re trying to decide what course to take with their treatment. I triage them, advise them, and become their quarterback. I’ve always enjoyed developing close relationships with my patients.

You’re a big proponent of active surveillance in prostate cancer, monitoring a person’s disease instead of directly treating it. Why?

For select men whose disease has not spread outside the prostate and is not aggressive, active surveillance may be the best option. When I tell my patients, “You don’t have to do anything. We’ll just keep an eye on you,” they’re usually very happy. They embrace active surveillance because they know the side effects of treatment can be significant.

What goes on in your lab?

Prostate cancer behaves very differently in different people. We’re trying to understand the genetic variations that make some cancers more aggressive than others as well as how these cancers develop resistance to therapies. We hope to develop better ways to predict which cancers are most likely to become aggressive, so we can prevent them from returning after initial treatment.

What research are you most excited about right now?

A few years ago, I was part of a multicenter collaboration that found about one-quarter of men with advanced prostate cancer have inherited gene mutations related to DNA repair, such as BRCA1 and BRCA2. Now that we know this, we can use drugs developed to treat BRCA-associated ovarian and breast cancers on prostate cancer as well.

How did you get interested in the field?

After my medical training, I did a postdoctoral research fellowship at the National Institutes of Health. At that time, the mid-1980s, it seemed that cancer was the area of medicine that was most amenable to molecular biology.

You’re a native New Yorker, but you’ve spent most of your career in Boston. How is it being back?

All three of my kids live here. It’s nice being close to them. Also, I’m a huge fan of New York sports teams, especially the Yankees and the Giants. It’s a lot easier to be a Yankees fan here than it is in Boston.

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Reality Check: Should People with Cancer Avoid Robotic Surgery?

Source: Memorial Sloan Kettering - On Cancer
Date: 03/08/2019
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On February 28, the US Food and Drug Administration released a statement cautioning about the use of robotic surgery in mastectomy and other cancer surgeries.

In the notice, Terri Cornelison, assistant director for women’s health in the FDA’s Center for Devices and Radiological Health, said that “the use of robotically assisted surgical devices for any cancer-related surgery has not been granted marketing authorization by the agency, and therefore the survival benefits to patients when compared to traditional surgery have not been established.”

Robot-assisted surgery is an extension of laparoscopic surgery, a minimally invasive approach that allows surgeons to perform operations using cameras and instruments inserted through small incisions. The robot adds improved vision and control to laparoscopic procedures. Its enhancements include the ability to see things in high definition and three dimensions as well as robotic arms that can be precisely controlled.

In an interview, Jeffrey Drebin, Chair of Memorial Sloan Kettering’s Department of Surgery, spoke about what this FDA advisory means for patients.

Why do you think this statement was released?

In November 2018, a study published in the New England Journal of Medicine and led by researchers from University of Texas MD Anderson Cancer Center reported that in women treated for early-stage cervical cancer, traditional open surgeries were associated with a lower risk of the cancer coming back compared with minimally invasive surgical procedures. This was true whether the surgeon used a robot or other laparoscopic techniques, so these findings were really not about the robot per se.

Additionally, more and more hospitals are beginning to use surgical robots. This is due in part to the trainings offered by the companies that make them. The FDA may have felt they needed to inform people on what is known about these procedures.

What are the potential benefits of robotic surgery?

For patients, the main benefit of the robot, or of any laparoscopic procedure, is smaller incisions. What comes along with these smaller incisions is the potential for less pain after the operation, less blood loss, a shorter hospital stay, and a quicker recovery.

But cancer surgery is very different from other operations that may be done minimally invasively, like a gallbladder removal or a hip replacement. With a cancer surgery, the size of the incision is not the most important thing for patients. The most important thing is giving patients the best chance of being cured of their cancer.

If that can be done with smaller incisions and less discomfort, then that’s a plus. But if the trade-off is a higher risk that the cancer will come back, that’s not a trade-off I would choose, or that most patients would choose.

What is MSK’s approach to using robotic surgery?

One of the questions the NEJM study didn’t look at was the experience level of the surgeons. It’s very clear that what makes the biggest difference in the outcome of any cancer surgery is the surgeon’s level of experience and training. If one of our surgeons offers a patient the option of robotic surgery, it’s because we have a really good idea that this is going to be better for that individual patient.

For many types of cancer, randomized, controlled trials that have shown that the outcomes for minimally invasive surgery are the same as open surgery in terms of cancer-related death. The trials also found that outcomes such as pain, bleeding, and length of hospital stay are often better. We’ve studied this in prostate cancer, colon cancer, lung cancer, head and neck cancers, and stomach cancer. For uterine cancer, outcomes for robotic hysterectomies are equivalent to open surgeries. We frequently offer robotic surgery to patients with many types of cancer when we believe it’s appropriate.

