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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.

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Chemotherapy-Immunotherapy Combination Aims to Knock Out Melanoma with a One-Two Punch

Source: Memorial Sloan Kettering - On Cancer
Date: 02/02/2018
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For some people with cancer, drugs that help the immune system recognize and attack tumor cells have been a game changer. But for most, the outcomes from these immunotherapies are not effective, and other treatments are required.

Now a collaborative group of melanoma experts is testing a novel combination therapy for certain people with that aggressive form of skin cancer. They have combined immunotherapy drugs with chemotherapy that treats only the area affected by cancer. The results of lab research, as well as the first-ever clinical trial to explore this particular approach, are being reported in the journal Cancer Immunology Research.

“Immunotherapy has had great successes, but we’re looking for ways to make it effective for more people,” says Charlotte Ariyan, a Memorial Sloan Kettering surgeon who is the lead author of the new study. “Our work in the lab is focused on developing better treatments, which we can then bring to patients as part of clinical trials.”

Using Two Treatments Together for Better Results

The approach combines the relatively new immunotherapy drug ipilimumab (Yervoy®) with a treatment that’s been around much longer, called isolated limb infusion.

Limb infusion is used as a therapy for in-transit melanoma, which means the cancer has spread throughout an arm or leg. People with this form of the disease can have dozens of small tumors, making it difficult to treat them all with surgery or radiation. The infusion treatment is given by putting a very high dose of chemotherapy directly into the affected arm or leg. A tourniquet prevents the medication from going into the rest of the body.

“Limb infusion is an interdisciplinary treatment that requires a lot of expertise,” Dr. Ariyan explains. “At MSK we have a dedicated team for limb infusion that includes an anesthesiologist, an interventional radiologist, nurses, and medical oncologists. This allows us to offer this specialized treatment to our patients in a very efficient way.”

But limb infusion often doesn’t have long-lasting results. Most of those who respond see their disease come back within a year. This is where the immunotherapy comes in.

Making Cancer Visible to Immune Cells

In research conducted in the lab, Dr. Ariyan and her colleagues, including Sloan Kettering Institute Immunology Program Chair and Director of the Ludwig Center for Cancer Immunotherapy (LCCI) Alexander Rudensky, found that when mice were given chemotherapy before ipilimumab, the responses to the immunotherapy were much better.

“The idea behind immunotherapy is that you’re trying to get the body to recognize the tumor, but a lot of times the tumor stays silent,” says Dr. Ariyan, who is also a member of LCCI. “Because chemotherapy causes some of the cancer cells to die, it leads to inflammation in the area around the tumor. This is an opportune time to give immunotherapy because the tumor is easier for the immune system to find.”

In the mice, the researchers found that combining the treatments resulted in an increase in the number of immune cells that were able to get into the tumor. This ultimately led to improved survival in the animals.

A few previous studies done in people with lung cancer have looked at combining immunotherapy with systemic chemotherapy. That’s when chemotherapy is delivered throughout the body. The results of that combination treatment have been mixed. “Because systemic chemotherapy can wipe out a person’s immune cells, it’s usually not the best approach,” she says. “However, if you can give chemotherapy in a way that the immune system is still intact, it appears to show benefits.”

Taking the Treatment Approach to People

The discoveries made in mice led to the idea to test this treatment in people. Money from Cycle for Survival — MSK’s indoor team-cycling fundraiser, which supports research on rare cancers — as well as from other foundations helped move the research into a clinical trial.

The phase II trial included 26 people who had advanced melanoma in an arm or leg. Participants were given limb infusion with chemotherapy followed by ipilimumab. After three months, 85% had their tumors shrink as a result of the treatment. Of those who responded, more than half had a complete response, meaning that their tumors disappeared. Today, 58% of them remain disease free, even after they stopped receiving ipilimumab.

Dr. Ariyan says that the team will continue to explore this approach in people with in-transit melanoma who are not responding to immunotherapy alone. In addition, they are considering it to treat other types of cancer, such as sarcoma, which frequently occurs in the muscles, bones, and connective tissues in the arms or legs and usually doesn’t respond to immunotherapy.

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Reassessing Palliative Care: MSK Emphasizes Supportive Care for All People with Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 02/15/2018
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The doctors, nurses, and other staff at Memorial Sloan Kettering are focused on all aspects of cancer care. This means that in addition to the most-advanced therapies for treating cancer, we deliver care that tends to the physical, emotional, and spiritual needs that come up during and after cancer treatment.

“We feel strongly that supportive care is compatible with the most-aggressive, state-of-the-art cancer care,” says Judith Nelson, who is Chief of the Supportive Care Service. “It’s not an either-or situation: Supportive care and cancer care go together. We emphasize the importance of the supportive services that are available from a patient’s very first appointment.”

“Supportive care is based on a person’s needs, not on their prognosis. People with all types and stages of cancer can benefit from it,” Dr. Nelson adds. “The goal of our service is to help patients live maximally and to have every day for them be the best day possible, for as many days — or weeks, years, or decades — as possible.”

A Mission of Supporting People with Cancer

Although the terms “palliative” and “supportive” can be used interchangeably, MSK wanted to emphasize the supportive part of our mission. About a year ago MSK renamed the Palliative Medicine Service in the Department of Medicine. It is now called the Supportive Care Service.

