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8 Questions with Valerie Rusch: Lung Cancer Surgeon Reflects on Advances and Providing Excellent Care

Valerie Rusch is Vice Chair for Clinical Research in the Department of Surgery at MSK. She is a thoracic surgeon who treats lung cancer and esophageal cancer, malignant pleural mesothelioma, and other tumors of the chest. She was the first woman named as a service chief and promoted to full Member in her department at MSK.

1. In October, you will become president of the American College of Surgeons. What does that entail?

The group is the world’s largest surgical organization. It represents 80,000 surgeons across all specialties, both nationally and internationally. Its mission is to improve care by setting high standards for surgical practice and education. I will be the college’s 100th president but only the fourth woman to hold the position. My role is to represent the organization at educational conferences around the world.

2. Did you always know you wanted to be a doctor?

My father was in the Navy Medical Corps during World War II and later became an otolaryngologist. This gave me some exposure to the medical world. In college, I worked as an operating room technician for two summers. My father’s family was Swiss, and a bilingual education was important, so I attended the Lycée Français in New York City. I considered multiple career paths, including being an interpreter, but ultimately was most attracted to medicine. I ended up going to medical school at the College of Physicians and Surgeons at Columbia University.

3. How do you cope with being a woman in a male-dominated field?

There have been challenges. But my father always said, “No one can argue with excellence.” Although I’ve certainly encountered instances of prejudice, I’ve focused on delivering excellent clinical care, helping my patients, and taking advantage of research opportunities to develop new treatments. It has been rewarding to see substantially more women in surgery and to see them increasingly accepted within the surgical community.

4. How did you get interested in thoracic surgery?

During my residency in general surgery at the University of Washington, I was exposed to many surgical subspecialties. I found that thoracic surgery provided a blend of technically challenging procedures and cognitive decision-making. I particularly appreciated the meaningful long-term relationships that develop during the care of people with cancer.

5. When did you come to MSK?

In 1989, I was recruited to travel to New York City and interview for a position at MSK. It came at the perfect time because I had recently decided to focus my career on cancer care. Thoracic surgeons do a lot of different things, including lung transplants, reconstruction after trauma, and treatment of benign diseases. Cancer was where I felt I could make the biggest difference.

6. How has treatment for lung cancer changed over time?

Minimally invasive surgical techniques have made recovery easier, and we can operate more safely on older patients due to advances in pre- and postoperative care. New radiotherapy techniques can help patients who cannot have surgery. Lung cancer screening with CT imaging has led to many more people being diagnosed with very early-stage tumors, when they may be cured by surgery or radiation therapy alone. And targeted therapies and immunotherapies have led to higher survival rates in people with more advanced lung cancers.

7. What is a challenge that remains?

One emotional challenge is the guilt that patients feel because the majority of these cancers are linked to smoking. They tend to hold themselves responsible for their disease. Also, smoking rates have declined in North America but remain high in many parts of the world.

8. How does MSK support people with lung cancer?

We have many medical and psychosocial resources for patients throughout their treatment and afterward. Now that many of our patients are living longer, survivorship care has become important. Subsequent primary lung cancer after successful treatment of an initial lung cancer is a significant risk. We developed the first lung cancer survivorship program nationally to provide lifelong follow-up, supportive care, and screening. It has become a significant part of our care.

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What Causes Leukemia after Breast Cancer? Research Shows That a Mutation May Be Present All Along

Source: Memorial Sloan Kettering - On Cancer
Date: 09/09/2019
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Doctors have known for a long time that cancer survivors may be at risk of a rare aftershock: developing a secondary leukemia years or even decades later. Because some chemotherapy drugs can damage the DNA in the bone marrow, where leukemia forms, experts have assumed that the drugs trigger the formation of cancerous blood cells that lead to leukemia.

A new study of people with breast cancer treated at Memorial Sloan Kettering is turning that idea on its head. The findings suggest that in some people, leukemia-causing gene mutations may be present in blood cells from the time that breast cancer is originally diagnosed, before chemotherapy is ever given. Although this discovery is important, the study looked at only a small group of patients, so larger studies are needed to confirm the findings.

“In the past, we’ve never been able to predict which breast cancer patients may be at risk for developing leukemia in the future,” says medical oncologist Elizabeth Comen, first author of the study published August 27 in the Journal of the National Cancer Institute (JNCI). “Our findings provide new clues about how and when these leukemias may originate. They also suggest that we may be able to identify who is at risk of developing leukemia, paving the way to prevent secondary leukemias.”

About 70% of secondary leukemias occur in people who have been treated for breast cancer. (The rest are in people treated for other types of cancer, mostly other solid tumors.) Around 0.5% of people treated for breast cancer eventually develop a secondary leukemia.

Searching for a Change in the Blood

The investigators focused on seven women treated for breast cancer at MSK who later developed a specific type of leukemia called acute myeloid leukemia. They studied the original tumor tissue that was removed at the time of surgery to look for signs of cancer in the blood. They focused on white blood cells, a component of the immune system, which are often present in the environment surrounding tumor cells.

