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First Targeted Cancer Drug Approved Based on Mutation Rather than Tumor Type

Source: Memorial Sloan Kettering - On Cancer
Date: 11/26/2018
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The US Food and Drug Administration has approved the drug larotrectinib (Vitrakvi®; LOXO-101) for cancers caused by a genetic mutation called a TRK fusion. This groundbreaking targeted therapy is the first to be developed and approved based solely on its effect on a specific genetic change in a tumor, regardless of where in the body the tumor originated.

The drug was approved for tumors that have spread to other parts of the body or that cannot be surgically removed. It is also approved for patients who have no other treatment options or whose cancers have progressed following other treatments.

“With this drug, we are seeing the true potential of precision oncology come to life,” says David Hyman, Chief of the Early Drug Development Service at Memorial Sloan Kettering. Dr. Hyman is the senior author of a study published in the New England Journal of Medicine (NEJM) in February on the effectiveness of the drug.

A Big Step Forward for Precision Medicine

The idea behind precision oncology is that people can be given drugs that target specific mutations driving their cancer’s growth. In other words, the same drug may work against many tumor types.

Until now, investigators have found that the effectiveness of a particular therapy can vary greatly depending on where the cancer started. This is true even in people whose cancers share the same mutation. Individuals with lung cancer may respond to a targeted treatment that has little effect for those with colorectal cancer, even if the tumors have the same genetic change.

This is what makes larotrectinib so exciting.

“In our research, we have not noticed a meaningful difference in response to larotrectinib with one tumor type versus another,” notes MSK medical oncologist Alexander Drilon, the first author of the NEJM paper. “In addition, it has seemed to work equally well in all age groups.”

The fact that the drug was tested in adults and children at the same time is significant. “Cancers driven by TRK fusion mutations are rare,” says Neerav (Neal) Shukla, who led the pediatric trial at MSK. “But because we sequence the tumor genomes of all of our pediatric patients, we are able to identify everyone who might benefit from this drug.”

A Lasting Response

In the NEJM article, Drs. Hyman and Drilon and their collaborators reported that the overall response rate to larotrectinib was 75%. At one year, 71% of the responses were ongoing, with 55% of people in the study remaining progression free, meaning that their disease had not advanced.

The paper combined three studies that involved 55 people in total. Within the group, there were 17 different types of advanced or metastatic tumors — including colon, lung, pancreatic, thyroid, and salivary cancers as well as melanoma and sarcoma — that had TRK fusion mutations. Patients ranged in age from four months to 76 years.

The most common side effects of the treatment were fatigue, dizziness, anemia, and shortness of breath, and they were not severe. The more serious side effects, which were much less common, included fever, diarrhea, sepsis, abdominal pain, dehydration, skin infections, and vomiting.

TRK fusions occur when one of three genes called the NTRK (pronounced “en-track”) genes becomes mistakenly connected to an unrelated gene. This error can lead to uncontrolled cell growth. Although the fusions are rare within most individual cancers, they do affect thousands of people each year.

Analysis with MSK-IMPACT™ can identify which tumors carry TRK fusions. Other similar tumor analysis tests can find these genetic changes as well.

A Milestone in Pediatric Cancer Care

Some of the rare cancers treated with larotrectinib in the study included pediatric diseases, such as infantile fibrosarcoma (a soft tissue tumor found in babies) and secretory breast carcinoma (a type of breast cancer sometimes found in children).

Developing more clinical trials for childhood cancers is the focus of MSK’s Pediatric Translational Medicine Program. This effort aims to build a wealth of early-stage trials focused on taking discoveries made in the lab and bringing them to patients. Working closely with the Early Drug Development Service, the experts in MSK’s Department of Pediatrics are seeking to take full advantage of the latest discoveries in molecular oncology.