Supportive care covers a range of services for people with cancer. This includes medical care to address physical symptoms, such as pain, nausea, or fatigue. It also consists of care to help people address their emotions, such as anxiety, stress, and depression. These services can incorporate support for the spiritual distress that people may face after their diagnosis as well. And supportive care can help people with cancer ensure that their care matches their values and goals.

Members of MSK’s supportive care team train oncology doctors and nurses to notice when people need more support and to provide the care that can help them. Supportive care assessments are an ongoing part of the care that people receive at MSK, whether in the hospital or as an outpatient.

“The best way to know if patients are in distress is to ask,” Dr. Nelson says. “Moving forward, we are making sure that all of our healthcare providers are empowered to do assessments from the very beginning of treatment. Based on these assessments, patients and their families will get the help they need from their oncology team and a supportive care specialist if needed.”

A Growing, Interdisciplinary Field

Robert Sidlow leads MSK’s Division of Survivorship and Supportive Care. The group was launched about three years ago within the Department of Medicine. It bolsters and advances a number of services across MSK. These include the General Internal Medicine, Hospital Medicine, Geriatrics, Integrative Medicine, Employee Health and Wellness, Urgent Care, and Supportive Care services.

“It’s important to emphasize the interdisciplinary nature of supportive care,” Dr. Sidlow says. “In addition to members of the specialized Supportive Care Service, many MSK doctors are part of the extended supportive care team. Psycho-oncologists are tremendously helpful to patients and their families. The robust Integrative Medicine Service delivers complementary treatments, such as acupuncture and mind-body therapies. The Department of Rehabilitation Medicine is wonderfully helpful at getting people back to their regular lives as much as possible.”

MSK also has a unique supportive care fellowship program, in which doctors and nurse practitioners train side by side. “We are the standard bearer for cancer care and training across the country and around the world,” Dr. Nelson says. Applications to the training program have tripled in the past few years, and the program’s graduates have gone on to work at many leading institutions around the country.

Continuing to Improve End-of-Life Care

Despite the focus on supporting all people with cancer, end-of-life care is still a key part of supportive care services.

“We help people plan in advance so important decisions are not made in a time of crisis,” Dr. Nelson explains. “Doctors need to hear from patients and their families about what’s important to them in their lives and what their priorities are.”

Dr. Sidlow adds, “With the constant stream of new treatments available, people with cancer and their care teams now have much more prognostic uncertainty than in the past. Twenty years ago when someone had an advanced cancer, by and large everyone anticipated an inevitable downward path. But today, the course of advanced cancer can be less obvious. Often the experience of having cancer is more like congestive heart failure. People alternate between periods of relative stability and periods of greater need for supportive care.”

He says that although many people with cancer are living longer than in the past, “the burdens that they and their caregivers face — physically, emotionally, and financially — can be quite significant and worsen everyone’s quality of life. This underscores the importance of understanding patients’ values and integrating supportive care early in cancer treatment.”

MSK patients and their families who feel they may benefit from specialized supportive care services can speak to their care team.

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The Last Frontier in Cancer Care: Treating Disease When It Spreads to the Brain

Source: Memorial Sloan Kettering - On Cancer
Date: 02/16/2018
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Metastatic brain cancer gets far less attention in the media than primary brain tumors, despite being at least ten times more common. Metastatic brain cancer occurs when tumors spread from other parts of the body to the brain. It was once considered an end stage of the disease. Doctors’ main focus was making patients comfortable. But increasingly, metastatic brain cancer is being treated aggressively, with the goal of eliminating it. Memorial Sloan Kettering doctors and scientists are leading the charge to find new and innovative ways to treat this type of brain cancer.

“There used to be this feeling of therapeutic nihilism about metastatic brain cancer. Once cancer spread there, everyone assumed not much could be done,” says Adrienne Boire, a neuro-oncologist who also leads a lab in MSK’s Human Oncology and Pathogenesis Program. “Unfortunately, many doctors in the community still feel that way. But as a physician-scientist at the best cancer hospital in the country, I can’t just stand by. At MSK, we are making use of all the amazing resources we have to be able to understand and address this very complex problem.”

“Treating metastatic brain tumors is slowly turning into the last frontier in cancer care,” adds physician-scientist Viviane Tabar, Chair of MSK’s Department of Neurosurgery. “We often see people whose cancer is very well controlled in other parts of their body but who are still struggling with poorly controlled brain metastases.”

The symptoms of brain metastases and their impact can be severe. They may include headaches, nausea, weakness, seizures, and problems walking, speaking, and seeing.

An Increasing Problem in Cancer Care

“From a surgeon’s perspective, we are treating these tumors with a higher frequency than ever before, now that people have better options for medical treatment of their primary disease,” Dr. Tabar says.

There are no data to show that metastatic brain tumors are becoming more common, but there’s a general sense in the field that they are. One reason could be that better imaging techniques are more likely to detect tumors that have moved there. Another common opinion is that doctors are getting better at treating cancer in other locations so people are living longer and tumors have more time to grow in the brain.

Targeted drugs and other new therapies — such as EGFR and checkpoint inhibitors for lung cancer and HER2 inhibitors and hormone therapies for breast cancer — often are very effective at keeping cancer in check where it began. They can also work well in other organs where cancer has spread. But these therapies are less effective on tumors in the brain. This is due, in part, to what is called the blood-brain barrier. This barrier may make it harder for these drugs to reach the brain.

