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Can Yoga or Acupuncture Help Neuropathy Caused by Chemotherapy? Research Seeks an Answer

Source: Memorial Sloan Kettering - On Cancer
Date: 12/13/2018
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Chemotherapy-induced peripheral neuropathy (CIPN) is a common long-term problem in people who have been treated for cancer. Symptoms of this type of nerve damage can include pain, numbness, weakness, and tingling, especially in the hands and feet. The condition can greatly impair someone’s daily life, affecting sleep, mobility, balance, and the ability to perform tasks that require fine motor control, like buttoning shirts and tying shoes.

At the recent San Antonio Breast Cancer Symposium, a team of Memorial Sloan Kettering experts led by medical oncologist and integrative medicine specialist Ting Bao presented updates on two studies that focused on different aspects of CIPN in breast cancer survivors.

“CIPN is a major problem, especially with the growing number of cancer survivors,” Dr. Bao says. “There are currently few good treatments for CIPN, and there are lots of areas that need to be investigated. That’s what I’m trying to do with my research.”

Chemotherapy’s Double-Edged Sword

CIPN is especially widespread in people who have received chemotherapy for breast cancer, colon cancer, or rectal cancer. In the case of breast cancer, the culprit is a class of chemotherapy drugs called taxanes. This group includes paclitaxel (Taxol®) and docetaxel (Taxotere®). For colorectal cancer, it’s a different class, called platinum drugs, like oxaliplatin (Eloxatin®).

Investigators are still learning why particular drugs cause nerve damage. They believe it’s a combination of several reasons. One issue is that these drugs interrupt the function of microtubules, the tiny filaments inside cells that provide support and help with cellular transport. They may also disrupt mitochondria, which provide cells with the energy they need to grow and divide.

In cancer cells, inducing this type of damage is what makes chemotherapy effective. It makes the cancer stop growing and die. But when the injury happens to nerve cells instead, consequences can be detrimental.

Some clinical trials have looked at the effects of various pain medications on CIPN, including duloxetine (Cymbalta®) and gabapentin (Neurontin®), but the results have been somewhat disappointing, Dr. Bao says. She notes that some people take these drugs anyway because they are looking for any type of relief.

“People try all kinds of things, like soaking their feet in warm water and rolling them on marbles to try to restore some of the feeling. This technique can be very helpful for some,” she adds.

Looking to Integrative Medicine

Dr. Bao and her colleagues on the Breast Medicine and Integrative Medicine Services are looking beyond drugs to find new ways to relieve CIPN. One of the studies she discussed in San Antonio was a small randomized, controlled study that looked at the potential benefits of yoga in survivors of breast and gynecologic cancers who have CIPN. The trial, which is still ongoing, is designed to evaluate whether yoga can improve balance and prevent falls in people with moderate to severe nerve damage, which doubles the risk of fall.

Dr. Bao is also studying whether acupuncture can prevent CIPN from worsening in people being treated with paclitaxel. She recently completed a small three-arm study and is waiting for the results to be analyzed.

Quantifying Improvement in CIPN

Another study presented by Dr. Bao in San Antonio focused on gauging CIPN’s effects. In addition to patient questionnaires, Dr. Bao’s team measured the degree of CIPN by testing the sensitivity of fingers and toes to touch and vibration, among other factors.

“As we begin to look at new ways to treat CIPN, it’s important to measure whether the interventions are effective and to have better tools to study why and how certain treatments work,” Dr. Bao says. “Historically, it’s been difficult to get funding to support trials that focus on quality of life after treatment, because of the lack of objective ways to measure improvements. We hope that once we have better tools to determine what works and what doesn’t, it will boost interest in our work.”

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Kirt’s Story: How a Clinical Trial for a Rare Tumor Gave Me a New Lease on Life

Source: Memorial Sloan Kettering - On Cancer
Date: 12/20/2018
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When Kirt Robinson, now age 43, started feeling pain in his neck about three years ago, he thought that he’d pulled a muscle while working out. After three months of increasingly severe pain, he noticed a large bump near his collarbone and finally decided to see his doctor.

“I’m very stubborn. It took me a while to admit how bad it had gotten,” says the longtime Brooklyn resident and native of Guyana. “I couldn’t raise my arm over my head to put on a T-shirt. I couldn’t turn my neck. The pain was sometimes excruciating.”

