Study Focuses on a Different Kind of Liquid Biopsy to Detect Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 08/13/2020
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Because cancer is easier to successfully treat when it’s caught early, a major goal in cancer research is to develop new ways to find tumors at early stages, before they start to spread. One approach that’s being studied are liquid biopsies. These tests aim to find and diagnose cancer anywhere in the body by detecting biomarkers — materials that tumors shed into the bloodstream — in a blood sample.

In a study published August 13, 2020, in Cell by a team of collaborators from Memorial Sloan Kettering and Weill Cornell Medicine, researchers report that tiny packages of materials released by tumors, called EVPs (extracellular vesicles and particles), may serve as biomarkers for detecting a number of different types of cancer in the early stages.

“One of the holy grails in cancer medicine is to diagnose an early cancer in a patient based on a blood test,” says MSK surgeon William Jarnagin, Chief of the Hepatopancreatobiliary Service and co-senior author of the study. “This research is a proof-of-principle study; much more work is needed before it can be used as a screening tool. But ultimately, it would be fantastic if we could use this approach to find cancer in someone before they had symptoms.”

A Different Type of Biomarker

Much of the previous work on liquid biopsies has focused on the detection and analysis of cancer genes that are released by cancer cells into the blood. Some of these liquid biopsies, including MSK-ACCESS, are already approved as a tool for monitoring treatment and matching patients who have cancer with the appropriate targeted therapy. Using liquid biopsies as a screening tool to detect previously undiagnosed cancer is still experimental.

The new study focuses not on analyzing genes but instead examining proteins contained in EVPs. David Lyden, a physician-scientist at Weill Cornell and the paper’s other senior author, studies EVPs in his lab and is a pioneer in the field. He has found that tumors may release EVPs as a way to prepare other parts of the body to receive cancer cells when they spread.

The researchers say that one potential advantage of focusing on proteins in EVPs rather than cancer genes is that it allows them to also characterize different types of cells found in the area around a tumor — called the tumor microenvironment. In addition, it could help them detect changes in other tissues, such as immune organs, which also contribute to EVP proteins that are seen in the blood.

Using Machine Learning to Process Data

The current study looked at whether EVPs might be useful in screening. It employed blood and tissue from people who were known to have cancer as well as some samples from cell lines and mouse models. The research included samples from 18 different cancers, including breastcolon, and lung, which came primarily from MSK. There was a comparison group of samples from people who didn’t have cancer.

A computational biology approach was used to match particular EVP protein signatures with certain types of cancer. “The amount of information that comes from this kind of study is monumental — it’s a huge amount of data,” Dr. Jarnagin says. “You really need high-throughput computer programs and machine learning to be able to sort through it all.”

Once the computing method was established, the team found that the computer could identify different types of cancer from the samples with a sensitivity of 95% (meaning that it found the cancer in 95% of cases) and a specificity of 90% (meaning that 10% of the cancers it identified turned out to be false positives).

“Even if this test became standard, we still would have to do CT and MRI scans to confirm where the tumor was located,” Dr. Jarnagin says. “But if you use a blood test to find who might be at risk of having a certain type of cancer, it would be a huge advance because we could target investigations to these high-risk patients.”

He adds that if this type of liquid biopsy is shown to be effective for clinical use, it’s likely to also be useful in monitoring the treatment response in people already diagnosed with cancer. It may also be a good tool to monitor people after treatment to determine whether their cancer has come back when it’s still too small to show up on a scan.

Next Steps for Validating Findings

Using liquid biopsies to detect cancer is a much bigger challenge than using them to monitor cancers that are already known. For now, the team is focused on the next step: validating that their lab findings with EVPs will work with additional patients. Part of the validation process will involve testing this method in those who don’t have cancer but have an increased risk due to a strong family history or a known mutation in one of the BRCA genes, for example. Standard diagnostic methods will be used as a comparison in the validation process.

Dr. Jarnagin explains that in the future, liquid biopsies are likely to be especially important for diagnosing cancers that don’t currently have established screening methods, including liver and pancreatic cancers.

“These cancers are rarely detected early and treating them as soon as possible could result in better patient outcomes,” says Dr. Lyden, who is a member of the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.

Promising Results from the First-Ever Trial of a Drug that Blocks Cancer Gene KRAS

Source: Memorial Sloan Kettering - On Cancer
Date: 09/20/2020
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Targeted therapies aim to block the activity of genes that cause cancer, providing a direct attack on tumors while sparing healthy cells. Identifying genes that trigger tumor growth is only the first hurdle to developing targeted drugs — just because investigators know a gene may cause cancer doesn’t mean they can prevent it from wreaking havoc.

The cancer gene KRAS (pronounced “kay-rass”) is a case in point. It’s been studied for about 40 years and is known to be responsible for many of the most common cancers. This includes about one-quarter of lung cancers and between one-third and one-half of colon and rectal cancers. Until recently, however, the KRAS protein was considered an “undruggable” target.

On September 20, 2020, in the New England Journal of Medicine (NEJM), investigators reported results from CodeBreak 100, the first-ever clinical study of a drug that directly targets KRAS. In this international phase 1 trial, researchers found that a drug called sotorasib (AMG 510) slowed or stopped cancer growth in many people with advanced cancer that had a KRAS mutation. The investigators say much more research is needed to determine how to best use this drug, but this trial is a significant first step.

“Sotorasib is not a cure, but this study is the first to crack KRAS in a clinically meaningful way,” says Memorial Sloan Kettering medical oncologist Bob Li, a senior investigator and corresponding author of the study. “It’s an important step forward, but it’s not yet a home run.”

