Inherited Cancer Risks: New Insights from MSK Presented at 2023 ASCO Meeting

Source: Memorial Sloan Kettering - On Cancer
Date: 06/05/2023
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Researchers from Memorial Sloan Kettering Cancer Center (MSK) revealed new findings about hereditary cancers and genetics at the recent 2023 American Society of Clinical Oncology (ASCO) annual meeting.

Genetic mutations that are passed down through families cause a significant percentage of cancers — between 5 and 10%, and as high as 15 to 20% in people with advanced cancers. Patients with certain hereditary cancers may especially benefit from many of the latest cancer treatments, including targeted drugs and immunotherapies. Their families also may benefit from being monitored for early signs of cancer.

Among the recent advances in MSK’s research into understanding how inherited DNA mutations affect cancer development and treatment, four presentations at the ASCO meeting highlighted new analysis of early-onset disease, hereditary cancers in transgender people, a new gene linked to lung cancer, and the importance of genetic testing for younger people with gastrointestinal cancers.

What Defines Early-Onset Cancers and How Should They Be Treated?

Amid growing concern about an increase in cancers occurring in younger people, clinical geneticist and gastrointestinal oncologist Zsofia Stadler, MD, presented research that found the age for so-called “early-onset” cancer can vary widely depending on the type of cancer. Dr. Stadler stressed the need to have clear criteria to define early-onset cancers, because her research also found these cancers are more likely to be linked to an inherited genetic mutation. Knowing whether a cancer is caused by a hereditary mutation is important because it can make a difference in choosing the right treatment. It’s also a signal that members of a patient’s family should consider genetic testing.

“We know the incidence of early-onset cancer is increasing for some tumor types, but when we think about what early onset means, we realize it’s actually poorly defined,” says Dr. Stadler, Clinical Director of MSK’s Clinical Genetics Service. “These cancers are usually defined as those arising before the age of 50 for any type of solid tumor. But the fact is, there is a dramatic variation in the average age of onset across different tumor types.”

The research had two aims: The first was to determine what age should be considered early onset for a variety of solid tumors. The second was to determine how often different types of early-onset cancers were likely caused by inherited genetic mutations.

First, the investigators used a National Cancer Institute database to determine the average age at which patients typically developed 32 types of solid tumors. Based on those ages, researchers then used a formula to calculate what age would be considered early onset for each of these cancers. That age ranged from the late 30s for cervical and thyroid cancers to about 60 for mesothelioma and bladder cancer. “If we considered 50 the cutoff age for every type of solid tumor, there are a lot of early-onset cancers that we would miss,” Dr. Stadler explains.

To answer the study’s second major question, the researchers then used these new classifications to analyze how often early-onset cancers were linked to an inherited genetic mutation. (This is an alteration in DNA that is passed on by a parent and present in every cell in the body.)

Overall, researchers found that early-onset cancers were much more likely to be linked to hereditary mutations — 19% versus 15.5% in people whose cancers developed at an average age. For hereditary mutations defined as “high penetrance” (meaning they were extremely likely to cause cancer), the difference was even more dramatic: 13% of early-onset cancers were linked to inherited mutations versus 5% of cancers occurring at an average age.

Researchers arrived at this conclusion using data from about 29,000 patients whose DNA was analyzed with MSK-IMPACT®, a test that identifies genetic mutations linked to cancer. It can find mutations that are only in tumors as well as inherited mutations that may increase the risk of developing cancer.

“The diagnosis of an early-onset cancer is an impetus for doing genetic testing to look for inherited risk factors,” Dr. Stadler says. “The findings from this study illustrate how important it is that early-onset cancers be correctly classified.”

Caring for Transgender Patients With Hereditary Cancer Syndromes

Genetic counselor Megha Ranganathan, MS, CGC, participated in a panel discussion focused on caring for transgender patients with inherited mutations in the BRCA1 and BRCA2 genes. Mutations in these genes can increase the risk for several cancers, including breastovarian, and prostate cancer.