His doctor ordered a needle biopsy of the tumor. When the results were inconclusive, Kirt was referred to a head and neck specialist for a surgical biopsy. His tumor sample was then sent to pathologists at Memorial Sloan Kettering for analysis.

Diagnosed with a Rare Tumor

The experts at MSK determined that Kirt had a desmoid tumor. Desmoid tumors, also called aggressive fibromatosis, are rare growths that usually occur in the arms, legs, or torso. Fewer than 1,000 cases are diagnosed every year in the United States. Most people who are diagnosed with a desmoid tumor are in their teens, 20s, or 30s, and the tumor is more common in women than in men, although experts don’t know why.

Desmoid tumors are a type of soft tissue sarcoma. Unlike most forms of sarcoma, they are not considered cancerous, as they don’t spread to other parts of the body like the lungs, liver, and other organs. They can, however, cause severe pain and other symptoms and may be life-threatening depending on their location.

When surgically removed, desmoid tumors often come back. If surgery is not possible or requires something drastic, like an amputation, a variety of treatments are used. These include hormonal therapies and traditional chemotherapies. Because desmoid tumors are so hard to treat, MSK researchers have focused on new approaches, such as targeted therapies.

After the diagnosis, Kirt first saw a surgeon at MSK. He learned that his tumor was not operable because of its location next to critical areas, like nerves and blood vessels in his neck. His surgeon told him that he might be eligible for a clinical trial. After that, Kirt went to see MSK medical oncologist Mrinal Gounder. Dr. Gounder is an expert in desmoid tumors and other types of soft tissue sarcoma.

The Opportunity to Participate in a Groundbreaking Trial

Kirt was concerned about having chemotherapy, so he was happy to learn that Dr. Gounder was leading a clinical trial for a different kind of drug. The trial was the first to evaluate the use of a pill called sorafenib (Nexavar®) to treat desmoid tumors. Sorafenib is a targeted therapy that was originally developed to treat kidney cancer, but it is also known to block proteins that frequently drive the growth of desmoid tumors. Targeted therapies tend to have fewer side effects than chemotherapy because their activities in cells are more specific.

Kirt was one of 87 people to participate in the trial, the results of which are now being published in the New England Journal of Medicine. The phase III study reported that there was a benefit of more than seven-fold in people who took sorafenib compared with those who didn’t. The drug helped stop tumor growth for an average of nearly two years. Many of the patients had their tumors shrink significantly, including Kirt. People who didn’t get the drug in the first part of the trial were able to later receive it, and many of them benefited as well.

“Until now there hasn’t been a standard way to treat people with desmoid tumors, and there haven’t been many studies on them because it’s such a rare disease,” Dr. Gounder says. “As it’s become increasingly clear that surgery is not the best way to treat these tumors, the need to find different approaches has become more apparent.”

Dr. Gounder’s trial came about in an unconventional way. After he published a paper in 2011 describing a few patients with desmoid tumors who had been given access to sorafenib under a compassionate use program, he was contacted by the Desmoid Tumor Research Foundation, a patient advocacy group. The group’s leaders encouraged him to conduct a phase III trial and assisted with recruiting participants. The trial ultimately included people treated at nearly 25 hospitals in the United States and Canada.

Dr. Gounder says it is now up to Bayer, the company that makes sorafenib, to decide whether to apply to the US Food and Drug Administration to get the drug officially approved for desmoid tumors. Since its approval for kidney cancer, the drug has also been approved for liver and thyroid cancers.

A Return to Normal Life

Kirt is feeling much better since going on the drug, which he still takes. He needs some physical therapy to regain full mobility of his arm and hand, but he no longer has pain and is able to get restful sleep again.

The side effects from the drug have been minor and manageable. They include occasional rashes, high blood pressure, and diarrhea, all of which affected many other people in the trial. He has also experienced tingling in his hands and feet and changes in skin pigmentation.

He has returned to many of his regular activities, including participating in New York City’s annual West Indian Day Parade, of which he has been an active participant for many years. He’s even grateful to be able to do mundane chores again, like cleaning his bathroom.

“It’s by the grace of God that I found MSK and Dr. Gounder,” Kirt says. “It was really by happenstance that I stumbled upon the opportunity to participate in this trial, which has impacted me in such a positive way.”