Shutting Down Cancer Growth

The challenge in targeting the KRAS gene comes from the uncommon shape of the KRAS protein. Most proteins have a lumpy, irregular shape, with many clefts and pockets where a drug can wedge in. When this happens, a drug can act as a key, locking up a protein and shutting down its activity. “By contrast, the KRAS protein is quite round and smooth,” Dr. Li explains. “There’s no lock-and-key approach.”

In 2013, researchers at the University of California, San Francisco, reported there may be a way in: They found a small pocket in a version of the mutant KRAS protein, called KRAS-G12C, and designed a drug to fit into this pocket when it was open.

In 2016, MSK physician-scientists Piro Lito and Neal Rosen published a study that built on this work. They described the trapping mechanism that enables the new class of drugs to shut down the growth of cancer cells driven by the KRAS-G12C mutation.

“When one of these drugs goes in the protein’s pocket, it traps KRAS-G12C in its ‘off’ state,” says Dr. Lito, who is also a senior author on the new NEJM paper. “The protein can’t wake up, and the tumor cell cannot grow.”

Sotorasib, which was developed by investigators at the biopharmaceutical company Amgen, is an improved and more potent KRAS-G12C inhibitor. Combining their respective strengths in phase 1 clinical trial development and translational science, Drs. Li and Lito partnered with Amgen to bring the first-in-class KRAS-G12C inhibitor sotorasib to patients.

Promising Findings from an International Trial

In the trial for sotorasib, 129 people whose tumors had KRAS-G12C received the drug, which is taken as a pill. Fifty-nine of them had non-small cell lung cancer, 42 had colorectal cancer, and 28 had other types of tumors. All of the study participants had disease that spread to other parts of the body; they already had received an average of three previous treatments. The trial included people treated at more than two dozen hospitals around the world.

Among those 59 people with lung cancer, seven patients did not respond and 52 experienced disease control (which means that their tumors either stopped growing or shrank). In that group of 52, 19 patients had their tumors shrink substantially. The average time until the disease got worse was about six months. “That level of response is significant for this population of patients because most of them have exhausted other treatment options.” Dr. Li explains.

A little more than half of the people in the trial (73 patients) had some side effects, but only 15 of them had significant side effects. All but one patient were able to safely continue the drug when the side effects resolved, and no one died from side effects. “Because the drug is selective for this specific KRAS mutation, it was well tolerated by patients,” Dr. Lito says. “It only binds to and inhibits the mutated form of the protein in cancer cells. This is important because it enables high doses of the drug to be safely administered.”

Next Steps for Research

Responses for other types of cancer — including colorectal cancer, as well as pancreaticendometrial (uterine), and appendiceal cancers and melanoma — were not as good as they were for lung cancer. But some patients with those other cancers did benefit with substantial tumor shrinkage. The investigators plan to study why sotorasib appears to work better in some types of cancer than it does in others, even when the cancers have the same mutated protein. Additional trials are already underway to continue studying sotorasib, both alone and in combination with other drugs.

Research on how to block KRAS is continuing in the laboratory as well. In January 2020, Dr. Lito’s lab published a study that looked at new approaches for combining KRAS inhibitors with other drugs. “We’re taking what we’ve learned in patients back to the bench to continue developing new treatments,” Dr. Lito says. “We’re already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.”

The results from this clinical trial are also being presented at the European Society for Medical Oncology 2020 Virtual Congress.

T Cell Therapies Offer a New Way to Treat Gynecologic Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2020
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The American Cancer Society estimates that more than 113,000 people in the United States are diagnosed with a gynecologic cancer every year. Memorial Sloan Kettering is a leader in treating people with these cancers, which include tumors of the cervixovaries, and uterus.

Among the new treatments being developed for gynecologic cancers are a type of immunotherapy called T cell therapies. These are treatments in which a patient’s own immune cells are modified to recognize and attack cancer cells. MSK doctors and scientists were the first to develop these treatments for leukemia and lymphoma. Now, many researchers are focused on further advancing this approach to make it effective against solid tumors.

“For certain blood cancers, cellular therapy can be remarkably potent, perhaps even curative,” says physician-scientist Christopher Klebanoff, whose lab is focused on developing new cell therapy approaches. One challenge of immunotherapy is directing the immune cells only to tumors so they don’t cause injury to healthy tissues.

Treating Cancer with CARs and TRUCKs

The most well-known cell therapy is chimeric antigen receptor (CAR) T therapy, which has shown success in treating certain blood cancers. CAR T modifies a patient’s immune cells (T cells) so they can recognize a protein (called an antigen) on the outer surface of cancerous cells. These supercharged T cells then seek out and destroy the cancer. For many cancers, especially cancers originating from a solid organ, the antigen isn’t quite as easy for the T cell to find, making cell therapies more challenging to develop.

This has led to a related tactic called T cell receptor (TCR) therapy, in which T cells are engineered to detect antigens on the inside of the cancer cell. “The ability to do this is one of the greatest tricks in biology,” Dr. Klebanoff says. “That is, how can you allow an immune cell to look inside other cells to detect if the proteins inside are normal or abnormal?”

As it turns out, the way this “looking” works is actually indirect: As part of normal cellular operations, proteins eventually get broken down and recycled to make new proteins. One step in this recycling process displays protein fragments on the surface of cells — allowing them to be seen by engineered T cells. TCR therapies are designed to take advantage of this natural process that the immune system uses to survey tissues in the body.

Some of the newest cell therapies known as TRUCKs — T cells redirected for antigen‐unrestricted cytokine‐initiated killing — work by combining the antitumor abilities of CAR T or TCR therapy with a molecule called a cytokine. The cytokine recruits another wave of immune cells to the tumor.