The FDA statement specifically mentions mastectomies performed with robotic techniques. MSK doesn’t currently offer this procedure, although some members of our team have talked about using it. Whether it ultimately turns out to benefit patients is something that would need to be studied in carefully designed trials over a period of time.

Why should someone choose MSK for cancer surgery?

Experience makes the biggest difference. The robot and other laparoscopic devices are really no different from a scalpel or a pair of forceps. They are all just tools.

The best surgeons use the right tool for the right case for each patient. They don’t simply use the same tool over and over. Surgeons at MSK are able to personalize the best approach for every patient because of the level of training and experience that we have with all of these techniques.

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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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A Death Wish That Allows Worms to Thrive — and What It Tells Us About Cancer Biology

Source: Memorial Sloan Kettering - On Cancer
Date: 03/28/2019
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In biology, how cells die is as important as how they live. Cell death provides a counterbalance to cell division, maintaining the proper number of cells throughout an organism’s lifetime. Gaining a better understanding of how cells die is also important for cancer research. It can teach us how the body naturally fends off cancer — by preventing runaway cell growth — as well as point to new ways to target and kill tumor cells.

The lab of Sloan Kettering Institute cell biologist Michael Overholtzer explores the mechanisms of different kinds of cell death. More than a decade ago, while studying breast cancer cells, he was the first to observe a type of cell death called entosis, in which one cell engulfs and kills another.

In a study published in March 2019 in Cell Reports, Dr. Overholtzer described for the first time the role of entosis in the development of a tiny worm called C. elegans. The discovery is significant because until now very little has been known about the role that entosis plays in natural developmental processes.

“Understanding cell death in normal development can provide new clues about how it works and why it evolved,” says Dr. Overholtzer, who was recently named dean of the Gerstner Sloan Kettering Graduate School of Biomedical Sciences. “We hope this research will help us find ways to harness it for cancer treatment.”

Characterizing Different Kinds of Cell Death

The most well-studied form of cell death is called apoptosis. Apoptosis is a type of programmed cell death sometimes likened to cellular suicide, in which a cell breaks down in a regulated, systematic fashion. Apoptosis can occur in response to cell damage, but it’s also a normal part of development in embryos. For example, apoptosis in the hands and feet allows individual fingers and toes to form, by killing cells in the spaces in between them.

In the March 2019 study, the researchers focused on the development of the gastrointestinal and reproductive tracts of the C. elegans worm, a popular lab model for studying development. Research from a team at Rockefeller University had suggested that forms of cell death other than apoptosis were important in the formation of parts of the worm’s body. Dr. Overholtzer’s team decided to continue this line of inquiry.

In particular, the researchers looked at the role of cell death in the formation of the cloaca, the dual-purpose orifice at the hind end of worms, as well as many other organisms, from which excrement is discharged. In males, it is also where sperm are released. It turns out that entosis is vital to ensuring that the genital tract connects to the cloaca. Without it, male worms are sterile.

A Mysterious Process

Unlike apoptosis, entosis requires two cells. It might sound more like a murder than a suicide, but cells that undergo death by entosis still have a death wish. They actually burrow themselves into the other cell, where they are broken down and eaten.

“This is a really enigmatic process,” Dr. Overholtzer says. “Why would a cell decide to do this? It turns out that in the worm, it’s required for normal development.”

In the C. elegans embryo, a type of cell called a linker cell pulls the developing genital tract into the cloaca. The linker cell then burrows into another cell, where it is destroyed by entosis. Destruction of the linker cell creates an opening that allows sperm to enter the cloaca.

“There’s an ongoing question in biology, which is, ’Where do all these different cell death programs come from and why do they exist?’” he notes. “For entosis, this study demonstrates that a process observed initially in breast cancer cells also has a role in normal development.”

Further research will focus on figuring out whether entosis contributes to other developmental processes, as well as molecular changes in the cell that lead to death by entosis. The researchers also plan to study a piece of the linker cell that is left behind after the cell undergoes entosis, called the lobe. “These pieces stick around for a long time, so we think they may have some purpose,” Dr. Overholtzer concludes.

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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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An Old Protein Gets a New Look: Researchers Target TGF-ß to Make Immunotherapy More Effective

Source: Memorial Sloan Kettering - On Cancer
Date: 04/05/2019
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The immunotherapy drugs called checkpoint inhibitors have transformed treatment for some people with cancer. Currently, a major focus in cancer research is looking for ways to make these drugs effective for a greater number of people and more types of cancer.

One of the many approaches that scientists are now studying is combining immunotherapies with drugs that block the actions of a molecule called transforming growth factor-beta (TGF-ß). The importance of TGF-ß was uncovered more than 30 years ago by Sloan Kettering Institute Director Joan Massagué.