“For decades, our pediatric patients have had access to the best care anywhere,” Dr. Shukla says. “Now, with the advances in genetic sequencing, we are coming into an age where we are finding similarities across different kinds of pediatric cancers. For example, we may find that the same mutation is driving both a leukemia and a brain tumor. In addition, because we treat all cancers in all age groups, we are poised to take advantage of these discoveries made in both adults and children.”

MSK’s Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) has also allowed MSK to take a leadership role in developing trials for pediatric cancers. The goal of POETIC, led by hematologic oncologist Tanya Trippett, is to promote the early clinical development of promising therapies for the treatment of children, adolescents, and young adults with cancer and related disorders. This includes basket trials for new targeted agents as well as new drug combinations.

New Opportunities for People with Rare Cancers

The development of larotrectinib was based on the concept of basket trials. These studies test therapies that act against tumors based on their mutations, regardless of where they develop. In addition to having a benefit for many people with common cancers, these kinds of studies also provide an important opportunity to test therapies for rare cancers, which are often underrepresented in clinical trials.

Although many of the studies’ participants had long-lasting responses to larotrectinib, a few became resistant over time when their tumors developed another mutation. The company that makes the drug, Loxo Oncology, has already designed a second drug called LOXO-195 to target this additional alteration. The company is working with investigators at MSK and other institutions to test this drug in people who have stopped responding to larotrectinib. A clinical trial is now open at MSK and is being co-led by Drs. Drilon and Hyman for adult patients. A trial for pediatric patients is being led by Dr. Shukla.

“As we develop more precisely targeted drugs, a large and diverse clinical trials program such as ours, with an integrated effort to characterize patients’ tumors in advance, is key. It allows us to identify an often small group of people for whom a striking benefit may be seen, as in the larotrectinib story,” says Paul Sabbatini, MSK’s Deputy Physician-in-Chief for Clinical Research.

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Personalized Medicine 2.0: MSK Leads the Way in the Study of Drug Resistance in Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2018
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Lung cancer was one of the first cancers that could be targeted by drugs aimed at specific mutations in tumors. Advances in genomic medicine and the molecular analysis of tumors can largely take the credit for this early progress. Unfortunately, that also means that people with lung cancer who were treated with these drugs were among the first to develop resistance. When a treatment that initially works stops working, it is called acquired resistance. Overcoming acquired resistance is one of the most critical challenges in cancer research today.

Memorial Sloan Kettering investigators are at the forefront of studying this problem. They are looking for ways to address acquired resistance. The methods they are considering include combination therapies that attack cancer on multiple fronts at the same time.

“We’re taking personalized medicine to the next level — version 2.0,” says MSK medical oncologist Helena Yu. “It’s not enough anymore to just look for a mutation and give everyone who has the mutation the exact same treatment. Many factors influence how people respond to therapy, and we’re trying to direct treatment in a much more specialized way.”

Is Treatment Resistance Inevitable?

About 20% of lung adenocarcinomas, the most common lung cancer in the United States, are driven by mutations in a gene called EGFR. This type of cancer is often found in people who have never smoked. The first targeted therapy to treat EGFR-driven cancer, called gefitinib (Iressa®), was approved by the US Food and Drug Administration in 2003. Since then, these drugs have become a conventional treatment. As a result, testing for EGFR mutations has become a standard part of diagnosis for advanced lung cancer.

Most people who take these drugs benefit greatly from them. Their tumors shrink measurably, leading to an improvement in some cancer symptoms, such as pain and shortness of breath. In addition, EGFR inhibitors are taken at home as pills and have few side effects compared with chemotherapy.

But the effectiveness of EGFR inhibitors is not long lasting. Although some people respond for years, the average time until the drugs stop working is 12 to 18 months. In some people, the drugs work for only a few months or not at all.

“Not all of the cells within a tumor are the same,” Dr. Yu says. “Even if 99% of the cells respond to an EGFR inhibitor and die off, the ones that don’t die will eventually become dominant and start to take over. Also, because cancer is a living thing, it has the ability to evolve and adapt while being exposed to treatment.”