A Personalized Approach to Cancer Care

Medical oncologist Roisin O’Cearbhaill is the research director for the Gynecologic Medical Oncology Service and a leader in studying new cell therapies and immunotherapy approaches for treating gynecologic cancers, including a treatment for cervical cancer and other tumors caused by the human papillomavirus (HPV). “We’re building up our clinical trial program at MSK so that we will be able to offer more cellular therapies for patients with gynecologic cancers,” she says.

“With cell therapies, we use our knowledge about specific molecular and genomic properties of the patient’s cancer,” Dr. O’Cearbhaill explains. “And we may also use certain markers on their blood cells in order to get the best possible match for a targeted therapy for that individual patient.”

“For each of our patients, we take a very personalized approach to match the best possible medicines, including experimental medicines offered in clinical trials, with the patient’s disease,” Dr. Klebanoff says. “I’m a big believer in the concept of partnership and shared purpose, and this is how we work in collaboration with our patients. We have a shared purpose to try to improve things both for them and for others with similar diseases in the future.”

Clinical Trials Offering Cell Therapies for Gynecologic Cancers

MSK currently has a number of clinical trials that are examining this approach.

  • Dr. O’Cearbhaill is co-leading a phase I study with Dr. Klebanoff that is assessing the safety and effectiveness of using a TCR therapy called KITE-439 to treat cancers caused by a strain of HPV called HPV 16. The majority of cervical cancers as well as many cancers of the mouth, throat, vagina, vulva, penis, and anus are associated with HPV 16. In this study, a patients’ immune cells are modified to recognize and attack tumor cells that contain HPV 16.
  • The doctors are also co-leading a phase I trial for a cell therapy called KITE-718, which targets cancers containing MAGE-A3/A6, a protein found in some ovarian and cervical cancers as well as other kinds of cancer.
  • To study another treatment for ovarian cancer and cancers of the fallopian tubes and the peritoneal cavity (the lower abdomen), Dr. O’Cearbhaill is leading a phase I trial for a CAR T therapy that targets a protein called MUC16, which is made by many of these tumors. MUC16, also called CA125, is best known as a biomarker used to monitor treatment for ovarian cancer.
  • Dr. O’Cearbhaill is also leading a phase I/II trial for a TRUCK drug called TC-210, which is being tested in combination with chemotherapy. This cell therapy targets tumors that make a protein called mesothelin, which is found in several cancers, including some ovarian tumors.

Imaging and Artificial Intelligence Tools Help Predict Response to Breast Cancer Therapy

Source: Memorial Sloan Kettering - On Cancer
Date: 10/23/2020
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For people with breast cancer, biopsies have long been the gold standard for characterizing the molecular changes in a tumor, which can guide treatment decisions. Biopsies remove a small piece of tissue from the tumor so pathologists can study it under the microscope and make a diagnosis. Thanks to advances in imaging technologies and artificial intelligence (AI), however, experts are now able to use the characteristics of the whole tumor rather than the small sample removed during biopsy to assess tumor characteristics.

In a study published October 8, 2020, in EBioMedicine, a team led by experts from Memorial Sloan Kettering report that — for breast cancers that have high levels of a protein called HER2 — AI-enhanced imaging tools may also be useful for predicting how patients will respond to the targeted chemotherapy given before surgery to shrink the tumor (called neoadjuvant therapy). Ultimately, these tools could help to guide treatment and make it more personalized.

“We’re not aiming to replace biopsies,” says MSK radiologist Katja Pinker, the study’s corresponding author. “But because breast tumors can be heterogeneous, meaning that not all parts of the tumor are the same, a biopsy can’t always give us the full picture.”

Harnessing the Power of Machine Learning

The study looked at data from 311 patients who had already been treated at MSK for early-stage breast cancer. All the patients had HER2-positive tumors — meaning that the tumors had high levels of the protein HER2, which can be targeted with drugs like trastuzumab (Herceptin®). The researchers wanted to see if AI-enhanced magnetic resonance imaging (MRI) could help them learn more about each specific tumor’s HER2 status.

One goal was to look at factors that could predict response to neoadjuvant therapy in people whose tumors were HER2-positive. “Breast cancer experts have generally believed that people with heterogeneous HER2 disease don’t do as well, but recently a study suggested they actually did better,” says senior author Maxine Jochelson, Director of Radiology at MSK’s Breast and Imaging Center. “We wanted to find out if we could use imaging to take a closer look at heterogeneity and then use those findings to study patient outcomes.”

The MSK team took advantage of AI and radiomics analysis, which uses computer algorithms to uncover disease characteristics. The computer helps reveal features on an MRI scan that can’t be seen with the naked eye.

Using an Algorithm to Personalize Treatment

In this study, the researchers used machine learning to combine radiomics analysis of the entire tumor with clinical findings and biopsy results. They took a closer look at the HER2 status of the 311 patients, with the aim of predicting their response to neoadjuvant chemotherapy. By comparing the computer models to actual patient outcomes, they were able to verify that the models were effective.

“Our next step is to conduct a larger multicenter study that includes different patient populations treated at different hospitals and scanned with different machines,” Dr. Pinker says. “I’m confident that our results will be the same, but these larger studies are very important to do before you can apply these findings to patient treatment.”

“Once we’ve confirmed our findings, our goal is to perform risk-adaptive treatment,” Dr. Jochelson says. “That means we could use it to monitor patients during treatment and consider changing their chemotherapy during treatment if their early response is not ideal.”

Dr. Jochelson adds that conducting more frequent scans and using them to guide therapies has improved treatments for people with other cancers, including lymphoma. “We hope that this will get us to the next level of personalized treatment for breast cancer,” she concludes.

Why Do Certain Chemotherapies Increase the Likelihood of Blood Cancer?