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What Was MSK’s Role in TCGA, the Groundbreaking Cancer Genomic Study?

Source: Memorial Sloan Kettering - On Cancer
Date: 01/04/2019
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When The Cancer Genome Atlas (TCGA) launched in 2005, the understanding of the genetic changes that drive cancer was much less developed than it is today. TCGA was a joint project funded by the National Human Genome Research Institute and the National Cancer Institute. (The initials of project’s name also represent the four chemical building blocks in DNA: thymine, cytosine, guanine, and adenine.) The study sought to accelerate the field.

In the summer of 2018, after yielding dozens of scientific papers on more than 30 different kinds of cancer, TCGA officially drew to a close. As part of the conclusion of the initiative, investigators published a series of papers on what is called the Pan-Cancer Atlas in April 2018. These studies used genomic data from all of the cancer types that were included in the project. The comprehensive report details how, where, and why tumors form throughout the body.

“TCGA generated the gold standard for how to analyze cancers. It laid the foundation for clinical cancer genomics as we understand it today,” says Memorial Sloan Kettering physician-scientist Marc Ladanyi. In TCGA’s pilot phase, Dr. Ladanyi led one of the project’s seven Cancer Genome Characterization Centers, which was housed within MSK’s laboratories. Each center focused on performing a different kind of analysis. Dr. Ladanyi also made important contributions to the study of several types of cancer within the project.

“Now when we study patients’ tumors, we can go back to these data sets,” he adds. “They help us interpret what we find.”

Laying the Groundwork for Clinical Testing and Research

With data from TCGA, scientists were able to develop tests that help doctors analyze patients’ tumors. These tests include MSK-IMPACT™. This next-generation sequencing-based panel matches patients with the existing therapies or clinical trials that are most likely to benefit them. Data from TCGA suggested to researchers which genes should be included in the test. Eventually, 468 genes were selected in the panel. MSK-IMPACT obtained authorization from the US Food and Drug Administration in 2017.

One important aspect of TCGA is that all of the data from the project were immediately available to other researchers and the public, says MSK computational biologist Nikolaus Schultz. He was involved in TCGA from its earliest stage. “If you look at the number of times that publications from this project have been cited, it illustrates how important its contributions have been,” Dr. Schultz notes.

Funding from TCGA enabled the establishment of the cBioPortal for Cancer Genomics. This online platform allows scientists to review the data through various visualization and analytical tools. The cBioPortal currently hosts more than 200 data sets from large-scale genomic studies, including all of the data from TCGA. Users can probe data across genes, samples, and data types, thereby making important contributions to research not only at MSK but at other centers around the world.

Mesothelioma: Last but Not Least

The final TCGA paper, on malignant pleural mesothelioma, was published in the December 2018 issue of Cancer Discovery. Malignant pleural mesothelioma is a rare cancer. It affects the lining of the chest cavity and is usually linked to asbestos exposure. There are few good treatments for this cancer. Having an improved molecular understanding of what drives it is likely to lead to better therapies.

“We found several things that were quite interesting and novel,” says Dr. Ladanyi, who was a senior author on the study. The researchers performed in-depth analysis of 74 tumor samples. Many of the tumors carried changes that suggested they might respond to types of immunotherapy still under development.

An editorial that accompanied the publication of the paper noted that the study provided the scientific rationale for new targeted therapy options.

MSK’s Prominent Role in Leading and Contributing to The Cancer Genome Atlas

From the beginning, MSK investigators played a leading part in TCGA. Harold Varmus, who was president of MSK at the time TCGA launched, led the National Institutes of Health during much of the Human Genome Project — the effort to sequence the human genome. He was also a member of the working group that recommended the formation of a similarly wide-ranging project that would focus on cancer genes. That project became TCGA.

In addition to running a TCGA Cancer Genome Characterization Center, MSK contributed samples for 21 different kinds of tumors. In all, 7.2% of the more than 10,000 samples that were ultimately studied as part of the project were from MSK. Researchers at MSK also made major contributions to genomic sequencing and analysis efforts for many individual cancers, including ovarian, endometrial, gastric, colorectal, and prostate, as well as sarcoma, glioblastoma, and mesothelioma.