Finding Genetic Markers for Resistance to Targeted Drugs

When people with lung cancer stop responding to an EGFR inhibitor, their MSK doctors are ready with an arsenal of other treatments. Many patients have a second biopsy. The resistant tumor is then analyzed with MSK-IMPACT™, a test that looks for more than 400 mutations that are known to play a role in cancer.

“Sometimes we find a mutation that wasn’t there the first time we analyzed the tumor. That may suggest that there are other targeted drugs to try,” Dr. Yu says. But other acquired changes, such as changes that don’t affect genes’ sequences, are not detected with MSK-IMPACT.

“Genomic sequencing of tumor tissue is part of the story, but not the whole story,” she adds. “We’re working on additional tests that can detect other kinds of molecular changes.”

MSK investigators are also developing liquid biopsies. These tests could allow doctors to analyze the molecular changes in a tumor with a blood test rather than having to take samples of the tumor from the lung.

Combining Targeted Therapies for a One-Two Punch

MSK already has clinical trials underway to address some of the acquired mutations commonly seen in lung cancer. One clinical trial combines a newerEGFR inhibitor called osimertinib (Tagrisso®) with an experimental drug called AZD6094. This second drug targets a mutation in the gene Met. About 20% of people treated with osimertinib eventually develop a Met mutation.

Another trial is looking at the combination of osimertinib and bevacizumab (Avastin®). Bevacizumab blocks the growth of a tumor’s blood vessels. Earlier research suggested that it is sometimes effective in combination with EGFR inhibitors.

Researchers have found thatEGFR inhibitors can drive some adenocarcinomas to transform into small cell lung cancer, a type of lung cancer that is treated with different drugs. And so another trial is testing osimertinib in combination with the chemotherapy drugs typically used to treat small cell lung cancer. This trial is open to people whose tumors carry genetic mutations that make their cancer more likely to transform. “We’re always trying to stay ahead of the curve,” Dr. Yu says.

Most people with EGFR mutations don’t initially respond to immunotherapy, but they may respond if the cancer develops additional mutations.

Dr. Yu emphasizes that combination treatments have more side effects than using EGFR inhibitors on their own. That is why it is important to carefully identify who is likely to benefit from these more aggressive drugs.

“Unfortunately, we can’t cure stage IV lung cancer as of yet, but the longer we can maintain people on treatments that are effective and have minimal side effects, the better,” she concludes. “We want to be able to stretch out the benefit for each treatment as long as possible while, at the same time, always having more options in our back pocket when we need them.”

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Gut Microbes May Protect People Having Bone Marrow Transplants

Source: Memorial Sloan Kettering - On Cancer
Date: 12/02/2018
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One of the most serious complications of blood stem cell or bone marrow transplants (BMTs), which are used to treat many types of blood cancer, is graft-versus-host disease (GVHD). In this condition, a donor’s immune cells attack the vital organs of a transplant recipient. It can cause death in some cases.

In the past few years, researchers from Memorial Sloan Kettering and other institutions have found that a transplant recipient’s microbiota plays an important role in their survival after a BMT. (The microbiota is the community of organisms, or flora, that live in the body, especially in the gut.) Now, for the first time, investigators have found an association between the health of the microbiota before a transplant and a person’s survival afterward. The findings were presented December 2, 2018, at the annual meeting of the American Society of Hematology (ASH).

“Patients who went into the BMT process with a gut flora that was already disrupted had a higher risk of death after the transplant,” says the study’s senior author, Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “The thing that we keep coming back to is that preserving the commensal flora in the microbiome is good for transplant patients.” Commensal flora are microbes that live in the body without causing disease. In some people, they may be beneficial.

The Forgotten Organ

Many of those who study the gut microbiota refer to it as the “forgotten organ.” It can have a huge impact on someone’s health. But scientists are still learning what makes it healthy or damaged, and what can be done to correct that damage.