“There has been tremendous interest in this new avenue of treatment,” Dr. Massagué says. “Right now, we have a serious opportunity to leverage the robust knowledge that we’ve built about TGF-ß and use it to make immunotherapy more effective. TGF-ß is actually a hormone that is released by cells. This means it is quite accessible to drugs that can block its activity.”

A Fundamental Molecule with Many Roles

TGF-ß is critical for regulating how cells function. It works by sending signals from a cell’s membrane to its nucleus, telling it which genes to make into proteins. Among the most important jobs of TGF-ß are directing embryonic development and regulating the immune system. It also plays a role in whether cancer spreads.

It is the effect of TGF-ß on the immune system that many researchers are now most interested in studying.

A study published in February 2018 in Nature reported that, in people being treated with the immunotherapy drug atezolizumab (Tecentriq®), levels of TGF-ß in tumors correlated with how well people responded. In short, the more TGF-ß that tumors had, the less likely it was that atezolizumab worked. This is because TGF-ß can prevent the immune cells called T cells from infiltrating and attacking tumors. Checkpoint inhibitors boost the activity of T cells, but if the immune cells can’t get into the tumor, they will not be effective.

Another study in the same issue of Nature reported that combining a TGF-ß-blocker called galunisertib with immunotherapy allowed the immune system in mouse models of colon cancer to attack tumors that it had previously not been able to go after.

“This research showed that TGF-ß prevents the incoming T cells from penetrating and infiltrating the tumor,” Dr. Massagué says. “If you block TGF-ß, however, T cells infiltrate and kill the tumor cells.”

Combining Approaches in the Clinic for Many Cancer Types

Several clinical trials now under way are looking at how to combine immunotherapy with drugs that block TGF-ß. MSK medical oncologist Anna Varghese is the co-principal investigator of one such trial for pancreatic cancer.

“Immunotherapy alone is not effective against pancreatic cancer for most patients,” Dr. Varghese explains. “This is because pancreatic tumors have an immunosuppressive microenvironment.” That means the cells and tissue around the tumor prevent immune cells from getting in and attacking the cancer.

Dr. Varghese’s trial combines the immunotherapy drug durvalumab (Imfinzi®) with galunisertib. The study is still ongoing, and it’s too early to know how effective the combination will be or what side effects it will have, but Dr. Varghese hopes to report preliminary findings soon.

Research on TGF-ß blockers goes beyond immunotherapy to look at their effectiveness when combined with other kinds of drugs. Recently, MSK medical oncologist James Harding was an investigator in a trial that looked at galunisertib, either alone or in combination with other drugs, for the treatment of liver cancer.

Early analysis of the study showed that when galunisertib was combined with the targeted therapy sorafenib (Nexavar®), people had more favorable outcomes compared with other treatments. However, Dr. Harding comments that “the design of this early study makes it difficult to say how impactful this combination strategy will ultimately be for liver cancer.

“Furthermore,” he adds, “with the advent of effective immunotherapy, the focus of the investigation has shifted to pairing galunisertib and other TGF-ß blockers with immune checkpoint inhibitors.”

Clinical trials focusing on TGF-ß blockers are ongoing at other cancer centers as well as at MSK.

Taking a New Look at a Familiar Target

“For a long time, drug companies have been interested in harnessing the power of TGF-ß blockers, not only for cancer but for other diseases as well,” Dr. Massagué says. “Until now, there’s been concern about doing that because we know that TGF-ß has so many different functions in cells.” Long-term use of these drugs, he explains, would have too many harmful side effects.

“However, combining a TGF-ß blocker with checkpoint immunotherapy and using it as temporary way to boost the effectiveness of these other drugs may be possible,” he concludes.

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How MSK Is Reducing Inequality in Cancer Care in Harlem and Beyond

Source: Memorial Sloan Kettering - On Cancer
Date: 04/17/2019
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On April 1, 2019, the Ralph Lauren Center for Cancer Care (RLC) officially became part of Memorial Sloan Kettering. Opened in 2003 as a partnership between MSK, the Polo Ralph Lauren Foundation, and the former North General Hospital, the RLC has served as a model for quality and equity in healthcare for residents of Harlem and surrounding neighborhoods.

We recently spoke with Lewis Kampel, an MSK medical oncologist and Medical Director of the RLC, about the center’s mission and his goals for its future.MSK Ralph Lauren Center.

Why was the RLC originally established, and what was MSK’s role?

The intellectual spark for the center came from Harold Freeman, a prominent African American cancer surgeon. He had begun noticing disparities in cancer incidence and outcomes in Harlem and the surrounding community. He was one of the first to bring this important topic to the public’s attention.