“There are more than 1.6 million people in the United States who identify as transgender, and that number is likely an underestimate,” Ranganathan says. “The data is so limited that many providers are often unsure how to best manage cancer risk in these people, especially those at higher risk due to an inherited genetic predisposition.”

Ranganathan and her co-presenters discussed two cases demonstrating the challenges for these patients. The first case involved a transgender woman (a person who is assigned male at birth but identifies as a woman). After her mother was diagnosed with ovarian cancer, genetic testing revealed the transgender woman had a BRCA2 mutation. “At that point, the patient had already been receiving gender-affirming estrogen therapy for about 10 years,” Ranganathan said. “We know that prolonged estrogen exposure is a risk factor for breast cancer, but it is unknown how much it increases her risk, especially because she has a BRCA2 mutation.

“Despite the lack of reliable data, increased breast cancer surveillance or risk-reducing surgery may be reasonable options,” she added. “We encourage these patients to talk to their doctors to determine the best option for them depending on their gender-affirming goals.” Another issue for this patient: Because she was assigned male at birth, she has a prostate, and this gene mutation puts her at increased risk for prostate cancer as well.

The second case involved a young transgender man (a person who is assigned female at birth but identifies as a man). He had a BRCA1 mutation and was considering top surgery (surgery to remove breast tissue and make the chest look more masculine). Would having top surgery reduce his risk for breast cancer? The panel suggested more extensive surgery such as a full mastectomy could be considered to prevent breast cancer in this situation.

Ranganathan and her co-presenters also discussed several ways healthcare providers can create a more inclusive environment for gender-diverse people. The panelists explained key concepts and terms, how to represent someone’s gender and sex assigned at birth on family trees, and how to request a patient’s chosen name and pronouns.

“Many transgender people avoid the healthcare system altogether because they fear discrimination and stigmatization. Research is lacking on how best to care for them,” says Ranganathan. “As an institution that is dedicated to reducing healthcare disparities, we at MSK want patients to be aware that this is something we’re thinking about and that we aspire to provide excellent care for all patients, regardless of gender identity.

A New Gene Potentially Linked to Inherited Risk of Lung Cancer

Pediatric oncologist and clinical geneticist Michael Walsh, MD, presented new research that found for the first time that mutations in the cancer predisposition gene POT1 are associated with increased rates of lung cancer. Previously, mutations in POT1 have been associated with sarcoma, certain types of leukemia, and clonal hematopoiesis, a blood condition linked to aging.

“Compared with other cancers like breast, ovarian, and prostate cancers, we know less about the inherited risks of lung cancer,” Dr. Walsh says. “We know that lung cancer is strongly linked to environmental causes like smoking. These findings shine a light on potential inherited factors that may also play a role in causing lung cancer.”

Dr. Walsh and his team were able to make this discovery thanks to the cancer genetic test MSK-IMPACT. In addition to sequencing patients’ tumors, MSK-IMPACT can also analyze the genetics of normal tissue, so experts can determine whether a cancer is linked to an inherited genetic mutation or developed at random. In this case, a study of data from patients’ normal DNA allowed investigators to undercover new findings about inherited mutations in POT1.

POT1 has been added to the list of genes detected by MSK-IMPACT relatively recently, so it hasn’t been studied as well as some other cancer genes,” Dr. Walsh explains. “But when we looked at data for about 7,000 patients, we found that the incidence of lung adenocarcinoma in people with this inherited mutation was much higher than expected.”

After the MSK-IMPACT analysis, Dr. Walsh and his colleagues found that other large databases of cancer genes supported their findings. They will continue studying the link.

Dr. Walsh says one day this discovery might provide insights leading to new treatments for cancer.

Increasing Genetic Testing for Younger People with Gastrointestinal Cancers

In response to the alarming increase in colorectal cancer cases in younger people, MSK clinical geneticist and family medicine physician Alicia Latham, MD, MS, urged more testing to determine possible inherited risks of cancer.