“There are as many bacterial cells as there are human cells in our bodies,” says first author Jonathan Peled, an MSK medical oncologist who specializes in BMTs. “In addition, these bacteria are really important for the way our bodies function.”

“Before someone has a BMT to treat their cancer, we do a lot of screening tests to make sure they are otherwise healthy. We look at things like their heart, lung, and kidney function,” says Dr. van den Brink, who runs a lab in the Sloan Kettering Institute’s Immunology Program. “This study suggests that we should also screen the microbiota. If we find out that it’s in bad shape, we could do something to repair it.”

Dr. Peled adds, “This study opens the door to repairing the microbiota in the pretransplant period. Because this is a time when we’re usually not in a rush to move forward with treatment, it’s also a good time to look for ways to do this before continuing the transplant.” Interventions that could improve the health of the microbiota include changes to diet, using or avoiding certain antibiotics, and fecal transplants of healthy gut microbes.

MSK doctors are already conducting research on fecal transplants that make use of a patient’s own stool. The stool is preserved before the BMT and given back to the patient after the process. A recent study led by MSK physician-scientists Eric Pamer and Ying Taur found that fecal transplants are effective in restoring the balance of healthy microbes that is lost during a BMT. Researchers also plan to study the safety of providing fecal transplants with material from a healthy donor. Donor stool may ultimately prove to be a better option for people who come to a BMT with a microbiota that’s damaged.

Throwing Off the Healthy Balance of the Gut

In the analysis presented at ASH, the researchers studied 1,922 stool samples from 991 people having allogeneic BMTs. “Allogeneic” means the blood or marrow stem cells come from a donor. (In the other type of transplant, an autologous procedure, a patient’s own blood cells are stored before treatment and later infused back into the body.) The people were treated at MSK and three other hospitals. The samples were evaluated for a range of bacteria types, including commensal strains and those that are known to cause disease.

The investigators found that, on average, the people about to have BMTs had decreased diversity of bacteria in their guts. They also found that different strains were dominant, compared with healthy volunteers. This was a new finding, but it was not surprising. Most people with blood cancer who need transplants have gone through months or years of treatment with chemotherapy drugs and antibiotics that throw off the normal, healthy balance.

Diversity in the microbiota is important because commensal bacteria help keep more dangerous strains in check. Previous studies have also shown that certain commensal strains actually provide specific benefits for people having transplants. Some strains release substances that protect the walls of the intestines, for example.

In the current study, only 10 to 30% of patients had what researchers considered a balanced gut flora before their transplant. The more the ecology of the microbiota was disrupted, the more likely it was that patients had fatal complications from GVHD. However, the researchers emphasize that this study showed only an association, not direct causation.

A Study with a Broad Geographic Scope

Investigators at three other transplant centers also participated in the research and contributed patient samples: Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Different locations were included because other research has shown that microbiotas across geographic regions vary widely. Factors like environment and diet are thought to play a role.

All of the samples were analyzed in MSK labs, Dr. Peled says, improving the validity of the results across the sites.

“One of the main findings of this study was that the injury patterns that we saw in people’s microbiotas were comparable across geography,” he concludes. “This suggests that if we find interventions to correct these imbalances at one center, they will also apply to people being treated in other parts of the world.”

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Sessions at Annual Breast Cancer Conference Focus on Prevention and Treatment of Lymphedema

Source: Memorial Sloan Kettering - On Cancer
Date: 12/07/2018
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Cancer-related lymphedema is one of the most challenging long-term side effects that can occur after cancer surgery. This chronic, sometimes severe swelling in an arm or leg can greatly impact a person’s quality of life. It often leads to pain as well as difficulty using the affected limb.

At the annual San Antonio Breast Cancer Symposium, held December 4 to 8, two educational sessions focused on the prevention and treatment of lymphedema. Both talks featured investigators from Memorial Sloan Kettering.