In addition, metastatic brain tumors usually are genetically very different from the original tumors. This is because cancer cells change as they grow and spread throughout the body.Back to top 

Identifying Variations in Tumor Biology

Because of these genetic differences, new approaches are needed to treat metastatic brain tumors. “We’re in a strange spot,” Dr. Boire says. “We know what the tumor used to be — a breast tumor, for example, or a melanoma tumor. And based on imaging, we know where it is. But we don’t know all the changes it’s gone through to get to where it is. That can be a challenge to figure out.”

To address this, MSK neurologists and pathologists are working together to develop liquid biopsies of the spinal fluid, which may contain DNA from brain tumors. This would allow them to run MSK-IMPACTTM, a test that simultaneously screens for hundreds of genes that drive tumor growth. Doctors can use it to determine the best targeted therapy for a tumor without having to obtain a tissue biopsy from the brain. “This would really be a game changer,” Dr. Boire notes.

Another tactic being studied by Dr. Boire and her colleagues, including Sloan Kettering Institute Director Joan Massagué, is finding drugs that target the microenvironment around the tumor, rather than the tumor itself. “There are many different kinds of cancer that can set up shop in the brain, which means it will be unlikely that we find one treatment that’s effective against all tumors,” she explains. “But there’s only one brain. Perhaps finding out how the brain responds to cancer holds the key to finding ways to treat brain metastasis.”

A Different Kind of Brain Tumor and Treatment

In addition to being different from the tumors in which they originated, metastatic brain cancers are also very different from primary brain cancers. Surgically, however, that may make these tumors easier to treat. “Compared with tumors like glioblastoma, brain metastases tend to look very different from the surrounding brain tissue. It is simpler to determine their boundaries when removing them,” Dr. Tabar explains. She adds that people who have surgery for brain metastases tend to recover very quickly. “Most patients can go home in only two or three days, and they usually do very well,” she says.

In some cases, brain metastases can occur in critical areas of the brain, such as those that control movement or speech. In those circumstances, Dr. Tabar doesn’t hesitate to use all of the surgical technology at her disposal. She might opt for brain mapping or keeping the patient awake during surgery. That way, she can “maximally protect their function,” she says. “Our aggressive approach to brain metastasis is motivated by the often excellent outcomes of surgery and radiation, and their positive impact on quality of life. There’s been enormous progress in systemic treatments, leading to improved survival.”

Many people with brain metastases have multiple tumors, not all of which can be removed with surgery. They are often treated with a combination of surgery and radiation. Several different types of radiation are available for people who require this treatment. These include intensity-modulated radiation therapy, which uses images from CT scans to focus high doses of radiation directly on the tumor; image-guided radiation therapy, which uses real-time imaging with a CT scan or x-rays during radiation therapy; and stereotactic radiosurgery, which can treat small tumors with a single high dose of radiation. These advanced technologies can focus the radiation beam at the specific area needing treatment while sparing the surrounding normal brain cells. Doctors at MSK avoid giving radiation to the entire brain to minimize side effects.

Radiation therapy and surgery are often combined for the same tumor, to minimize the chance it will regrow after surgery or if parts of it could not be removed. This may be the case if the tumor is in a key area of the brain or surrounding an important blood vessel. Radiation therapy may also be combined with immunotherapy.

A Multidisciplinary Team Focused on the Same Goal: The Individual

Another important contributor to MSK’s ability to treat metastatic brain cancer is our expertise in supportive services. “Our experts in rehabilitation, physical therapy, and other specialties make sure that our patients are strong enough to tolerate treatment,” Dr. Boire says. “We want to give everyone the best chance we can to have the best outcome possible after treatment is over.” This also includes experts in epilepsy, who are able to treat the seizures that are often caused by brain tumors.

“Metastatic brain cancer is a huge problem in oncology, and it doesn’t get the amount of attention it deserves,” Dr. Tabar concludes. “For that reason, here at MSK we are beginning to talk about building a formal center specifically for brain metastases. Assembling a group of experts on both the clinical side and in the lab will enable us to offer a multidisciplinary approach to a growing number of people who could benefit from an aggressive approach toward controlling brain metastasis.”

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The Latest on Genetic Testing for BRCA Mutations in Breast Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 02/21/2018
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Last month, the US Food and Drug Administration approved olaparib (Lynparza®) for people who have certain types of breast cancer that has spread and who have been previously treated with chemotherapy. Olaparib was the first drug in a class called PARP inhibitors to be approved for breast cancer.

Medical oncologist Mark Robson headed the first multicenter phase III clinical trial of this drug for breast cancer. Results from that study, which were reported at the American Society of Clinical Oncology meeting last summer, led to the drug’s approval.

Dr. Robson, who was named Chief of Memorial Sloan Kettering’s Breast Medicine Service in November 2017, was recently part of a panel discussion held at New York City’s 92nd Street Y entitled “Knowledge Is Power: Understanding and Managing BRCA-Related Cancer Risk.” We spoke with him about what this drug approval means for people with breast cancer, as well as its implications for expanding the use of genetic testing for BRCA mutations.

How do we know whether someone’s cancer is caused by a BRCA mutation?

At MSK, everyone with advanced cancer is offered the opportunity to undergo testing with MSK-IMPACT™. In addition to looking for cancer mutations in the tumor itself, this test can scan the normal tissue for cancer mutations, if the patient agrees. Because BRCA mutations are carried in the germline, meaning all the cells in the body, they show up with this test.