“It’s noteworthy that such a large number of samples were profiled in so many different ways. It helped us better understand all the different kinds of changes that can contribute to cancer,” says Dr. Schultz, who was senior author of the flagship Pan-Cancer Atlas paper related to oncogenic signaling pathways.

“The scope of TCGA may not be replicated again anytime soon,” he concludes. “It’s such a valuable data set that continues to become more and more valuable over time.”

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

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

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

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

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

Bringing Tumors Out of Hiding

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

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

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

Using Data to Confirm a Long-Standing Assumption

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

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

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

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

A Collaborative Project Focusing on Many Cancer Types

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

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

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

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

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Y Cancer? New Research Initiative Focuses on the Role of Genes Found on the Male Chromosome

Source: Memorial Sloan Kettering - On Cancer
Date: 01/22/2019
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Cancer affects men and women differently. Half of all men will be diagnosed with cancer at some point in their lives, compared with one-third of women, according to the American Cancer Society. In addition, men are more likely to die from the disease.

Much of the difference in cancer rates is due to lifestyle factors, especially smoking, which historically has been more common in men. But even some cancers that are not known to be linked to lifestyle tend to appear more often in men. These include kidney cancer and pancreatic cancer.

A team from Memorial Sloan Kettering is undertaking new research to ask why. The focus of their efforts is the most fundamental difference between men and women: the Y chromosome.

“We don’t really understand all the functions of the genes on the Y chromosome. They haven’t been well studied,” says MSK Department of Medicine Chair Philip Kantoff. Dr. Kantoff and his colleagues recently received a grant from the US Department of Defense to study how these genes may contribute to cancer.

A Serendipitous Finding Inspires a New Project

Chromosomes are structures that package long strands of DNA. In humans, each cell nucleus contains 23 pairs, or 46 total chromosomes. Twenty-two of these pairs, called autosomes, are the same in both men and women. The 23rd pair, the sex chromosomes, are different. Women have two X chromosomes; men have one X and one Y chromosome. Scientists have determined that throughout the course of evolution, the Y chromosome has deteriorated and gotten much smaller, although it appears to have stabilized since the rise of early humans.

Beyond their contribution to the formation of male sex characteristics in developing embryos, the genes on the Y chromosome are not well understood. Because the Y is so small, there are only 72 genes on it that code for proteins. By comparison, there are about 800 protein-coding genes on the X chromosome and around 1,000 on most autosomes. “When people write papers describing the landscape of mutations in different types of cancer, they underestimate the importance of Y chromosome genes,” Dr. Kantoff says.

The idea to study the Y chromosome came about thanks to a discovery from Dr. Kantoff’s lab that was reported in July 2018 in the Journal of Clinical Investigation. While studying prostate cancer, his team found that a gene on the Y chromosome called KDM5D determines whether prostate cancer will respond to the chemotherapy drug docetaxel (Taxotere®). Additionally, mutations in the gene in prostate cancer cells were associated with poor overall prognosis.

It wasn’t completely surprising that a connection between cancer and Y chromosome genes would exist. Researchers have observed that the Y chromosome is sometimes completely lost in certain cells, especially in older men and men who smoke. Men whose blood-forming stem cells lack a Y chromosome are known to have a higher risk of leukemia and Alzheimer’s disease and a shorter overall life expectancy.

“I was fascinated when I heard about this project,” says MSK computational biologist Nikolaus Schultz, who is spearheading the data analysis portion of the research. “When we look at tumor samples, the mutations that are reported are for the autosomes and usually the X chromosome. Most of the Y chromosome is unexplored, even though researchers have been focused on cancer genomics for more than ten years.”

The Y chromosome is difficult to study because it has many genes that are similar to one another. “When we find a mutation, it’s hard to know which gene it came from,” Dr. Schultz explains. The repetitive nature of the genes makes computational biology and data analysis an important component of the project.

Taking a Step toward Decoding Gene Function

The first step in the research will be looking at the 72 protein-coding genes on the Y chromosome and determining the role of each one in cancer cell growth. Goutam Chakraborty, an assistant member in Dr. Kantoff’s lab, is leading the efforts to study the function of these genes. He is using CRISPR, a powerful genome-editing tool, to knock out each gene one at a time and see what the effect is when it’s lost. The team plans to start with prostate cancer cells, since that disease is the primary focus of their lab.