Source: Memorial Sloan Kettering - On Cancer
Date: 10/26/2020
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In recent years, improvements in cancer therapy have led to a significant increase in cancer survivorship. Experts estimate that by 2022, the United States will have 18 million cancer survivors, but a subset of those survivors will have long-term health problems to be addressed.

One rare complication of cancer treatment is the development of a secondary blood cancer — therapy-related acute myeloid leukemia or myelodysplastic syndrome. These blood cancers are very aggressive and do not respond well to treatment. Historically, doctors thought that cancer treatments such as chemotherapy and radiation caused an accumulation of mutations in the blood that led to these therapy-related cancers.

In recent years, however, researchers have found that these mutations in the blood can also occur spontaneously with increasing age. This phenomenon is called clonal hematopoiesis (CH), and it’s found in 10 to 20% of all people over age 70. The presence of CH increases the risk of developing a blood cancer. Using data from MSK-IMPACTTM, Memorial Sloan Kettering’s clinical genomic sequencing test, researchers have shown that CH is also frequent in cancer patients.

In a study published in Nature Genetics on October 26, 2020, MSK investigators sought to understand the relationship between CH in cancer patients and the risk of later developing a treatment-related blood cancer. The study included data from 24,000 people treated at MSK. The researchers found CH in about one-third of them.

“Because many people treated at MSK have genetic testing done using MSK-IMPACT, we have this amazing resource that allows us to study CH in cancer patients at a scope that nobody else has been able to do,” says physician-scientist Kelly Bolton, lead author of the study.

Decoding Genetic Changes Specific to Cancer Treatment

Focusing on a subset of patients on whom they had more detailed data, the investigators observed increased rates of CH in people who had already received treatment. They made specific connections between cancer therapies such as radiation therapy and particular chemotherapies — for example certain platinum drugs or agents called topoisomerase II inhibitors — and the presence of CH.

Unlike the CH changes found in the general population, the team found that CH mutations after cancer treatment occur most frequently in the genes whose protein products protect the genome from damage. One of these genes is TP53which is frequently referred to as “the guardian of the genome.”

The work was supported by the Precision Interception and Prevention (PIP) program at MSK, a multidisciplinary research program focused on identifying people who have the highest risk for developing cancer and improving methods for screening, early detection, and risk assessment.

The authors embarked on a three-year study to understand the relationship between CH and cancer therapy. For this part of the research, more than 500 people were screened for CH when they first came to MSK and then at a later point during their treatment. One finding from the study was that people with pre-existing CH whose blood carried mutations related to DNA damage repair such as TP53, were more likely to have those mutations grow after receiving cancer therapies, when compared to people who did not receive treatment.

“This finding provides a direct link between mutation type, specific therapies, and how these cells progress towards becoming a blood cancer,” says Elli Papaemmanuil of MSK’s Center for Computational Oncology, one of the two senior authors of the study. “Our hope is that this research will help us to understand the implications of having CH, and to begin to develop models that predict who with CH is at higher risk for developing a blood cancer.”

For a subset of patients with CH who developed therapy-related blood cancers, the researchers showed that blood cells acquired further mutations with time and progressed to leukemia. “We are now routinely screening our patients for the presence of CH mutations,” adds computational biologist Ahmet Zehir, Director of Clinical Bioinformatics and the study’s co-senior author. “The ability to introduce real-time CH screening for our patient population has allowed us to establish a clinic dedicated to caring for cancer patients with CH. As we continue to study more patients in the clinic, we expect to learn more about how to use these findings to find ways to detect treatment-related blood cancers early when they may be more treatable.”

Applying Findings to Future Treatments

In the future, this research may help to guide therapy by indicating whether some chemotherapy drugs are more appropriate than others in people with CH. People who are at a high risk of developing a treatment-related leukemia also may benefit from a different treatment schedule. “We hope that this research will allow us to ultimately map which CH mutations a person has and use that information to tailor their primary care and also mitigate the long-term risk of developing blood cancer,” Dr. Papaemmanuil says.

“We explored this in collaboration with investigators from the National Cancer Institute, Dana-Farber Cancer Institute, Moffit Cancer Center, and MD Anderson, and showed that such risk-adapted treatment decisions could achieve significant reduction of leukemia risk, without affecting outcomes for the primary cancer,” Dr. Bolton adds.

The investigators also hope to use the data from this study to develop better methods for detecting CH-related blood cancers when they first begin to form — and potentially to develop new interventions that could prevent CH from ever progressing to cancer. “We’re excited about the idea of continuing to grow and expand the CH clinic as part of the integrated vision of PIP,” says physician-scientist Ross Levine, who leads MSK’s CH clinic and is a member of the Human Oncology and Pathogenesis Program.

“In addition to continuing to follow people who are at the highest risk of developing a secondary cancer, we want to continue to use the clinic as a vehicle for studies like this,” he adds. “Our long-term goal is to move toward therapeutic interventions and preventing disease in a way that we’ve never been able to do before.”

Single-Cell Study Sheds Light on Leukemia’s Family Tree

Source: Memorial Sloan Kettering - On Cancer
Date: 10/28/2020
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When Memorial Sloan Kettering postdoctoral fellows Linde Miles and Robert “Bobby” Bowman began working on a new research project in May 2019, they didn’t know how massive a task it would be.

Now, their undertaking — the biggest study ever to examine the genetic causes of leukemia at the level of individual cells — is being published October 28, 2020, in Nature. The findings reveal how a series of mutations in normal blood cells can lead to them eventually becoming cancerous. The study also shows how these mutations accumulate as the disease progresses.