There are other tests for inherited BRCA mutations that are available through a number of companies. But we don’t recommend taking these tests unless you speak with a genetic counselor.

Based on your findings, who do you think should get BRCA testing?

Now that olaparib is an approved therapy, I would recommend that anyone with advanced breast cancer get the BRCA test. It can help guide their treatment, and it may allow them to avoid getting chemotherapy for a longer period. Olaparib is taken at home as a pill, and it has relatively few side effects.

People with earlier-stage breast cancer as well as other forms of cancer that have been associated with BRCA mutations may want to consider getting tested if their personal or family history suggests they might be carrying a BRCA mutation. That is best determined through a consultation with a genetic counselor. Knowing that they have a mutation can help them plan ways to reduce their risk of developing another cancer. It also might tell them if there is a clinical trial that might help them.

These are genes that are inherited and run in families. Because of that, close relatives of people who are known to have BRCA mutations should strongly consider talking to a genetic counselor and getting tested.

Some people have suggested that because BRCA mutations are more common in people of Ashkenazi Jewish descent, the use of this test should be expanded to include this whole group. There is certainly the potential to benefit, since many people with mutations don’t have a family history that would prompt them to get tested. But there are also possible risks if people aren’t prepared to learn that they have a mutation. There are a number of studies that are trying to find the best way to get this information to people who want it. One of them is the BFOR study, which is being led by Kenneth Offit of the Clinical Genetics Service here at MSK.

How would a BRCA mutation affect my options for drug therapies?

PARP inhibitors work by blocking enzymes called poly (ADP-ribose) polymerases, or PARPs for short. Members of this family of enzymes help repair breaks in DNA. If DNA cannot be repaired, cells cannot divide and will die. An emerging strategy in cancer therapy has been to block the repair role of PARPs. Normal cells can overcome this type of attack, but certain cancer cells cannot.

In particular, mutations in the genes BRCA1 and BRCA2 are connected with the inability to repair this kind of damage. This weakness makes cancers linked to BRCA mutations good candidates for these drugs.

Besides breast cancer, what other cancers are BRCA mutations linked to?

BRCA mutations have been known to be associated with breast cancer and ovarian cancer for more than two decades. More recent studies have shown that they are also linked to many cases of advanced prostate cancer, as well as pancreatic cancer.

Olaparib was previously approved for treating BRCA-associated ovarian cancer. There are two other PARP inhibitors approved for ovarian cancer as well. Clinical trials at MSK and many other centers are looking at expanding PARP drugs to all cancers that are associated with BRCA mutations.

You have been studying BRCA for a long time. Is there anything that’s surprised you about recent developments?

It’s been an incredibly exciting and interesting time to be involved in this field. When the Human Genome Project was completed in 2003, there were all these theoretical ideas of how genetic information could be applied to human health. But none of them were very practical.

The ways that we are beginning to use genetic information now are what we always hoped we would be able to do, even though at that time we couldn’t envision the details. So I would not say that I’m surprised, even though I couldn’t have predicted exactly what we’d be doing today.

We have reached the place we’re at in this field because of investments in fundamental research. It’s been a privilege to help turn promise into reality.

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New MSK Initiative Focuses on the Early Detection and Prevention of Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 02/22/2018
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Cancer often begins to form years or even decades before symptoms appear. And for most cancers, the longer they remain undetected, the more opportunities they have to spread, ultimately making them much harder to treat.

That’s why early detection is an important focus of cancer research. Memorial Sloan Kettering recently launched the Precision Interception and Prevention (PIP) initiative to advance those developments. This institution-wide, broad-ranging effort will concentrate not only on catching cancer very early but also on preventing it from developing in the first place.

“This concept has always been incredibly appealing, but until very recently, the tools to address it were not there,” says MSK Physician-in-Chief José Baselga. “Today, with the capabilities we now have for genomic sequencing of tumors, everything is falling into place. We believe that PIP will change cancer as we know it.”

Developing a Tool Kit for Early Cancer Diagnosis

One of the most important tools that has made this effort possible is MSK-IMPACTTM, a diagnostic test that looks for genetic changes in people’s tumors. However, the test goes beyond just analyzing tumors; it also reveals mutations in people’s normal cells. Because of that, it’s uncovering both the genetic changes that drive existing tumors and the genetic changes that people are born with. Some of these inherited mutations make them more susceptible to developing future cancers.

Rates for any given cancer are low in the general population. That makes it hard to home in on markers for them. But people who have undergone MSK-IMPACT testing for existing cancers and have been found to carry inherited mutations can help in the development of better detection methods.

Family members of those people who have been found to carry cancer genes can also be tested. “Beyond the benefits for our patients, another important goal of our initiative is to identify family members who appear healthy but may harbor inherited mutations in cancer genes,” says Zsofia Stadler, an MSK medical oncologist and clinic director of the Clinical Genetics Service. “These at-risk family members can make more-intensive efforts at cancer screening and risk reduction, with the goal of early detection or even cancer prevention.”

Moreover, some of the inherited mutations could affect treatment. Doctors may use this genetic information to select targeted therapies for patients.

A Focus on Blood Cancers

Another major part of PIP is early-detection methods for blood cancers, such as leukemia and myelodysplastic syndrome. MSK-IMPACT testing has helped detect a condition called clonal hematopoiesis (CH). CH is a genetic signature found in the blood that identifies people who have an increased risk of developing certain blood cancers.