Once every gene on the Y chromosome has been studied for its potential role in prostate cancer, the investigators plan to branch out to other cancers. With the help of MSK’s Gene Editing and Screening Core Facility, they will make a full library of every possible mutation that can be tested in cell lines of other cancers. They will then determine the function of the genes in those cancers as well.

“We don’t necessarily expect to find that the same Y chromosome genes are important across different cancers,” Dr. Chakraborty says. “We may find Y genes that are important for prostate cancer but not kidney cancer, or the other way around.”

“I think a lot of people are going to be interested in learning about this research,” Dr. Kantoff concludes. “It’s a cool idea that needs to be explored.”

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CAR T Cells Get an Invisibility Cloak

Source: Memorial Sloan Kettering - On Cancer
Date: 01/29/2019
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Genetically engineered immune cells have shown tremendous promise in treating blood cancers. Indeed, the US Food and Drug Administration approved two such cell therapy treatments for these diseases in 2017. Some people with blood cancer do not have a lasting response from this therapy, however. For solid tumors, results have been comparatively modest so far.

Emerging clinical trial results suggest that one of the most important factors in determining the success of immune cell treatments is how long the cells persist in the body after being infused. This observation led a team of investigators from Memorial Sloan Kettering and other institutions to focus on helping cancer-fighting immune cells stick around longer. Findings from their latest research were published January 29 in the Journal of Clinical Investigation.

“Once the genetically engineered white blood cells are reinfused into a patient’s body, they begin receiving signals that cause them to self-destruct,” says MSK physician-scientist Christopher Klebanoff, the senior author of the paper. “We’ve developed a cloaking technique that wraps the cells in a protective barrier, making them impervious to the signals telling them to die. This enables the immune cells to wage a sustained attack against cancer cells in the body.”

Hiding from Death in Plain Sight

Chimeric antigen receptor (CAR) therapy involves isolating the white blood cells called T cells from people with cancer and inserting a gene so that the cells recognize cancer. After the gene is transferred into the cells, they’re infused back into the patient, where they seek out and attack the cancer.

The body has a natural way to make sure that individual T cells don’t overstay their welcome. A molecular trigger induces them to self-destruct through a process called programmed cell death, or apoptosis. In most situations, this system is an advantage. It prevents immune cells from sticking around too long and causing prolonged inflammation after an infection or from bringing on an autoimmune response. But with specially engineered CAR T cells, it’s useful for them to persevere.

In the current study, the investigators hypothesized that the trigger causing the immune cells to self-destruct was located in the tumor microenvironment. This includes the immune cells and other tissues that are not cancer but help make up a tumor. Using sequencing data from more than 9,000 tumors and 26 kinds of cancer, they identified a likely candidate for that molecular trigger: a gene called FASLG. This gene is enriched in more than three-quarters of both solid tumors and blood cancers. Further analysis revealed that the target of FASLG is found at high levels on the surface of CAR T cells. This explains why the death-inducing trigger would be so effective against them.

Helping Immune Cells Get Where They’re Going

Once the team identified the likely culprit, they set about making a genetic modification that would provide a protective cloak to help the immune cells hide from the kill signal. They tested these modified cells in mouse models of cancer as well as in cell cultures of human cancer. They found that the cloaked T cells persisted longer and were more effective at destroying tumor cells for a longer time period. “In multiple animal models, including models of leukemia as well as solid cancers, this approach led to much stronger cancer regression,” Dr. Klebanoff says.

One of the biggest complications of CAR therapy is a reaction called cytokine release syndrome. It involves a rush of immune activity that can overwhelm the body. Dr. Klebanoff says that the tests in mice indicated that using more persistent T cells for therapy would not increase the severity of this side effect. But to be cautious, the team plans to engineer the cells with a kill switch in case they need to be turned off quickly.

“We are so excited by these preclinical data that we’re already moving ahead and making preparations to do a first-in-human clinical trial,” Dr. Klebanoff says, adding that he hopes the trial will start sometime in 2020. “We envision that this is a potentially generalizable strategy that needn’t be constrained to one type of cancer or one type of CAR T cell. We could apply this cloak to any kind of immune cell therapy to make it work better.”

The MSK researchers collaborated with scientists from the National Cancer Institute at the National Institutes of Health, the University of Pennsylvania, Oregon Health and Science University, the University of Colorado in Denver, and the Medical University of South Carolina.

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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.