“This single-cell approach gave us new insights into the journey that blood cells take on their path to becoming leukemia,” says physician-scientist Ross Levine, senior author of the paper and a member of the Human Oncology and Pathogenesis Program. “Our hope is that this glimpse into how and why leukemia develops will open up new areas of research in early diagnosis and treatment.”

Learning about Cancer, Cell by Cell

Traditional genomic analysis of cancers — including MSK-IMPACTTM, a test that looks for mutations in 468 genes in patients’ tumors — uses what is called bulk sequencing. That means that it surveys the mutations that are present across all the cells in a tumor sample.

By contrast, the approach used in this study deciphered the mutations found in every single cell. The samples were obtained from 146 people who were treated at MSK for acute myeloid leukemia (AML), as well as those with two blood conditions that can lead to AML: clonal hematopoiesis and a blood cancer called myeloproliferative neoplasms. The analysis yielded data on nearly 750,000 unique blood cells.

“Instead of just broadly profiling all leukemias, we wanted to be able to ask pointed biological questions,” Dr. Bowman explains. “Understanding how these mutations work together will give us insight into their biological function.”

One aspect the study focused on is what’s called the clonal architecture of the cancer. This is the order in which the mutations occur. Dr. Levine compares it to a family tree, with each branch taking the cells in a different direction — some remain healthy and others become aggressive cancer.

“Trying to figure out the clonal architecture is like looking at a maze,” says Dr. Miles, a biochemist who was recently awarded a Marie-Josée Kravis Women in Science Endeavor (WiSE) fellowship. “It required a lot of work to begin to make sense of what we found and begin to detect patterns.”

A United Effort

Dr. Miles spent the summer and fall of 2019 sequencing patient samples. She was able to complete five or six samples a day. When she finished, the amount of data that had been generated was overwhelming.

As a computational biologist, Dr. Bowman’s role was to figure out which mutations occurred together in the same cells and determine the order in which they appeared. At one point, he decided to consult his younger brother, Michael Bowman, a PhD student in mechanical engineering at the Colorado School of Mines.

Michael helped the MSK team develop the right mathematical formulas with an approach he normally uses to study robot behavior. Eventually he came to visit New York City, and spent much of the time that was supposed to be a vacation pouring over data with his brother, Dr. Miles, and Dr. Levine. Michael Bowman is a co-author on the paper.

“This was very much a team effort, and Ross was involved at every step, too,” Dr. Miles says. “It’s probably the most collaborative project I’ve ever worked on.”

Building a New Playbook for Cancer Research

Dr. Levine says the goal of this work is to take the new information about the clonal architecture back to the lab and use it to create more accurate disease models that can then be deployed to develop new diagnostic methods and potentially test new drugs.

“The analogy I like to use is that cancer is like the Death Star in Star Wars,” he says. “You can’t take it apart until you know where the critical nodes are — where the cells are most vulnerable to attack.”

He also explains that, historically, leukemia research has led to methods that can be used to study many other cancers. “Because we can get leukemia samples with a simple blood draw, they’ve always been more accessible,” he says. “Our hope is that similar single-cell studies in solid tumors and other blood cancers will follow and that our work will provide a playbook on how to approach these studies with other kinds of cancer.”

Working It Out: Does Exercise Boost the Effectiveness of Melanoma Treatment?

Source: Memorial Sloan Kettering - On Cancer
Date: 11/05/2020
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Exercise is not just an important part of life for Memorial Sloan Kettering physician-scientist Allison Betof Warner — it’s an important part of her research.

Dr. Betof Warner, a medical oncologist who specializes in treating people with melanoma, is also a member of MSK physician-scientist Jedd Wolchok’s lab. There, she studies the effects of exercise on melanoma and other cancers using mouse models. She hopes to eventually apply her findings to her patients.

In an interview, she talked about her work.

How did you get interested in studying the connection between exercise and cancer outcomes?

I’m a lifelong athlete. I was a competitive gymnast for many years, including as a Division 1 student-athlete in college. When I got to medical school [at Duke University School of Medicine], I became a marathon runner and CrossFit athlete. I competed in the CrossFit Games (the world championships of the sport) and have coached CrossFit since 2010.

I was also working on a PhD in cancer biology. I started out studying the structure of tumor blood vessels. Then I heard a talk from Lee Jones about exercise and cancer. [Dr. Jones, who was then at Duke, now leads MSK’s Exercise Oncology Service, which is studying how exercise affects cancer outcomes through both lab research and clinical trials.]

Lee was using mice to study whether exercise could help improve outcomes in breast cancer. He co-mentored me during my PhD, and we published a study that showed exercise improves the quality of the blood vessels going to a tumor, which, in turn, makes chemotherapy more effective.

How has the view of exercise and cancer changed?

When I started my PhD research about fifteen years ago, some people were concerned that if you improved the structure of the blood vessels in a tumor, it might help the tumor grow faster or make it easier to spread. Our research in mice showed that this is not a concern. We still haven’t shown that patients experience all the benefits we’ve seen in mice, but collectively the data suggest that exercise is not harmful — either in melanoma or any other kind of cancer.

Research has demonstrated that exercise has many benefits for people with cancer, including reducing cancer-related fatigue. It also provides psychological benefits by improving overall mood and sense of well-being.

What are you studying now?

My current research has been looking at mice running on a treadmill to see how it affects the immune system — both the immune cells coming into the tumor and those circulating in the body. We’re still learning, but early work has suggested that exercise slows the growth of melanoma tumors in mice and that it does so by acting on the immune system.

I first became interested in this topic when I was a medical resident, and immunotherapy was becoming an important form of cancer treatment. We’ve known for some time that exercise has effects on the immune system, so it raised interesting questions about the role exercise plays in the effectiveness of immunotherapy. After I came here as a fellow, I joined Jedd’s lab, where they were doing research on how to make immunotherapies more effective.