“As MSK offers genetic testing to more of our patients, we’re finding that some of these gene mutations are more common than we previously believed,” says Dr. Latham, who spoke at an ASCO session focused on gastrointestinal (GI) cancers. “But there are questions about whether these mutations are truly related to the cancer or are instead incidental findings.”

Dr. Latham specializes in treating people with Lynch syndrome. This hereditary condition carries an increased risk of certain types of cancer, including colon cancer and rectal cancers. Lynch syndrome cancers are characterized by a feature called microsatellite instability, which makes them especially responsive to immunotherapy drugs called checkpoint inhibitors.

Because these mutations have important implications for treatment, there is a move toward testing more patients with GI cancers for these genes, especially younger patients, Dr. Latham explains.

“This is a real change from what we’ve done in the past,” she says. “But because findings from these tests can have such important implications for treatment, we want everyone to be aware of these connections and the importance of testing.”

She adds that several collaborative advisory groups in North America and Europe are also backing the recommendations to test more patients for inherited conditions.

Dr. Latham leads MSK’s Comprehensive Assessment, Treatment, and Prevention of Cancers with Hereditary Predispositions (CATCH) program, which provides surveillance and monitoring for people who have genes that are linked to inherited cancer predisposition syndromes.

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.

MSK Study Is the First to Link Microbiota to Dynamics of the Human Immune System

Source: Memorial Sloan Kettering - On Cancer
Date: 11/25/2020
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In recent years, the microbiota — the community of bacteria and other microorganisms that live on and in the human body — has captured the attention of scientists and the public, in part because it’s become easier to study. It has been linked to many aspects of human health.

A multidisciplinary team from Memorial Sloan Kettering has shown for the first time that the gut microbiota directly shapes the makeup of the human immune system. Specifically, their research demonstrated that the concentration of different types of immune cells in the blood changed in relation to the presence of different bacterial strains in the gut. The results of their study, which used more than ten years of data collected from more than 2,000 patients, is being published November 25, 2020, in Nature.

“The scientific community had already accepted the idea that the gut microbiota was important for the health of the human immune system, but the data they used to make that assumption came from animal studies,” says Sloan Kettering Institute systems biologist Joao Xavier, co-senior author of the paper together with his former postdoc Jonas Schluter, who is now an assistant professor at NYU Langone Health. “At MSK, we have a remarkable opportunity to follow how the composition of the microbiota changes in people being treated for blood cancers,” Dr. Xavier adds.

A Unique System for Studying Changes in the Body

The data that were used in the study came from people receiving allogeneic stem cell and bone marrow transplants (BMTs). After strong chemotherapy or radiation therapy is used to destroy cancerous blood cells, the patient’s blood-forming system is replaced with stem cells from a donor. For the first few weeks until the donor’s blood cells — including the white blood cells that make up the immune system — have established themselves, the patients are extremely vulnerable to infections. To protect them during this time, patients are given antibiotics.

But many of these antibiotics have the unwanted side effect of destroying healthy microbiota that live in the gut, allowing dangerous strains to take over. When the patient’s immune system has reconstituted, the antibiotics are discontinued, and the gut microbiota slowly starts to grow back.

“The parallel recoveries of the immune system and the microbiota, both of which are damaged and then restored, gives us a unique opportunity to analyze the associations between these two systems,” Dr. Schluter says

A Years-Long Effort to Find Answers

For more than ten years, members of MSK’s BMT service have regularly collected and analyzed blood and fecal samples from patients throughout the BMT process. The bacterial DNA were processed by the staff at MSK’s Lucille Castori Center for Microbes, Inflammation, and Cancer, which played a key role in creating the massive microbiota dataset. “Our study shows that we can learn a lot from stool — biological samples that literally would be flushed down the toilet,” Dr. Xavier notes. “The result of collecting them is that we have a unique dataset with thousands of datapoints that we can use to ask questions about the dynamics of this relationship.”