“In four of the seven women who went on to develop leukemia, we could detect cancer-causing mutations in the immune cells that were removed with their original tumors,” says physician-scientist Ross Levine, senior author of the study. “Previous studies have reported cases in which leukemia mutations were observed years before people with solid tumors developed therapy-related leukemia. We were able to show that in many cases, secondary leukemia arises because preexisting altered blood cells are already there at the time of the first cancer.”

The changes observed in the immune cells are due to a phenomenon called clonal hematopoiesis (CH), which Dr. Levine studies. People with CH have an increased number of white blood cells that carry mutations that are also found in blood cancers. Some people with CH will go on to develop leukemia, although most do not.

“CH mutations are part of aging,” Dr. Comen says. “You can think of them like gray hairs or wrinkles but in the immune system.” Studies have suggested that between 10 and 20% of people over age 70 have signs of CH in their blood.

A Unique Collaboration

The JNCI study came about because of a unique collaboration among members of MSK’s Breast Medicine Service, Leukemia Service, and Department of Pathology. Physician-scientist Jorge Reis-Filho, Chief of the Experimental Pathology Service and an expert in uncovering detailed molecular information from archival tumor samples, was another co-author on the study.

Dr. Reis-Filho used a lab technique called laser capture microdissection (LCM) to separate immune cells from tumor cells within the tumor tissue. “This technology has been around for more than a decade,” he explains, “but this was the first time that we used this method to ask such an important clinical question and to define the clinical impact of mutations affecting immune cells.”

Although the mutations are present much earlier than previously known, the investigators don’t completely dismiss the role of chemotherapy in the development of leukemia. They believe that these drugs may make the environment for leukemia more hospitable and may help it grow and spread more effectively.

Next Steps for a Surprising Finding

Much more research needs to be done to validate these findings in a larger number of people. The investigators also plan to expand this work to look for the presence of immune cells with CH mutations in other types of solid tumors. Drs. Comen and Reis-Filho are currently developing new ways to look for these mutations that are less labor-intensive than LCM.

According to Dr. Levine, there are several long-term goals of this research. “Once we know who is at risk of developing leukemia, we can monitor them so we can catch the disease early. It’s also possible that these findings could influence the treatment that patients get for their initial cancer,” he says. “Ultimately, we hope this research will lead to ways to prevent or reverse the progression from CH to leukemia.”

These efforts are all part of a larger push in CH research across MSK under the Precision Interception and Prevention Program, which is led by Luis Diaz, Head of the Division of Solid Tumor Oncology.

“This study — of breakthrough potential — is a great example of the kind of science that can only be accomplished by a dedicated multidisciplinary team melding laboratory expertise and clinical insight,” says co-author Larry Norton, Senior Vice President in the Office of the President of MSK and Medical Director of the Evelyn H. Lauder Breast Center. 

“While this study provides key insight into how we may better predict who is at risk for a future leukemia, it is not cause for alarm. The risk of leukemia still remains exceptionally small for people with breast cancer,” Dr. Comen says. “Those who have specific concerns should speak to their doctors.”

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How an Altered Gatekeeping Protein Can Cause Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/16/2020
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Cancer is caused by gene mutations, but sometimes it’s hard to figure out which mutations actually drive tumor growth and which are just along for the ride. One way to determine this is to look for so-called mutational hot spots. These areas of the genome are mutated in tumors more frequently than would be expected by chance. The frequency suggests that they may play an active role in cancer.

MSK-IMPACTTM, Memorial Sloan Kettering’s diagnostic test that looks for genetic changes in more than 400 genes in patients’ tumors, has proven quite useful in the discovery of new hots pots. Researchers in the Human Oncology and Pathogenesis Program (HOPP) have used the identification of one particular hot spot to explain why a gene called XPO1 causes cancer. The findings were published online July 8 in Cancer Discovery.

“Researchers already knew that XPO1 regulates which proteins are located in a cell’s nucleus and which get moved to the cytoplasm. This is a basic function for any cell,” says senior author Omar Abdel-Wahab, a physician-scientist in HOPP. “But until now, nobody has ever shown how the alteration of the XPO1 protein could cause cancer. This study shows how this happens.”

Decoding the Function of an Important Protein

XPO1 is often mutated in blood cancers — especially many types of lymphoma. XPO1 mutations are also found in some solid tumors. A drug that targets these mutations, called selinexor (Xpovio®), was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma. It is being tested in clinical trials for other cancers at several institutions, including MSK. But researchers weren’t sure which patients were most likely to respond to the drug.

An analysis of MSK-IMPACT data led by study co-author Barry Taylor, a computational oncologist and Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, suggested that a specific mutation in XPO1, called E571, was common in cancer. To study the function of that particular mutation, Dr. Abdel-Wahab’s team put a version of the gene with the E571 mutation into mice. The mice developed cancer at a high rate. The researchers then did additional studies in the mice and in human cancer cells to find out how the mutation causes cancer.