MSK has opened a CH clinic, the first of its kind. There, people with CH can be followed to learn more about how these cancers form and, eventually, to develop ways to prevent them.

“Our CH clinic is an important component of PIP, and one of the most novel aspects of the whole initiative,” says Luis Diaz, Head of MSK’s Division of Solid Tumor Oncology, who is spearheading PIP. Dr. Diaz joined MSK in April 2017 but was interested in the importance of developing early-detection and prevention methods even before coming to MSK. “My job is to make it happen,” he notes.

Eliminating Traces of Cancer

PIP will also be looking for better ways to detect and treat the small amounts of cancer that may be left after people have had treatment. This is called minimal residual disease.

Even after someone has had surgery, radiation, and chemotherapy to treat a tumor, some cancer cells may remain. These cells may continue to circulate in the blood or may hide out in the body. Eventually, they can start growing again and form new tumors.

An important tool for both cancer screening and ensuring that all traces of cancer are gone will be liquid biopsies. This approach seeks to detect cancer with a simple blood test. As cancer cells break down in the normal course of cell death, they shed their DNA into the bloodstream. New gene-sequencing technology has made it increasingly possible to detect cancer genes in the blood.

In the case of minimal residual disease, liquid biopsies could be able to tell that there’s still cancer in the body so doctors could offer their patients additional treatments. This way, people can make sure that when cancer is gone, it’s gone for good.

Focusing on Groups at High Risk

Perhaps the biggest risk factor for cancer, along with aging, is tobacco use. The link between tobacco and cancer has been well established for decades. There are a few methods for detecting tobacco-related cancers early, but none for preventing them.

For several years, MSK has offered low-dose CT screening for people at the highest risk of lung cancer due to smoking, but this technology can miss some cancers. In addition, CT screening has a high rate of false positives: More than 90% of findings are not cancer. And there are no established screening methods for other tobacco-related cancers, including head and neck cancers, esophageal cancer, and bladder cancer. PIP plans to address those shortcomings.

“This program will leverage what we can learn from people who are heavy smokers with the ambition of looking for novel markers for detection,” Dr. Diaz says. “We plan to screen thousands of people to look for tumor markers not only in the blood but also in the saliva and urine.”

Eventually, he adds, the program will focus on developing and testing therapies that will actually prevent smoking-related cancers.

“Everyone in the scientific community recognizes and values the merits of these preventive approaches for cancer,” Dr. Baselga concludes. “As we have already shown with the development of MSK-IMPACT, MSK has an amazing operational strength to do whatever we set our minds to doing. Across the institution, our sense of commitment and personal excellence will make us leaders in this area.”

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Single-Cell Analysis Enables Researchers to Understand the Differences within Tumors

Source: Memorial Sloan Kettering - On Cancer
Date: 02/27/2018
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Precision oncology is based on the idea that the molecular changes driving cancer can be targeted with drugs to stop a tumor from growing. But what happens if not all of the cells in a single tumor are driven by the same set of mutations? This phenomenon is called tumor heterogeneity, and it’s extremely common in cancer.

Researchers want to get around this problem with an approach called single-cell analysis. This allows them to analyze tumors with greater detail than ever before. Being able to find the genetic mutations that direct individual cells within a tumor may lead to more-effective targeted therapies. Plus, single-cell analysis can help doctors learn when some of the cells in a tumor have begun to develop new mutations that allow them to resist targeted therapies.

“Genetic heterogeneity within tumors is one of the main challenges that we face in precision oncology,” says Memorial Sloan Kettering experimental pathologist Jorge Reis-Filho. His laboratory focuses on the genes that drive the formation and growth of breast cancer. “We use single-cell genomics to understand heterogeneity within tumors and how it contributes to disease progression,” he says.

Looking for Changes in Many Cells

Single-cell analysis is being developed hand in hand with another technology known as liquid biopsy. This technique searches the blood for tumor cells or free-floating DNA that has escaped from a tumor. In many cases, liquid biopsy lets doctors and researchers see a broad range of genetic changes across an entire tumor. This can provide them with much more information than they might get from a tissue biopsy taken from a single area of a tumor.

In spelling out the DNA sequences for many, many individual cells, these studies create a huge amount of data. For that reason, computational biology and bioinformatics are an important part of this field of research. Dana Pe’er, Chair of the Sloan Kettering Institute’s Computational and Systems Biology Program, is leading this effort at MSK. She and her team are creating mathematical algorithms that allow computers to scan the large amounts of data that come from single-cell analysis, providing a filter to identify the most important findings.

These approaches are expensive and are not used as a regular part of cancer care. But researchers are looking at ways to reduce the costs. The goal is that these tools will eventually become widely available and the standard way to diagnose cancer and monitor how well treatment is working.

An Important Laboratory Tool for DCIS and Beyond

Currently, Dr. Reis-Filho and his team are using single-cell analysis to study tumor samples from surgical biopsies. In February 2017, they reported that they had developed the first method for doing single-cell sequencing from older tumor samples — even those that have been preserved and stored for years.

At the San Antonio Breast Cancer Symposium in December 2017, Dr. Reis-Filho discussed research in which he used this technique to study preserved tumor samples from a type of breast tumor called ductal carcinoma in situ (DCIS). DCIS is a very early-stage, noninvasive cancer. Women who develop it have about a 25% chance that the cancer will come back after surgery, and then it can become invasive.