Does your research influence what you tell your patients?

Currently, we don’t have enough data to recommend one particular type of exercise over another. Several organizations, including the American College of Sports Medicine, have put out recommendations for people with cancer that recommend 150 minutes a week of moderate exercise or 75 minutes a week of more vigorous exercise. I share those guidelines with my patients.

If patients were exercising before their cancer diagnosis, I tell them to maintain what they were doing. For people who were completely sedentary, there is no magic number or exercise prescription for me to give them that’s data driven right now. But we know that getting up, moving around, and being active is good for people with cancer, and I tell them that.

What do you do to stay fit these days?

I exercise six days a week. It not only keeps me healthy, but it keeps me sane.

Before the COVID-19 pandemic, I was teaching CrossFit. I got a Peloton bike right before all the gyms closed, and I’ve become an avid user. My husband and I just bought a house in the suburbs, and I’m putting in a CrossFit gym in our garage. He’s very tolerant!

What are your plans for your research?

In addition to continuing my research in the lab, I’m working with Bill Tap [Chief of the Sarcoma Medical Oncology Service] and Julia Glade Bender [Vice Chair for Clinical Research in the Department of Pediatrics], who are leading the new Adolescent and Young Adult program at MSK. [This program aims to meet both the medical and psychosocial needs of people with cancer who are in their teens, 20s, and 30s.] I’m leading the development of an exercise component. It will focus on research as well as clinical care for patients in the program.

Because of the pandemic, the program will be remote at first, but our goal is to eventually hold in-person classes. One thing that’s important to emphasize about exercise is that it helps to create communities. For adolescent and young adult patients, we expect this program will become part of their support system.

Remembering Jimmie Holland, a Founder of Psycho-Oncology

Source: Memorial Sloan Kettering - On Cancer
Date: 01/09/2018
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On Christmas Eve, Memorial Sloan Kettering and the wider cancer community lost a beloved and brilliant doctor, Jimmie Holland, who died of cardiovascular disease at 89. Dr. Holland was a tireless advocate for supporting the emotional and psychological needs of people with cancer. She also made huge strides in reducing the stigma surrounding the disease.

Dr. Holland was considered a founder of the field of psycho-oncology, which combines oncology and psychiatry. It is increasingly considered a vital part of comprehensive cancer care, largely thanks to her work.

In 1977, Dr. Holland joined MSK as the inaugural Chief of the Psychiatry Service, the first such service at a cancer center anywhere in the world. She was then named Chair of MSK’s Department of Psychiatry and Behavioral Sciences when it was created in 1996. The department was also the first of its kind, and Dr. Holland remained in her role there until 2003. At the time of her death, she held the Wayne E. Chapman Chair in Psychiatric Oncology.

“Jimmie’s death is a profound loss to us all,” says MSK Physician-in-Chief José Baselga. “Through her visionary work she has forever changed the landscape of cancer care.”

Changing World, Changing Needs

Dr. Holland grew up in a tiny town in north Texas, the only child of a cotton farmer and his wife, neither of whom had finished high school. When she earned her medical degree from Baylor College of Medicine in the early 1950s, “cancer”was a word that most people wouldn’t say out loud. Many newspapers and magazines wouldn’t print it, and patients often were not even told of their diagnosis.

That began to change in the 1970s. Better treatments became available and people with once-fatal cancers starting living longer and even being cured. As the wife of James Holland — a leading oncologist and one of the pioneers of chemotherapy combinations — Dr. Holland had a front-row seat from which to witness the medical revolution that was taking place. While her husband and his colleagues focused on curing people of their cancer, Dr. Holland asked a question that none of them were able to answer: How do the patients feel about it?

As a psychiatrist, she had long been interested in studying how people with otherwise good mental health responded emotionally and psychologically to life-threatening illnesses. She called this focus “psychological care of the medically ill.” She began encouraging oncologists who were conducting clinical trials to include questions about patients’ quality of life in their data collection and research.

The Science of Caring

But measuring things like anxiety, depression, and fatigue was not always straightforward. Dr. Holland met this challenge by developing ways to gauge what patients were feeling that went beyond what doctors and nurses could just observe. She worked to create objective scales to evaluate aspects of people’s experience that were once considered immeasurable. This in turn could validate whether psychological treatments were working. Her research brought the emerging field of psycho-oncology into the realm of evidence-based science, which allowed it to become a recognized subspecialty.

During her years at MSK, Dr. Holland created the nation’s largest training and research program in psycho-oncology. In 1984, she produced for MSK the first-ever syllabus on psycho-oncology. In 1989, she was senior editor of the first textbook on the subject. She also shared her knowledge with the world. She co-founded the International Psycho-Oncology Society in 1984 and founded the American Psychosocial Oncology Society in 1986. She is credited with putting psychosocial and behavioral research on the agenda of the American Cancer Society in the early 1980s. She was also a founder and co-editor-in-chief of the journal Psycho-Oncology.

Dr. Holland recognized that people’s psychological distress could linger even after they were considered cured of their cancer. To address this, she advocated for the formation of a program at MSK that today is called Resources for Life After Cancer. It became a model for other similar initiatives around the world.

“Jimmie was a cancer pioneer, a remarkable woman, and a once-in-a-generation influencer,” says William Breitbart, the current Chair of Psychiatry and Behavioral Sciences and the Jimmie C. Holland Chair. “Her death is a profound loss for all of oncology.”

The Sixth Vital Sign

Dr. Holland pushed to recognize patient distress as the sixth vital sign in medicine. (The others are temperature, pulse, blood pressure, respiration, and pain.) She played a key role in the development of the National Comprehensive Cancer Network’s distress thermometer. This enables people to report their levels of anxiety and depression on a scale of zero to ten, similar to the way they rate their pain.