“We found that the mutant form of XPO1 promoted excessive cell growth,” says first author Justin Taylor, an MSK medical oncologist and member of Dr. Abdel-Wahab’s lab. “Further analysis showed that this occurs because of XPO1’s role as a gatekeeper that regulates which proteins can exit the nucleus.” The researchers found that mutations affect the function of this gate, changing which proteins stay in the nucleus and which leave and go to the cytoplasm.

Dr. Taylor adds that the research also revealed why the drug is effective. “The mutation changes the electrical charge of the XPO1 protein, which makes selinexor bind to it more strongly. This makes the cancer cells more prone to die.”

Developing a More Personalized Approach

Clinical trials for selinexor are ongoing. Currently, MSK is participating in a trial for people with liposarcoma. The results of a trial for people with myelodysplastic syndrome were presented at a recent meeting of the American Society of Hematology.

Dr. Abdel-Wahab says that the E571K mutation may prove to be an effective way to determine who is likely to benefit from selinexor. This could influence future clinical trials of the drug and lead to a more personalized approach to who gets the drug.

The researchers also plan to study the role of other XPO1 defects in cancer, including cases where the gene is overexpressed but not necessarily mutated.

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Meet Julia Glade Bender, Who’s Focused on Developing Better Treatments for Kids with Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/20/2019
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Julia Glade Bender is a pediatric oncologist and Vice Chair for Pediatric Clinical Research at MSK Kids. She specializes in treating children with solid tumors of the bone and soft tissue, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and germ cell tumors.

She is a leader in developing clinical trials and other treatments for children with cancer that does not respond to standard treatment.

We spoke with Dr. Glade Bender about the challenges of treating rare childhood cancers and how personalized medicine is leading to better therapies for tumors that are especially hard to treat.

What makes cancer in children different from cancer in adults?

Most cancer in adults is spurred by a lifetime of exposure to outside factors — like tobacco smoke and UV light — combined with the natural DNA damage that comes with aging. Harmful genetic mutations begin to accumulate and eventually can tip the balance and cause cancer. Childhood cancers, in contrast, are often triggered by a unique event, such as a rearrangement in the chromosomes that creates an entirely new gene. These alterations can happen early in a child’s life or even before they are born.

Additionally, solid tumors in children usually arise in a different type of cell. Most adult cancers are carcinomas, which develop out of the tissues that line the inner and outer surfaces of the body, like the skin and the lining of the intestines and other organs. Childhood cancers are usually sarcomas, which form in cells in the muscles, bones, and other connective tissues.

What are some of the biggest challenges of treating cancer in children?

We can cure 80% of kids with existing treatments, especially chemotherapy, radiation, and surgery. But for the remaining 20%, new options are urgently needed.

Because these cancers are so rare, even if we have an idea of which drugs we should use to treat them, it’s difficult to develop clinical trials. A certain number of patients are required for clinical trials. For rare subtypes of uncommon cancers, which may occur in only a few dozen children in the whole country, this isn’t always possible.

Although we already have successful treatments and can cure the majority of children with cancer, we know that these treatments can have long-term effects on their health, well into adulthood. We hope to eventually develop treatments that don’t have these side effects.

How is targeted therapy changing treatment?

At MSK Kids, all children receive testing with MSK-IMPACTTM. This test helps us find particular mutations that may be driving the growth of tumors and suggest ways to treat them.

Clinical trials developed by MSK’s Early Drug Development Service can now include children as young as 12. Previously the age was 18. Although we always make the case that kids are not just little adults, we know that when it comes to things like side effects, kids over the age of 12 are more closely aligned with adults than they are with younger kids.

For a few mutations, we have drugs that have already been approved for use in kids by the US Food and Drug Administration. The biggest success is probably larotrectinib (Vitrakvi®), which is approved for solid tumors that have a mutation in a gene called NTRK.

For other, rarer mutations, we may develop a protocol for single-patient use (SPU). These compassionate-use plans require tremendous resources, including finding a drug — and a company willing to supply it — then getting permission from the Institutional Review Board and the FDA to administer the drug. It can be a lengthy and labor-intensive process.

We always collect a lot of data when we do SPUs, so that we can learn as much as possible about how and why these drugs work or don’t.

How does research done at MSK Kids help children who aren’t able to come here for treatment?

Because we collect so much information with our SPU protocols, they can eventually lead to clinical trials that may be expanded to other hospitals. That has already happened with five drugs that started as SPUs.

Members of MSK Kids also participate in a number of collaborative groups. I’m involved with the Pediatric MATCH Trial, which is a national effort to get drugs to as many patients as possible. It’s co-sponsored by the National Cancer Institute and the Children’s Oncology Group. We are already looking at eight different parts for different drug targets, and we’re adding new ones all the time.

Through these efforts we not only develop trials but also help set the standard of care for the treatment of children with cancer throughout the country and the rest of the world.

You came to MSK Kids about a year ago, after spending most of your career at another hospital. Can you talk about the move?