The long-term goal of this work is to find genetic changes in individual cells that predict which people are more likely to have the tumor return and to define if the genetic heterogeneity itself could predict the behavior of DCIS. That way some women with DCIS could receive more-aggressive treatment right away, while others who are not at a high risk could avoid it.

“One interesting finding from our study was that intratumor heterogeneity can occur very early in the formation of a tumor, even in the DCIS stage,” says Dr. Reis-Filho, who is a member of MSK’s Human Oncology and Pathogenesis Program. “This is contrary to what was previously believed — that heterogeneity was an event that developed later in the growth of tumors.” This discovery uncovered new clues about the genetic underpinnings of this type of cancer.

The problem of intratumor heterogeneity is not limited to breast cancer. “We know more about it in types of cancer that have been more extensively studied, like breast cancer and lung cancer,” Dr. Reis-Filho adds. “But we suspect that it applies to most types of solid tumors.”

Investigators continue to advance their ability to study tumors at the level of a single cell. Through this research, they expect to find even more information about what drives tumor growth. This, in turn, will help them improve ways to diagnose cancer. Single-cell analysis may also enable the development of more-effective targeted therapies or combinations of targeted therapies to treat the most-aggressive cells within a tumor.

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Experimental Cancer Drug Developed at MSK Leads to New Approach for Treating Alzheimer’s Disease

Source: Memorial Sloan Kettering - On Cancer
Date: 03/01/2018
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Like cancer, Alzheimer’s disease involves changes in proteins. When functioning normally, proteins are important for cells to work properly. Also like cancer, Alzheimer’s occurs more commonly in older people, reflecting the idea that it usually takes a long time for these kinds of cellular changes to build up to a point that they cause real damage.

So although it may be a bit surprising, it’s not an impossible stretch to think that a drug developed to treat cancer may also work against Alzheimer’s disease. A family of these drugs has its origins at Memorial Sloan Kettering.

MSK chemical biologist Gabriela Chiosis has developed compounds for both cancer and Alzheimer’s. This week she spoke about her work at the National Institutes of Health’s Alzheimer’s Disease Research Summit. Dr. Chiosis was among top researchers from around the world who were invited to present their research on the biology of Alzheimer’s.

“Of Dr. Chiosis’s many intriguing discoveries, one that stands out is that Alzheimer’s disease shares a common cellular abnormality with many cancers,” says Larry Norton, Deputy Physician-in-Chief for Breast Cancer Programs at MSK, who has collaborated with Dr. Chiosis on the development of drugs. “The fact that there is a common mechanism raises the possibility of a common therapy. So her research could have profound implications for many human diseases, particularly those associated with aging.”

Targeting the Disease Process

Dr. Chiosis’s current work is focused on a type of regulatory network found inside cells called epichaperomes. “Epichaperomes form under conditions of chronic stress, something that is found in both cancer and Alzheimer’s disease,” she says. “One of the roles of these networks is to enhance the processes that become disrupted in diseased cells. These processes include defective signaling, increased production of certain proteins, and inflammation.”

In 2005, Dr. Chiosis and her colleagues developed a drug called PU-H71 for the treatment of cancer. PU-H71 is now in a phase I/II trial for people with metastatic breast cancer. Based on their discoveries about PU-H71, she and her team later developed a related drug, which they called PU-AD, for Alzheimer’s disease.

Both drugs bind to a protein called Hsp90 but only when it’s incorporated into the epichaperome network. Hsp90 is a protein found in essentially every cell in the human body. Its normal role is to help with proper protein folding. But when it becomes part of the epichaperome, Hsp90 contributes to stabilizing the proteins inside cells that let the disease develop.

“The formation of the epichaperome keeps damaged cells alive while they remain dysfunctional,” Dr. Norton explains. “Dr. Chiosis’s discoveries about epichaperomes are important because they are so overarching and could apply to many diseases.”

Taking a Look Inside Cells

Dr. Chiosis’s research has also led to imaging methods for detecting epichaperomes in cancer and Alzheimer’s, called PU-PET and PU-AD PET, respectively. She has collaborated with other investigators at MSK, including radiochemists Jason Lewis and Naga Vara Kishore Pillarsetty and radiologists Mark Dunphy and Steven Larson, on their development.

The approach involves attaching a weak radioactive label to PU-H71 or PU-AD, which then can be imaged with PET scanning. For cancer, PU-PET allows doctors to identify who is most likely to benefit from PU-H71 treatment. It can also help doctors monitor how well the drug is working.

In her presentation at the NIH summit, Dr. Chiosis discussed how an understanding of the epichaperome network can be used to identify some of the changes that occur in a number of different pathways in brain cells. These pathways can lead to Alzheimer’s disease, and learning more about them could suggest possibilities for the development of new targeted drugs.

She also talked about how PU-AD PET can be used to visualize Alzheimer’s disease in the brain. “The negative effects on memory, behavior, and the ability to think clearly that are commonly witnessed in people with Alzheimer’s are due to accumulation of toxic proteins called amyloid and tau in the brain,” Dr. Chiosis says. “But toxic changes in the neuron may begin 20 years before these deposits or the clinical symptoms of the disease develop. As such, we believe that using PU-AD PET to detect Alzheimer’s during this long preclinical phase may provide a promising window of opportunity for treatment.”