Other topics that were important to her included survivor guilt, diminishing the stigma of a cancer diagnosis, and evaluating ways to lessen cancer side effects like depression, anxiety, and fatigue with medication and other treatments.

In her later years, she also became particularly interested in supporting the psychosocial needs of elderly patients. As part of that effort, she founded the Vintage Readers Book Club, an offshoot of a support group she led on aging and cancer. The participants talked about classic works by writers including Cicero and Benjamin Franklin, and used their discussions as a springboard for talking about wider-ranging topics that were important to them.

“Jimmie was an inspiration on multiple levels, not least of which was her appreciation of the fact that we are more than our careers,” says psychologist and author Mindy Greenstein, who first came to know Dr. Holland when she conducted her fellowship in MSK’s Department of Psychiatry and Behavioral Sciences. The two later worked together and coauthored the book Lighter as We Go: Virtues, Character Strengths, and Aging. “While raising her own family as well as comforting patients and their family members with her Texas warmth and sound insights, she still found the time to accomplish so much in her work. Hers was a life of unique and dedicated service.”

Dr. Holland, who died at home surrounded by family, was still seeing patients up until two days before she died. She is survived by her husband; six children; nine grandchildren; and countless friends, colleagues, and collaborators.

“Jimmie was a true pioneer in the field of psycho-oncology, and her passion for her patients and her research was evident,” says MSK President and CEO Craig Thompson. “She will be dearly missed by the MSK community and by the world.”

MSK Opens New Clinic to Monitor People with a Genetic Risk for Developing Blood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 01/23/18
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Most cancers arise by chance and, therefore, are hard to predict. But scientists and doctors are learning more about the genetic changes that cause cancer as well as those that signal a higher risk for it. Thanks to MSK-IMPACT™, Memorial Sloan Kettering’s diagnostic test that looks for genes associated with cancer, more people who carry cancer-related genes are being identified.

To take advantage of these new opportunities, MSK has launched the Precision Interception and Prevention Initiative. This program is focused not only on catching cancer very early but also on eventually preventing it from forming in the first place. One of the program’s components is a clinic for people with an age-related condition called clonal hematopoiesis (CH). MSK’s clinic, the first of its kind, is beginning to see people with CH this month.

“This initiative unites high-impact science and clinical medicine to actively identify and help a population of people who are either at a high risk of developing cancer or who already have cancer but don’t know it,” says Luis Diaz, head of MSK’s Division of Solid Tumor Oncology, who is leading this effort.

A person with clonal hematopoiesis has an increased number of blood cells that carry some of the same mutations that are found in blood cancers. CH occurs when hematopoietic stem cells (which give rise to all types of blood cells) form cells that are genetically distinct from the rest of the blood stem cells. Sometimes these distinct cells carry cancer-associated mutations.

“This is an exciting and quickly growing field, and it’s vital for us to learn as much about it as possible,” says physician-scientist Ross Levine, who will be heading the new clinic. “By launching this effort to monitor and care for people with CH, we will be able to advance our understanding about this important area of science.”

Clonal Hematopoiesis: A Common Phenomenon Linked to Aging

Dr. Levine was part of the research team that was the first to identify the genetic basis of CH and its connection to blood cancer. They first reported that relationship in 2012. Since then, many investigators have begun to study the condition and have shown that CH is very common. Researchers have found that it is linked to an increased risk of certain blood cancers, especially myelodysplastic syndrome and acute myeloid leukemia, as well as cardiovascular disease, heart attacks, and strokes.

The most common cause of CH is aging. Studies have suggested that between 10 and 20% of people over age 70 have signs of it in their blood. Smoking also increases the risk. “CH is very common. Millions of people have it,” Dr. Levine says. “But most people don’t know they have it, and doctors don’t know what to do with it. We thought it was important to do more research on this phenomenon so that we can start figuring out who may need intensive follow-up and treatment right away and who can be observed.”

“Right now we don’t have good ways to predict who is most likely to develop a blood cancer, so any new findings that come out of this clinic have the potential to make a big difference,” says Marcel van den Brink, Head of MSK’s Division of Hematologic Oncology.

In addition, certain types of chemotherapy and radiation therapy can increase the incidence of CH. This explains why cancer survivors carry a risk for secondary leukemia. The still-rare condition is happening more often because more people with cancer are surviving longer or are cured of their disease.

study last year from Dr. Levine, MSK researcher Michael Berger, and their colleagues found that 25% of people with any type of cancer had CH, a higher number than had previously been observed. Of that group, 4.5% had specific mutations that are known to drive the formation of leukemia.

Treating Blood Cancer Earlier

Most people with CH will never develop blood cancer, but doctors are starting to understand which individuals with CH are at the highest risk. “This is one of the reasons this clinic is so important,” says MSK hematology fellow Kelly Bolton, who will be helping to run the new program. “We hope about 100 patients with high-risk forms of CH will participate in our first year.”

The MSK investigators who designed MSK-IMPACT, including molecular pathologist Marc Ladanyi and Dr. Berger, believed it was important to look for cancer-related genes in people’s normal tissue as well as in their tumors. This would help them determine whether a person’s cancer occurred completely by chance or whether inherited factors played a role. The easiest normal tissue to obtain is blood, and the gene mutations linked to CH started to show up as part of MSK-IMPACT testing.

As MSK launches its CH clinic, people who have undergone MSK-IMPACT testing for other cancers and have been found to have high-risk forms of CH in their blood will be contacted by their surgical or medical oncologist and invited to enroll in the program. MSK patients who are treated for low blood counts and found to have CH as part of their blood work will also be seen.