One thing that’s really special at MSK Kids is the collaboration with specialists beyond pediatrics, whether that’s scientists working in labs or medical oncologists who work with adults. We have a lot we can learn from one another.

Another thing that’s interesting about being at MSK is that this is where some of the earliest successful treatments for childhood cancer were developed 30 or 40 years ago. And some of those pioneering doctors are still here.

Now we’re at the forefront of this new era in personalized medicine. You’ve got this interplay between the mothers and fathers of chemotherapy and the new leaders in targeted therapy. To cure the greatest number of children, you really need both. 

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For MSK’s Gynecologic Oncologists, Uncommon Cancers Aren’t Always Rare

Source: Memorial Sloan Kettering - On Cancer
Date: 09/27/2019
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In its annual listing of the country’s best hospitals, U.S. News & World Report ranked Memorial Sloan Kettering number one in gynecology for 2019. MSK’s oncologists, surgeons, nurses, and pathologists are the leaders in diagnosing and treating well-known gynecologic cancers, such as cervical cancer, endometrial cancer, and ovarian cancer.

They also have vast experience in treating uncommon gynecologic cancers. This includes types that some healthcare providers may see only once or twice in their whole careers.

Here are some of the less common gynecologic cancers that MSK’s experts are successfully treating.

Vulvar and Vaginal Cancers

Vulvar cancer affects about 6,000 women per year, and vaginal and related cancers affect another 5,000. About 60% of these cancers are associated with human papillomavirus infections; these cases tend to develop in younger women. The other 40% are often caused by a skin condition called lichen sclerosus, which usually occurs after menopause.

MSK gynecologic surgeon Mario Leitao specializes in treating vulvar and vaginal cancers. These are usually squamous cell cancers similar to those that grow on other parts of the skin. Most women with these cancers have surgery as part of their treatment.

Dr. Leitao and his colleagues have conducted clinical trials on the use of sentinel node biopsies in these surgeries, including the use of new types of imaging agents to guide the procedure. Sentinel node biopsies involve removing only one or two lymph nodes in the groin area to test if the cancer has spread. This allows women to avoid side effects, like lymphedema of the legs, a debilitating and painful swelling that can occur when all the lymph nodes in that area are removed.

For those whose cancer comes back after treatment, MSK has additional options. “Our goal is to cure women when they first present with cancer,” Dr. Leitao says. “But when things don’t go the way we want, we’re a leading center for the larger, more complex surgeries that may be required.”

A rare subset of vaginal and vulvar cancers — about 1% — is melanoma. Dr. Leitao, medical oncologist Alexander Shoushtari, and radiation oncologist Marisa Kollmeier run a clinic for women with vulvar and vaginal melanoma. Patients are often able to see all three specialists on the same day.

As with other types of melanoma, immunotherapy with checkpoint inhibitor drugs is often used to treat gynecologic melanoma. The drugs may be given in combination with radiation therapy to improve their effectiveness.

“Each of these patients is unique, and we come up with a specialized treatment plan for each of them,” Dr. Leitao explains. “They all get their tumors tested with MSK-IMPACTTM, which can teach us a lot about the mutations driving these cancers. We are learning much more about the genetic and molecular makeup of gynecologic melanomas, with the goal of developing even better treatments in the future.”

Uterine Sarcoma

Most cancer of the uterus is endometrial cancer. This starts in the tissue that lines the uterus. Uterine sarcoma, which develops in the muscle or connective tissue, is much less common. There are several types of uterine sarcoma, including leiomyosarcoma, high-grade undifferentiated sarcoma, and endometrial stromal sarcoma. Uterine sarcoma is rare, making up less than 4% of all cancers of the uterus. Only 1,200 women are diagnosed with this disease in the United States each year.

Most uterine sarcoma is treated with surgery. Gynecologic oncologist Oliver Zivanovic specializes in these procedures. “The experience of the surgeon is very important,” he notes. “When these tumors are removed, achieving negative margins is very important. Some uterine sarcomas are quite large or infiltrate into the surrounding tissue, so it’s not always an easy surgery.”

For women who need chemotherapy after surgery, Dr. Zivanovic often collaborates with MSK medical oncologist Martee Hensley, an internationally recognized leader in treating these cancers.

One of the challenges of treating uterine sarcoma is that it often doesn’t have symptoms, or its symptoms are similar to much more common noncancerous conditions, like fibroids. Additionally, because it’s so rare, uterine sarcoma has no established screening methods. But experts at MSK have reported there is one group of women who are at a higher risk of leiomyosarcoma: those who have previously been treated for retinoblastoma, a type of eye cancer in children that is often hereditary.

For these women, Dr. Zivanovic and MSK ophthalmic oncologist Jasmine Francis have established a surveillance program, which offers annual exams with imaging including MRI and ultrasound. In addition to helping women at the highest risk of developing a second cancer, the investigators say that what they learn from these women will enable them to develop better detection strategies for all cases of uterine sarcoma.