Both the PU-PET and PU-AD PET scans are now being tested in clinical trials at MSK. Dr. Norton and Dr. Chiosis have established a company called Samus Therapeutics that is focused on developing these scans as well as new therapies that target the epichaperome.

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New Classification System Will Improve Diagnosis and Treatment of Brain Tumors

Source: Memorial Sloan Kettering - On Cancer
Date: 03/14/2018
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There are more than 100 subtypes of brain tumors, making them a challenge to accurately diagnose. This week, an international team led by researchers at the German Cancer Research Center is announcing they have developed a new way to classify these tumors. A paper describing the tool was published in Nature.

Proper diagnosis and classification is vital for brain tumors. It not only helps with prognosis but also enables doctors to determine the best treatment. For example, some tumor types respond better to radiation therapy than others, while some respond to certain chemotherapy drugs. Some don’t need to be treated at all and can just be closely monitored.

We spoke with Memorial Sloan Kettering Pediatric Neuro-Oncology Service Chief Matthias Karajannis, who participated in the research, about why this study is important and what it means for people with brain cancer, both at MSK and around the world.

Why are brain tumors so hard to classify?

Brain tumors, especially in children, are not a uniform disease. They are actually many different diseases. Until recently, these tumors were diagnosed exclusively by looking at cells under a microscope. But even for the most experienced pathologist, it can be challenging to tell some of the different types apart. You could have three pathologists look at the same tumor sample and come up with three different diagnoses.

Advances in gene sequencing, such as MSK-IMPACTTM, have led to improvements. But there are limitations with sequencing cancer-related mutations, especially in pediatric brain tumors. Many of the subtypes don’t have a known gene mutation that is commonly linked with them that can be used to classify the subtype of tumor.

What’s different about the system that’s been developed now?

This research team has developed a completely new classification system. It is the first time anyone has shown a way to reliably distinguish from among the 100-plus different types of brain tumors.

The system looks at what is called the tumor’s methylation profile. Once the profile is determined in the lab, it can be fed into an algorithm in a computer and automatically matched with samples that already exist in the database. This approach is based on the fact that each tumor subtype has a different methylation profile.

Another aspect that was important about the study is that we demonstrated this approach is equally feasible and reliable across multiple cancer centers.

What is a “methylation profile”? How is it different from other types of tumor analysis?

Methylation is a way that DNA is modified without changing the sequence of the four DNA letters. It’s one of the factors that influences how and when genes are translated into proteins.

I like to use a music analogy. The DNA sequence is the notes on the page. The methylation profile helps determine how fast or slow the music is played, how loud or how soft.

When I came to MSK, I was pleased to learn that the Molecular Diagnostics Service, under the leadership of Service Chief Marc Ladanyi, was already establishing the technical platform to study the methylation profile of tumors. The equipment needed to do these kinds of studies had just arrived. Dr. Ladanyi and his team will be working with the New York State Department of Health to help methylation profiling become an approved clinical test, the first step toward insurance coverage. It’s currently considered an experimental test for research purposes.

Will this study affect how MSK diagnoses its patients?

We are already using this tool with all of our pediatric brain tumor patients, and with many adults who have brain tumors as well. We’ve been using it for a while. But now we’re in the process of working out an agreement with the German Cancer Research Center team so that we’ll be able to do all the analysis with the tool right here at MSK in Molecular Diagnostics. Currently, we send them the results from our methylation studies and they send back the information about tumor classification.

We are also looking at how methylation profiling can be used to diagnose other types of tumors, especially sarcomas. Sarcomas are another kind of tumor that have many, many different subtypes. And just like in brain tumors, these subtypes can be hard to distinguish based on how they look under the microscope, or even by looking at their genetic profile.

You came to MSK just over a year ago. Why did you decide to join the team?

I completed my fellowship training at MSK and then spent nine years at New York University School of Medicine. It was an exciting opportunity to return as Chief of the Pediatric Neuro-Oncology Service and to work with the world-renowned experts here, many of whom were part of my training.

MSK has one of the largest, if not the largest, pediatric neuro-oncology programs in the country. We see about 100 children who have been newly diagnosed with brain and spine tumors every year.

In addition, the research capabilities here are outstanding. Combining the infrastructure and equipment that was already here with my own work in molecular diagnostics made my coming here a perfect storm of opportunity. We are able to diagnose and treat people with brain cancer better than at any time before, and MSK is doing it better than any other institution.

What made you want to become a pediatric neuro-oncologist?

I went to medical school at a time when rapid progress was being made for treating other pediatric cancers, especially leukemia. There also were many new tools for diagnosing leukemia. By the time I graduated, the majority of children with blood cancers were being cured, thanks to better and more refined chemotherapy treatments.

I didn’t see the same progress being made for brain tumors. Techniques in surgery and radiation were getting better, and there was some limited success with chemotherapy. But there was still a lot of work to be done. Because I had lab training in molecular pathology, I knew that in the future, improving diagnosis would be a real game-changer in this field. And it has been. It’s been exciting and rewarding to be part of this quantum shift.

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Colonoscopy and Other Screening Methods for Colon and Rectal Cancer: What You Should Know

Source: Memorial Sloan Kettering - On Cancer
Date: 03/15/2018
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Colorectal cancer is the third most common cancer in both men and women. Unlike many other cancers that do not yet have reliable screening methods, there are a number of ways to detect colon and rectal cancers early, before they cause any symptoms and when they are more likely to be curable.