Dr. Freeman connected with fashion designer Ralph Lauren. At that time, through his foundation, Mr. Lauren was developing an interest in cancer research and access to care. The two of them joined up with Harold Varmus, who was then President and CEO of MSK. Dr. Varmus also felt strongly about reducing disparities in cancer care.

So MSK has been a vital part of the Ralph Lauren Center from the very beginning.

What changed this month?

Until now, the RLC has operated as a separate corporation, even though it was owned and controlled by MSK. Now that we have received approvals from the New York State Department of Health and other state agencies, it will operate more like MSK’s other outpatient facilities.

Could you talk more about the mission of the RLC?

The mission of the Ralph Lauren Center is to reduce disparities in cancer incidence and outcomes in the communities we serve. We do this by providing high-quality prevention, screening, and treatment services to those who might otherwise face challenges in getting them. The communities we care for may be underserved for a number of reasons. These include financial barriers and a variety of others.

It is important to emphasize that the mission and culture of the Ralph Lauren Center will not change. We will continue to provide high-quality care in a community-friendly atmosphere. As part of MSK, we will be able to tap into the expertise, experience, and technology available at a world-class cancer center.

What services are offered at the RLC?

When possible, we try to prevent cancer from developing in the first place. For example, we know that obesity is a risk factor for many cancers. So we offer nutrition counseling focused on healthy eating and weight reduction.

We also offer vaccinations for the human papillomavirus (HPV). This virus is associated with several cancers, including cervical cancer, anal cancer, and head and neck cancers. HPV vaccination can lower that risk. And of course, tobacco is another huge risk factor. We will be resuming a tobacco cessation program later this year.

If we can’t prevent cancer, we try to detect it early, when it’s more likely to be cured. Currently, we offer screenings for breast, cervical, lung, and prostate cancers, as well as periodic screening for skin and head and neck cancers. Eventually, we will offer screening for colorectal cancers as well. Later this year, the Breast Examination Center of Harlem will be moving into our space, which will help streamline the screening process.

For those diagnosed with cancer or certain blood diseases, we offer chemotherapy and other systemic therapies. We also have a breast surgeon on staff who can evaluate people with breast lesions. We refer those who require surgery or radiation therapy to MSK or other hospitals, depending on the patient’s choice.

Eventually, we hope to offer clinical trials to patients getting their treatment here. These studies are designed to determine the best treatment for a given cancer. Historically, people of African American descent have been underrepresented in clinical trials. Because of that, the conclusions of those studies may not apply to them.

What’s offered at the RLC that’s different from what people might get at other MSK outpatient locations?

We have several patient navigators, and they are key members of our team. Before patients even come for their first appointment, the navigators reach out to them to make sure that we have all the information we need from the referring doctor. Navigators can arrange things like transportation and child care, and help with financial and insurance issues.

We know that for breast cancer as well as other cancers, reducing the length of time between the initial diagnosis and the beginning of treatment can make a big difference in outcomes. So our navigators make sure that patients are seen here as quickly as possible after they receive a diagnosis and start treatment in a timely manner.

Good nutritional status is important for getting through cancer treatment, so our nutritionist provides advice on healthy eating. Many of our patients may not have access to healthy food, so our food pantry can provide food packages

Who are the patients treated at the RLC?

Our patients come from all over New York City, especially upper Manhattan, Harlem, and the Bronx, as well as Brooklyn and Queens. They also come from southern Westchester County and even parts of New Jersey. Many of them find it convenient to get their care here.

Roughly 40% of our patients are African American and 40% are Hispanic. Many of them speak Spanish. We’re also starting to see patients of West African descent who speak French. Our patients tend to be lower on the income scale and have other medical problems in addition to cancer.

Some of our patients don’t have insurance, and others are underinsured. We make every possible effort to treat anyone who needs our care.

How did you get involved in the center, and when did you become medical director?

I grew up in Newark, New Jersey, and at a very early age I became aware of how the experiences of poor people within the healthcare system were very different from the experiences of those who were not poor. I also came of age in the 1960s and was strongly influenced by the social justice movement.

When I joined MSK in 1993, I began focusing on prostate cancer. I soon became aware that men of African descent — African American men and Caribbean men — have a much higher risk of prostate cancer than men who are white. Their disease also tends to be more aggressive. About ten years ago, I began working with the consul general of Jamaica and members of the Jamaican community in New York to study these issues. Genetics play a role, but there may be other factors as well.

At about the same time, I was Chair of the Quality Assessment Committee at Memorial Hospital. Through that work, I became interested in the issues surrounding equity in care. Being able to offer high-quality care doesn’t mean much if that care isn’t available to everybody.

When the opportunity to lead the Ralph Lauren Center as medical director presented itself three years ago, I jumped at it. It is the perfect role for me. It allows the convergence of several issues I am passionate about.