Uncommon Ovarian Cancers

All ovarian cancers are considered rare, but some types are even less common. One of these, called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), has had only about 500 documented cases to date. Despite its low incidence, MSK researchers have conducted extensive research on SCCOHT.

In 2014, MSK gynecologic surgeon Jennifer Mueller was part of a team that found a particular mutation in a gene called SMARCA4 present in this aggressive cancer. Although the discovery has not yet yielded any targeted therapies, further studies revealed that nearly half of these mutations are inherited. This discovery has important implications for family members of women diagnosed with these tumors.

Dr. Mueller recently performed risk-reducing surgery on a young woman who learned she had the SMARCA4 mutation after her sister was diagnosed with SCCOHT. The woman had her eggs retrieved and banked before the removal of her ovaries. “If it hadn’t been for the research done at MSK, as well as the genetic counseling offered to the family, this young woman would have never known she carried this risk,” Dr. Mueller says.

Dr. Mueller treats other less-common forms of ovarian cancer, including clear cell, endometrioid, and germ cell tumors. “For any woman who has one of these rare types, I would encourage her to get a second opinion with a pathologist who has experience in diagnosing them,” she says. “Getting a proper diagnosis can have a major impact on treatment decisions, which can, in turn, affect outcomes as well as a woman’s quality of life.”

Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a tumor that develops from fetal tissue after a pregnancy, including a full-term delivery, a miscarriage, or an ectopic pregnancy. If the tumor is cancerous, it is called a gestational trophoblastic neoplasm (GTN).

These tumors are treated with surgery. More advanced cases may require chemotherapy. MSK medical oncologist Carol Aghajanian is a nationally recognized leader in treating GTN when chemotherapy is needed.

“The good news is that GTNs are almost 100% curable,” Dr. Mueller says. “But because they are uncommon, it’s important to make sure that you have the correct diagnosis. If a woman is diagnosed with a cancerous form and it turns out not to be cancer, she may be given additional treatments that she doesn’t need.”

Supportive Services

For women with gynecologic cancers of all types, MSK’s Female Sexual Medicine and Women’s Health Program, run by psychologist Jeanne Carter, offers comprehensive, personalized care.

MSK also has physical therapists who specialize in pelvic physical therapy. This process can be helpful in dealing with pelvic pain and pressure, which is especially common after radiation treatments.

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MSK’s Expanded Genomics Program Takes a Deep Dive into the Causes of Childhood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2019
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MSK-IMPACT™ detects changes in more than 400 cancer-associated genes. The test has made a meaningful difference for many adults treated at Memorial Sloan Kettering. By identifying the mutations driving a tumor’s growth, test results may indicate which targeted therapy or immunotherapy is likely to work against a tumor. Results can also be used to find an appropriate clinical trial.

But the picture is quite different for children with cancer. About half of their tumors do not have a significant mutation that can be identified with MSK-IMPACT or any other standard clinical test. For these kids, developing new forms of molecular diagnosis is essential.

“As a whole, pediatric cancers are a collection of very diverse and very rare tumor types,” says MSK molecular geneticist and data scientist Elli Papaemmanuil. “Their genomes are very different from the genomes of most cancers seen in adults. We still have so much to learn about them.”

This is the motivation behind the establishment of MSK’s Expanded Genomics Program. The program, led by Dr. Papaemmanuil, was launched in September 2018 to develop a way to comprehensively map the unique changes driving each individual tumor. The ultimate goal is to understand and eventually identify personalized treatment approaches for every child treated for cancer at MSK Kids.

Going Beyond the Standard Approach

In the lab, the Expanded Genomics team has already performed an in-depth examination of tumors from more than 120 children treated at MSK. This analysis includes looking at the gene mutations detected by MSK-IMPACT, sequencing the rest of the tumor genome, and measuring levels of RNA. Changes in RNA can help indicate which genes are affected.

“We hope to be in a position where we can identify the novel genetic events that define each tumor and explain what’s driving the cancer,” Dr. Papaemmanuil says. “By learning more about these disease-defining changes, we aim not only to pinpoint which drugs are likely to be effective but also to develop diagnostic and prognostic markers.” These markers would help doctors determine which cancers may be more aggressive and require more treatment, and which tumors can successfully be cured with less-aggressive therapies, enabling patients to avoid side effects.

Finding New Clues about Cancer’s Origins

Another important aspect of genomic research in pediatric cancer is that it can identify which tumors may be caused by inherited mutations. Current literature, as well as work by MSK geneticist and pediatric oncologist Michael Walsh, suggests that about 10 to 15% of children with cancer have germline (hereditary) mutations.

Knowing when a cancer is caused by a hereditary mutation can benefit whole families because relatives can get tested for the same mutation. If they have it, they may be able to enroll in screening programs to catch cancer at an earlier stage or have preventive care.

A large proportion of cancer susceptibility genes affect repairing DNA damage under normal conditions. Expanded genomic analysis can readily pinpoint the evidence of damaged DNA in people with impaired DNA repair genes. This provides another way to identify people with inherited gene mutations.