Below are some frequently asked questions about colorectal cancer screening and advice for getting tested.

Why is it important to be screened for colorectal cancer?

About 140,000 people in the United States are diagnosed with either colon cancer or rectal cancer every year. This translates to a lifetime risk of about one in 22 for men and one in 24 for women. More than 50,000 people in the United States die from colorectal cancer every year.

Survival rates for colorectal cancer have greatly improved in recent years. That’s thanks in large part to tests that detect the disease much earlier than ever before. In addition, colonoscopy screening can actually prevent cancer from developing in the first place by removing growths called polyps before they have a chance to become cancer. MSK biostatistician Ann Zauber, who uses statistical modeling to inform health policy related to colorectal cancer screening, led a study in 2012 that confirmed removal of polyps with colonoscopy actually prevents colorectal cancer deaths.

What are my options for colorectal cancer screening?

There are two major methods of screening for colorectal cancer. The first is to examine the stool for evidence of cancer. The second involves looking inside the colon and rectum.

Of the stool-based tests, the fecal occult blood test (FOBT) and fecal immunochemical test (FIT) both can detect small traces of blood in the stool. Colon or rectal bleeding can be a sign of cancer. A newer test, called Cologuard, looks for both blood and small amounts of tumor DNA.

Imaging tests include colonoscopy,flexible sigmoidoscopy, and virtual colonoscopy (also known as CT colonography). With a colonoscopy, a thin, flexible tube with a light and a video camera on its tip is placed in the colon to search for polyps and cancer. Before the test, you need to prepare by consuming a clear liquid diet and taking a medication to clear out your bowels. Colonoscopy requires you to be sedated during the examination

A flexible sigmoidoscopy is similar to a colonoscopy, except that a doctor uses a shorter tube to examine only the lower part of your colon. It often does not require sedation. In virtual colonoscopy, you still have to undergo the preparation in advance, but the CT scans can be performed while you are awake. “CT colonography is effective for detecting cancer and large polyps, but it’s not as good as colonoscopy at detecting small or flat polyps,” says MSK gastroenterologist Robin Mendelsohn, who focuses on working with people who are at high risk of developing colorectal cancer.

Also, if something is found during a stool-based test or a CT colonography, you still will need to undergo a colonoscopy to diagnose or rule out cancer and remove any polyps that are found.

Who should be screened for colorectal cancer?

MSK’s current guidelines say that if you don’t have a strong family history of colon and rectal cancers or a known genetic predisposition to colorectal cancer, screening should start at age 50. For those who have had regular screenings and never had any polyps found, the tests may not be needed after age 75.

But there are many exceptions to these rules. For example, people who have a strong family history should speak with their doctors about the best age to start screening. This age is largely dependent on when your family members first developed cancer or polyps.

If you have a personal history of colorectal cancer or polyps, you should talk with your doctor about whether you should continue screening past the age of 75.

Finally, for people who have an inherited condition called Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer), experts usually recommend that frequent screenings start as early as while you’re still in your 20s. This condition can be detected through a genetic test.

How often should I get a colonoscopy or other screening test?

It depends on the type of test you get. To be most effective, FOBT and FIT need to be done every year. The current recommendation for the DNA stool test is every three years. But according to Dr. Mendelsohn, the test is still so new — it was approved by the FDA in 2014 — that experts aren’t yet sure about the optimal timing.

For imaging tests, it depends on whether anything is found during the exam. If you have one or two small polyps and they show no signs of being advanced, you should have colonoscopies every five years. If you have three or more polyps or polyps that appear to be more advanced, you should get tested every three years. Otherwise, you need to get screened only once every ten years.

What is the preferred method of screening at MSK?

“Many of us consider colonoscopy to be the gold standard, because there is a capability for both diagnosis and treatment,” Dr. Mendelsohn says. “But I always say the best test is the one that gets done, and gets done well. For people who are unable to undergo colonoscopy, any screening test is better than no test at all.

“Stool tests are much easier for people to take, and they can be done at home,” she adds. “They can improve the prognosis for people with colorectal cancer by detecting early-stage disease that is usually very treatable. But they’re not very good at detecting polyps.”

What are my options if polyps or cancer are found?

If polyps are found during a colonoscopy, they can often be removed right away, while you’re still in the procedure room. Removing them prevents cancer from forming. The polyps will be sent to a pathologist for analysis. Based on the number of polyps and how the cells look under the microscope, your doctor will make recommendations for how often you should have follow-up screenings.

Colon and rectal cancers are much more curable when they’re detected early. For people who do have cancer, advances in drugs and other treatments have improved survival over the past few decades. Today, even some people whose disease has spread to other parts of the body, called metastatic or stage IV cancer, can be cured.

What is MSK doing to promote colorectal cancer screening?

Dr. Mendelsohn, Dr. Zauber, and other members of MSK’s colorectal cancer team have been advisors to the New York City Citywide Colon Cancer Control Coalition, also known as C5. The goal of C5 is to increase the rate of colorectal cancer screening among citizens of New York City, especially members of racial and ethnic minorities that are less likely to get screening.

Women who meet the eligibility requirements can also receive colorectal cancer screening at MSK’s Breast Examination Center of Harlem through the New York State Cancer Screening Program.