“In the past, CH has been just an incidental finding. When we were worried someone had an undiagnosed blood cancer, we would refer him or her to the Leukemia Service,” Dr. Bolton explains. “Now when we discover patients with high-risk forms of CH, we will have a clinic with experts in CH to manage and coordinate their care.”

For now, those who enroll in the clinic will have the opportunity to have their blood tested on a regular basis. People who are found to have a blood cancer will be able to start treatment immediately, when the disease is much easier to control.

Looking toward Future Treatments

In the future, MSK investigators hope to launch clinical trials of treatments that could block the progression from CH to active cancer. In addition, treatment for solid tumors may be tailored to protect people who already have an increased risk of developing a second cancer. But doctors don’t yet know enough about what drives the formation of CH to make any changes to treatment now.

Recent studies suggest that people with CH are at risk for cardiovascular diseases. However, testing for CH is not currently part of screening for them. “It’s important for people with CH to follow up with their primary-care doctors and make sure they have had the appropriate screenings for cardiovascular diseases,” Dr. Bolton says. “We will encourage everyone participating in our CH clinic to do this.”

An Unlikely Treatment for Triple-Negative Breast Cancer: Prostate Cancer Drugs

Source: Memorial Sloan Kettering - On Cancer
Date: 01/29/2018
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For many people with breast cancer, drugs that target proteins driving the cancer’s growth have made a huge difference in fighting the disease. But for those with triple-negative breast cancer — a subtype defined by what it lacks rather than by its own characteristics — there are fewer good options.

Now doctors are finding an unlikely therapy for treating some of these tumors: drugs that were originally developed to treat prostate cancer. Results from a new multicenter trial published in the Journal of Clinical Oncology (JCO) report success with this approach. Memorial Sloan Kettering is at the forefront of this research.

“There is a great unmet need for novel, active therapies for patients with triple-negative breast cancer,” says MSK Breast Medicine Service medical oncologist Tiffany A. Traina, who is leading many of these efforts and was first author of the new study. “We have many women with advanced triple-negative breast cancer looking for clinical trials because standard chemotherapy options aren’t always enough for them.”

Different Breast Cancer Subtypes, Different Treatments

The three most common proteins known to fuel breast cancer growth are the estrogen receptor, the progesterone receptor, and the HER2 receptor. Estrogen and progesterone are female hormones that help regulate the menstrual cycle, among other functions. Drugs that block estrogen, such as tamoxifen and the class of drugs called aromatase inhibitors, can slow or stop the growth of tumors with these receptors.

Breast cancers with growth driven by the HER2 receptor can be treated with drugs that block this receptor, such as trastuzumab (Herceptin®) and others.

About 15% of breast cancers, however, are defined as triple negative. This means they don’t have any of these receptors. It also means they don’t respond to drugs that target them. These cancers do respond to chemotherapy, and some studies have suggested they actually may respond better to chemotherapy than other subtypes. But chemotherapy has more side effects than these other, targeted drugs.

Triple-negative disease is more common in African Americans, younger women, and those whose cancer results from inherited mutations in the BRCA genes.

Finding an Unlikely Target for Triple-Negative Breast Cancer Treatment

It turns out that about half of triple-negative breast cancers carry another hormone receptor — the one for the male hormone androgen. In a landmark study more than ten years ago, the late MSK pathologist William Gerald was the first to report that some breast cancers could carry the androgen receptor. His research also found the androgen receptor was responsible for growth of the cancer. This opened up a possible new option for treating breast cancer with this type of hormone therapy. (Although estrogen and progesterone are considered female hormones and androgens are regarded as male ones, both types of hormones are found in people of both genders.)

In 2013, Dr. Traina was the first to lead a multicenter study showing that this approach may be effective in treating triple-negative breast cancer. That study used another androgen-targeting drug, called bicalutamide (Casodex®).

The recent JCO study reported results from 78 women with advanced triple-negative breast cancer that expressed the androgen receptor. The purpose of the phase II trial was to evaluate the safety and efficacy of the prostate cancer drug enzalutamide (Xtandi®). All participants were treated with the drug, which is given as a pill, once a day. The investigators found that 33% of people benefited from the drug. Survival also appeared longer than expected for triple-negative breast cancer. The only serious side effect was fatigue.

Enzalutamide was co-invented by physician-scientist Charles Sawyers, Chair of MSK’s Human Oncology and Pathogenesis Program. The drug targets multiple steps in the androgen receptor signaling pathway, making it more effective in treating prostate cancer than some other androgen-blocking drugs.

“What’s so exciting is that this research started at MSK,” Dr. Traina says. “It’s a true bench-to-bedside story that begins with a discovery in the lab and has led to many trials that may offer a new, effective treatment for patients with this highest-risk subset of breast cancer.”

Further Expanding Uses of Enzalutamide

“The findings from this study support the continued development of enzalutamide for the treatment of advanced triple-negative breast cancer,” Dr. Traina adds. Another recent study that Dr. Traina participated in also found that enzalutamide can provide benefit when added to an aromatase inhibitor called exemestane (Aromasin) in people whose breast cancer carries both estrogen and androgen receptors. The findings were presented at the recent San Antonio Breast Cancer Symposium.

In addition, she and her colleagues are studying enzalutamide in early-stage triple negative breast cancer. They are also looking at several other prostate cancer drugs that block the androgen receptor, both alone and in combination with other novel targeted therapies.

Dr. Traina and MSK breast medical oncologist Ayca Gucalp are also recruiting people for a new trial that would test androgen receptor–blocking drugs specifically in men with breast cancer. About 90% of male breast cancers carry the receptors for estrogen or progesterone, and studies suggest that most of them also carry the androgen receptor.