Additionally, the presence of these mutations can suggest who may benefit from treatment with immunotherapy drugs, such as checkpoint inhibitors. These drugs work better against tumors that have a lot of mutations. Traditionally, they have not been used to treat pediatric cancers because tumors in younger people tend to have fewer mutations.

Taking Lab Findings into the Clinic

As promising as this research is, more work needs to be done before these types of analyses can be used to make decisions about patient care. “One of our big aims right now is to evaluate whether these comprehensive sequencing approaches are informative enough to be clinically helpful,” Dr. Papaemmanuil says. “We are still in the early stages of this research. Yet in our early findings, we showcase that with comprehensive sequencing techniques, we can identify diagnostic-, prognostic-, and therapy-informing markers that would have not been picked up by standard clinical sequencing tests.”

Her team is working with pediatric oncologists to validate their laboratory findings. They want to determine the best way to match each genetic signature to existing or investigational drugs. As an integral part of the MSK Kids Pediatric Translational Medicine Program, the Expanded Genomics team collaborates with doctors who can use the results from this wide-ranging genomic testing to find targeted therapies for childhood cancers.

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MSK Program Focuses on Speeding Up Development of New Leukemia Treatments

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2019
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On September 3, Memorial Sloan Kettering launched the Center for Drug Development in Leukemia (CDD-L). This new program will focus on creating more phase I clinical trials for most types of leukemia in adults. Its goal is to rapidly bring novel therapies to people being treated at MSK.

We spoke to leukemia experts Eytan Stein, who will lead the new center, and Jae Park about how treatment for acute (fast-growing) leukemia has changed in the past few years. They shared their ideas on how this new center will further accelerate improvements in treating these blood cancers.

Dr. Stein specializes in treating acute myeloid leukemia (AML), one of the most common leukemias in adults. Dr. Park specializes in treating acute lymphocytic leukemia (ALL). This blood cancer is rare in adults but makes up three-quarters of leukemia in children.

How have treatments for leukemia changed over the past few years?

Dr. Park: For ALL in adults, one of the big improvements is the development of new immunotherapies, including blinatumomab (Blincyto®) and inotuzumab (Besponsa®). Blinatumomab is an antibody-based drug that works by linking T cells to leukemia cells. This enhances the T cells’ killing activity. Inotuzumab is an antibody with a drug attached, to allow the selective delivery of chemotherapy to leukemia cells. Both drugs have fewer side effects than chemotherapy. This is important because ALL is often diagnosed in older people, who may not be able to tolerate stronger drugs.

Dr. Stein: For AML, we have moved away from a one-size-fits-all approach, which was common for decades. As with ALL, people with AML tend to be older and therefore not strong enough for intensive chemotherapy. Now we have other options. One is a drug called venetoclax (Venclexta®), which targets a protein on leukemia cells called BCL2. The drug is given with another type of drug, called a hypomethylating agent, which affects cellular function. This combination treatment leads to remission in about 70% of people with AML, and those remissions tend to be long-lasting.

How has personalized medicine improved the treatment of leukemia?

Dr. Park: We’ve learned that about 40% of all cases of ALL have a genetic abnormality called the Philadelphia chromosome. This mutation is also commonly found in chronic myeloid leukemia. We’ve found that drugs that target the mutation also work for ALL, but they need to be combined with other drugs. We are now doing clinical trials to find the best combination for these drugs and are also using MSK-IMPACT™ to look for less-common mutations that can be targeted with different drugs.

Dr. Stein: For the 30% of people who don’t respond to the venetoclax combination or whose disease comes back after treatment, we have many options based on the mutations driving the cancer. For the approximately one-quarter of people who have mutationsin the genes IDH2 and IDH1, the US Food and Drug Administration recently approved the drugs enasidenib (Idhifa®) and ivosidenib (Tibsovo®), respectively. We are looking at adding targeted therapies for other mutations as well. For people with secondary AML, which develops after they have been treated for myelodysplastic syndrome or another cancer, a new drug that is a formulation of two older chemotherapies together seems to be effective.

What are the roles of blood and marrow stem cell transplantation and cell therapies, like chimeric antigen receptor (CAR) T therapy, in treating people with acute leukemia?

Dr. Park: For people with high-risk ALL or those whose disease comes back after chemotherapy, bone marrow transplantation has been the only chance of a cure. More recently, a new and improved form of cell therapy called CAR T has emerged as a promising treatment to achieve a deep and complete remission even in people who have failed all standard therapies, including bone marrow transplantation. This has generated a lot of excitement in the field. MSK is leading the effort to develop effective and safe CAR T cells for people with various blood cancers. What is most exciting about this form of cell therapy is that a single infusion of T cells can result in a long-lasting remission. With continued commitment and research in the field, we are optimistic that we will improve the outcome and quality of life of people with blood cancer.

What are you most enthusiastic about?