A Distressing but Common Complication

Lymphedema often strikes after lymph nodes are removed during cancer surgery. About one-third of women treated for breast cancer who have all of the lymph nodes in their armpit removed — an operation called complete axillary dissection — will experience some degree of lymphedema in the affected arm. Lymphedema of the leg can occur in people treated for cancer in the abdominal area who have lymph nodes in the groin removed.

Monica Morrow, Chief of the Breast Service in MSK’s Department of Surgery, moderated a session with experts from MSK and two other institutions on the best ways to manage the treatment of underarm lymph nodes in people being treated for breast cancer.

“It’s important to focus on ways to reduce the risk that patients will later develop lymphedema,” Dr. Morrow says. “At the same time, removing the cancer and making sure that it doesn’t come back remains our primary focus.”

Evolving Treatment Approaches

For decades, people undergoing surgery for breast cancer had all the armpit lymph nodes on the affected side of the body removed. That’s because these lymph nodes were one of the first places that cancer cells traveled when they left the breast, and that removal would impede further spread.

In the 1990s, experts began to use a technique called sentinel lymph node biopsy. Surgeons at MSK, led by Hiram Cody, played a key role in establishing the clinical utility of this approach. The technique uses a combination of two tracers, which signal where they have traveled in the body. This dual-tracer approach involves injecting both a dye and a radioactive compound into the breast.

Doctors can inject the tracers and follow the natural flow of lymphatic fluid out of the breast. This allows them to see the first few nodes to which the fluid travels — dubbed the sentinel nodes. If the sentinel nodes are clear of cancer, there is no need to remove the remaining lymph nodes. This technique is now standard at hospitals around the world.

In the past several years, advances in chemotherapy, hormone therapy, and targeted drugs have further changed breast surgery. In particular, people with certain subtypes of breast cancer increasingly receive cancer drugs before surgery to shrink the tumor and make it easier to remove. This is called neoadjuvant therapy. These drugs can also knock out cancer in the lymph nodes, reducing the need for complete axillary dissection and, in turn, reducing the risk of lymphedema.

Finding the Sentinel Nodes

The annual conference in San Antonio is attended by researchers and physicians from around the world who want to learn about the latest in diagnosis, prevention, and treatment for breast cancer. MSK surgeon Andrea Barrio conducted an educational session on the latest methods for studying the sentinel nodes in people who have been treated with neoadjuvant chemotherapy and determining whether additional nodes need to be removed.

She presented research that looked at patients who had cancer in their lymph nodes before neoadjuvant therapy who had a sentinel lymph node biopsy after receiving drug treatment. The study found that when three or more sentinel nodes were able to be identified and were found to be clear of cancer, these people no longer needed to have the rest of their lymph nodes removed, even though those nodes previously had cancer. (For a complete axillary node dissection, usually between 20 and 40 nodes are removed.)

“It’s important to remove at least three sentinel nodes that have been identified with two different tracers,” she says. “Otherwise, some cancers may be missed.”

She stressed the importance of using established processes for identifying sentinel nodes because imaging techniques like ultrasound and MRI are not reliable in determining whether nodes are cancerous.

“The good news is that lymph nodes do respond to neoadjuvant chemotherapy, reducing the need for more extensive surgery in many people,” she says.

Treatments Based on Underlying Mechanisms

In another session, Babak Mehrara discussed the latest research on treating lymphedema in cases where removal of all of the lymph nodes is necessary to control the cancer.

Dr. Mehrara, Chief of MSK’s Plastic and Reconstructive Surgical Service, discussed the history of this research, including drug trials that have attempted to reduce lymphedema, as well as what scientists know about the underlying mechanisms of this condition.

He does research in the lab as well as in the clinic, hoping to find the most effective lymphedema treatments. One potential solution involves a topical cream, which appears to reduce the swelling from lymphedema in mice. He hopes to begin clinical trials with this drug soon.

“This is an exciting time for lymphedema research,” Dr. Mehrara concludes. “There have been advances in multiple fronts, thanks to new surgical and medical therapies that are coming together.”

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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.