This wider effort has been led by Marcel van den Brink, Head of the Division of Hematologic Malignancies, and a team of infectious disease specialists, BMT doctors, and scientists. “For a fair number of patients, we collected daily samples so we could really see what was happening day to day,” Dr. van den Brink says. “The changes in the microbiota are rapid and dramatic, and there is almost no other setting in which you would be able to see them.”

Previous research using samples collected from this work has looked at how the gut microbiota affects patients’ health during the BMT process. A study published in February 2020 reported that having a greater diversity of species in the intestinal microbiota is associated with a lower risk of death after a BMT. It also found that having a lower diversity of microbiota before transplant resulted in a higher incidence of graft-versus-host disease, a potentially fatal complication in which the donor immune cells attack healthy tissue.

New Clues about a Complicated Relationship

The databank that the MSK team created contains details about the types of microbes that live in the patients’ guts at various times. The computational team, including Drs. Schluter and Xavier, then used machine learning algorithms to mine electronic health records for meaningful data. The data from the health records included the types of immune cells present in the blood, information about the medications that patients were given, and the side effects patients experienced. “This research could eventually suggest ways to make BMTs safer by more closely regulating the microbiota,” Dr. van den Brink says.

Analyzing this much data was a huge undertaking. Dr. Schluter, who at the time was a postdoctoral fellow in Dr. Xavier’s lab, developed new statistical techniques for this. “Because experiments with people are often impossible, we are left with what we can observe,” Dr. Schluter says. “But because we have so many data collected over a period of time when the immune system of patients as well as the microbiome shift dramatically, we can start to see patterns. This gives us a good start toward understanding the forces that the microbiota exerts on the rebuilding of the immune system.”

“The purpose of this study was not to say whether certain kinds of microbes are ‘good’ or ‘bad’ for the immune system,” Dr. Xavier explains, adding that this will be a focus of future research. “It’s a complicated relationship. The subtypes of immune cells we would want to increase or decrease vary from day to day, depending on what else is going on in the body. What’s important is that now we have a way to study this complex ecosystem.”

The researchers say they also plan to apply their data to studying the immune system in patients receiving other cancer treatments.

A Perfect Match: Molecular Tests Developed at MSK Guide Personalized Treatment for Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 11/25/2020
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EGFRALKBRAF. MET. NTRK. RET. ROS1. This may seem like what you see when you dump a box of Scrabble tiles on a table, but these letter combinations are actually the names of genes that — when mutated — drive the formation, growth, and spread of lung cancer.

In aggregate, mutations in these seven genes cause about one-third of all non-small cell lung cancers. And each of them has at least one drug designed to counteract them that’s been approved by the US Food and Drug Administration. For patients who are matched with one of these drugs, treatment tends to be much more effective than it is with chemotherapy, which kills not just cancer but all fast-growing cells. Additionally, targeted drugs usually have fewer side effects than other forms of treatment.

“Our goal is always to find the best treatment for every patient,” says Memorial Sloan Kettering medical oncologist Helena Yu, who specializes in evaluating targeted therapies for lung cancer. “But you don’t know what the best treatment is until you look at all the options, and you won’t know all the options until you do molecular testing.”

A History of Developing Molecular Tests

Nearly two decades ago — when the first drugs for EGFR mutations were being evaluated — researchers at MSK recognized that targeted therapy would be an especially important approach for people with lung cancer. This was because the drugs worked extremely well in a subset of patients. Also, many people stood to benefit because lung cancer is so common. Targeted drugs work by zeroing in on the activities of mutated proteins in cancer cells and shutting down the cells’ growth, mostly sparing healthy cells.

MSK researchers also understood how vital it was to examine tumor tissue and determine whether it contained the mutations that were being targeted. Studies had shown that EGFR drugs were quite effective in people whose tumors had EGFR mutations. Those whose tumors had other mutations would not benefit. (What happened is not uncommon in cancer drug development — when the trials of drugs targeting EGFR began, investigators didn’t know who would most benefit from them.)