Dr. Stein: I’m excited about all of our clinical trials, specifically the phase I trials that the CDD-L is putting forward. We hope to eventually have a trial available for every patient who doesn’t respond to standard treatment. MSK is also a founding member of the Beat AML initiative overseen by the Leukemia and Lymphoma Society. Through these efforts, we want to have a clinical trial available for every individual who doesn’t respond to standard treatment.

Dr. Park: I’m excited about all the new treatment options for all people with ALL. In the next few years, we will focus our efforts on how to best use these therapies to minimize exposure to traditional chemotherapy and shorten the duration of therapies for people with ALL, which currently last several years. We hope to achieve these goals through a series of clinical trials. We’ll use sophisticated tools to detect an extremely low level of leukemia cells, called measurable residual disease, and identify who can benefit from these new therapies.

Beyond the hematologic oncologists, who are the other members of the MSK team that contribute to the care of people with leukemia?

Dr. Stein: Our molecular pathologists and hematopathologists make it possible for us to find the genetic mutations in each patient’s cancer so that we can match them with the right therapy. This kind of testing used to take many weeks, but now they are able to get us results within a few days. It enables us to get patients on trials right away so they can start treatment almost immediately.

Dr. Park: Our nursing staff on the Leukemia Service is phenomenal, and they’re a big reason to come to MSK. They have incredible experience in managing the side effects that may come from the newly approved and experimental therapies. They also understand the emotional and social needs that often come with a diagnosis of leukemia. Because of their expertise and support, we can ensure that most patients will complete their cancer treatments. Effective leukemia treatment requires strong teamwork, and we have an amazing team that I’m proud to work with every day.

Where is the CDD-L located?

Dr. Stein: People who participate in trials through the CDD-L will receive their care in the new David H. Koch Center for Cancer Care. Their treatment is provided within the Developmental Therapeutics Unit, a treatment area with a specialized cadre of nurses who have expertise in the care of people on phase I clinical trials.

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Getting to the Root of Pediatric Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 10/03/2019
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Rihanna was born with a tumor on her upper right arm almost as large as her head. After chemotherapy failed to shrink it, her parents brought her to Memorial Sloan Kettering, hoping for a different outcome. “MSK’s doctors gave me a sense of confidence that they knew what they were doing,” says Rihanna’s mother, Ana.

And the MSK team delivered: They determined that Rihanna’s cancer was caused by a mutation in a gene called NTRK and focused her care plan on attacking the cancer-driving effects of that mutation.

At the time, MSK Kids pediatric oncologist Neerav “Neal” Shukla was leading a clinical trial for larotrectinib (Vitrakvi®), a drug that specifically targets NTRK. Within days of starting Rihanna on larotrectinib, the tumor began to shrink. Five months later, the remaining tumor was removed, allowing Rihanna to have full function of her arm. Now 2, she has shown no sign of the disease. “She is a happy, healthy toddler,” Ana says.

Rihanna’s story illustrates the power of precision medicine. This practice is grounded in uncovering the genetic changes that drive a tumor’s growth and then finding the best drugs to stop them. Over the past two decades, precision medicine has helped many adults with cancer, leading to dozens of more effective, less toxic drugs for cancers of the lung, colon, breast, and more.

But the progress has been slower for children. MSK Kids is changing that: A major effort is underway to fully deliver on the promise of precision medicine for our youngest patients.

Successfully treating one child, like Rihanna, can do a lot to accelerate drug development to help many more kids. The trial she participated in resulted in the simultaneous approval of larotrectinib for both children and adults with NTRK-driven tumors. In the past, children often had to wait until after a drug was approved in adults before pediatric clinical trials were launched.

Making Progress in the Lab

These efforts are guided by MSK’s Pediatric Translational Medicine Program (PTMP), which is led by Dr. Shukla. The PTMP is involved in genomically characterizing patients’ tumors as well as developing new therapies. Through this program, all children cared for at MSK are offered comprehensive tumor testing. Being able to deliver therapies to the right target requires identifying the root cause of each tumor. This interdisciplinary approach is being spearheaded by geneticist Elli Papaemmanuil and her team of data scientists.

“We want to understand the genomic drivers of cancer in children, identify the key targets, and understand which patients will respond to targeted therapies. In this way, we can develop a treatment approach that is patient tailored and data driven,” Dr. Papaemmanuil explains.

Her lab has performed in-depth analyses on tumors from more than 120 children treated at MSK. “Our preliminary data have opened our eyes to the diversity and complexity of pediatric cancers,” she says.

“We have developed and optimized the processes required to deliver tumor analyses quickly enough to benefit patients,” she adds. “We have shown that this is possible.”

How Research Translates to Treatment

Part two of precision medicine is developing drugs that can potentially target the changes driving children’s tumors. Once a tumor has been characterized, members of the PTMP’s clinical research team take over and start working on treatments matched to changes in the cancer genome.

Doctors, molecular pathologists, and data and laboratory scientists work together to make treatment decisions based on what they’ve already learned about the underpinnings of pediatric tumors.