In 2004, MSK was one of the first hospitals in the world to begin regularly testing people with non-small cell lung cancer for EGFR mutations. The development of this clinical test was led by molecular pathologist Marc Ladanyi.

In the years after that test was created, Dr. Ladanyi and his team in MSK’s Molecular Diagnostics Service have continued to roll out new molecular tests, including MSK-IMPACTTM, which expanded the benefits of molecular testing to all solid tumors. Today, this test can detect alterations in 505 cancer-related genes while requiring only one small piece of tissue. MSK-IMPACT was cleared as a tumor genetic profiling assay by the FDA in 2017. In 2019, MSK began using MSK-ACCESS, a tool that can detect mutations in 129 genes by analyzing just a small amount of blood. MSK-IMPACT and MSK-ACCESS enable doctors to match patients with drugs designed to target their tumors and provide them with many other details about a tumor’s genetics as well.

“When a patient comes to me with newly diagnosed, metastatic lung cancer, the first thing I do is order an MSK-ACCESS test for them,” Dr. Yu says. “We get the results within two weeks, and if their cancer cells contain one of these mutations, we can start them on a targeted therapy right away.” Because MSK-IMPACT requires a tissue sample, it may not be available to patients who received their biopsy and diagnosis at another hospital. But if enough tissue is left over from earlier tests, MSK-IMPACT can be used to confirm the diagnosis and provide further detail. “MSK-IMPACT is still the gold standard for molecular testing,” she adds.

Clinical Trials Lead to New Therapies

As leader of MSK’s Early Drug Development Service, medical oncologist Alexander Drilon has been at the helm of several clinical trials for targeted therapies that are now used to treat lung and other cancers. Recently, he led the clinical trial that resulted in the FDA’s approval of selpercatinib (RetevmoTM), which treats lung and thyroid cancers driven by a mutation called a RET fusion. Studies showed that among patients who had stopped responding to other drugs, 64% had their tumors shrink when treated with selpercatinib. For those who had never received chemotherapy or another treatment, the response was even higher — 85%.

“As more targeted therapies are developed, tests like MSK-IMPACT that look for many mutations at the same time have become so important,” Dr. Drilon said. “If you run individual tests for each mutation separately, you’ll exhaust the amount of the patient’s tumor tissue that’s available for analysis.”

Selpercatinib and other targeted therapies were initially approved to treat stage IV disease that could not be operated on — cancers that had spread beyond the lungs to other parts of the body. Investigators at MSK are now conducting studies to determine whether they can help people with less-advanced cancers. The drugs may be given before surgery, to shrink tumors and make them easier to remove, or after surgery, to destroy any cancer that may be left behind.

Unfortunately, many people can develop resistance to these drugs, and MSK researchers are now focused on developing new drugs that can take over when one targeted therapy stops working. MSK-ACCESS plays an important role here, too: Doctors can use blood tests to monitor the cancer and determine whether it has acquired additional mutations without having to conduct a surgical or needle biopsy to get another tissue sample.

Advancing the Search for New Drugs and New Targets

MSK investigators are also leading the way in the search for drugs that target mutations in other genes. In September 2020, medical oncologists Bob Li and Piro Lito published results from the first-ever trial for sotorasib, a drug that targets a mutation called KRAS-G12C. This mutation is found in about 10% of non-small cell lung cancers, most often in former or current smokers.

Dr. Li and Dr. Drilon are also conducting a trial to determine whether the drug trastuzumab deruxtecan (Enhertu®), which was approved for breast cancer in December 2019, is effective in treating lung cancers driven by genetic changes in a gene called HER2.

“You need really good sequencing tests to find all these mutations,” Dr. Drilon says. “As testing becomes cheaper and more and more drugs become available, the medical community needs to move toward a paradigm where every person with lung cancer receives molecular testing.”