If a child appears to be a good candidate for a treatment matched to a genetic change in their tumor, the next challenge is gaining access to the drug. The best option is to enroll the child in an ongoing clinical trial. This is what happened with Rihanna.

“We aim to have a clinical trial available for every patient, but even common mutations are present in only 1 or 2 percent of pediatric cancers,” says Julia Glade Bender, a pediatric oncologist who is part of the PTMP. “Doing a clinical trial for every genomic abnormality that we find is just not feasible.”

For rarer mutations, a more specialized approach may be needed. “This is when we develop a single-patient use [SPU] treatment plan,” Dr. Glade Bender says. These compassionate-use plans require tremendous resources, including finding a company willing to supply a drug and getting permission from the US Food and Drug Administration to administer it. It can be a lengthy and labor-intensive process.

“We anticipate that many of the drugs we test in individual patients can eventually benefit a greater number of children with cancer,” says Dr. Glade Bender. So far, at least five drugs first given as SPUs at MSK Kids have progressed into pediatric clinical trials.

MSK’s efforts to develop drugs for kids go beyond the doctors and scientists who specialize in pediatrics. For example, clinical trials developed by MSK’s Early Drug Development Service can now include children as young as 12. (Previously, the age requirement was 18, as it is for most clinical trials.)

“As the largest pediatric oncology program in the world, we are well-positioned to deliver on the promise of precision medicine and to learn from every child who we have the privilege of caring for,” says MSK Kids Chair Andrew Kung.

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Targeting Errors in How Proteins Are Made Is a Promising Approach for Cancer Treatment

Source: Memorial Sloan Kettering - On Cancer
Date: 10/09/2019
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Manufacturing proteins is a multistep process that’s hard-coded into how our cells operate. Genes, which are made of DNA, get translated into RNA, which in turn provides instructions on how proteins are made. One key step in this construction process is called RNA splicing. Like the editing of a film, when some pieces may be cut out and discarded, splicing involves removing portions of the RNA and stitching the remaining pieces back together.

New work from Memorial Sloan Kettering is illustrating that when splicing isn’t done properly, it can lead to cancer.

MSK physician-scientist Omar Abdel-Wahab focuses on studying this process in his lab. He recently published two studies looking at the role of specific RNA splicing factors in different cancers. One study focused on acute myeloid leukemia (AML); the other studied melanoma, particularly uveal (eye) melanoma.

“Our earlier research found that splicing factors are mutated at high frequency in a variety of cancer types,” says Dr. Abdel-Wahab, of the Human Oncology and Pathogenesis Program. “What we’re learning is that when these splicing factor proteins are mutated, they’re actually changing the function of the splicing machinery in cells. Importantly, they’re doing it in a way that promotes cancer.”

The research reported in both papers has already suggested possible approaches for targeting these defective splicing factors with drugs.

Combination Approach for Acute Myeloid Leukemia

The first paper, published October 2 in Nature, looked at a splicing factor called SRSF2. The SRSF2 gene is mutated in about one-quarter of AML cases. It turns out that these SRSF2 mutations are more likely to be present when cancer cells also have mutations in the IDH2 gene, which is commonly mutated in AML.

“We were surprised to find that mutations in SRSF2 are particularly frequent in AML that also has IDH mutations,” Dr. Abdel-Wahab says. “We decided to investigate this link.”

Two IDH genes — IDH1 and IDH2 — are commonly mutated in AML. Together, these mutations also are found in about one-quarter of AML cases. In the past few years, the US Food and Drug Administration has approved two drugs designed to target these mutations: enasidenib (Idhifa®) for IDH1 and ivosidenib (Tibsovo®) for IDH2.

“IDH mutations have been very clearly shown to drive leukemia development,” Dr. Abdel-Wahab explains. “What we showed in this paper is that the splicing errors caused by SRSF2 mutations are also part of this process. The interplay between these two types of mutations is very important.”

Dr. Abdel-Wahab’s lab is focused on developing drugs to target mutant splicing factors, including SRSF2. He is already conducting an early-stage clinical trial with one of these drugs, and more studies are planned.

“Now we’re really interested in trying to develop ways to target forms of AML that have both mutations,” he says. “The idea is that we could use these drugs together, so that we’re targeting the cancer from two sides.”We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.

Targeting Melanoma with a New Kind of Therapy

In the second paper, published October 9 in Nature, Dr. Abdel-Wahab and his colleagues looked at another splicing factor, called SF3B1. Mutations in the SF3B1 gene are found in many types of cancer, including some types of leukemia and many solid tumors. They are most commonly found in uveal melanoma, a rare but aggressive eye cancer.

In this study, a collaboration with researchers at the Fred Hutchinson Cancer Research Center in Seattle, the investigators studied RNA sequencing data from people with several forms of cancer.

“We wanted to see if we could find a link to what the mutation is doing in these diseases,” Dr. Abdel-Wahab says. “We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.”

As part of the study, the researchers were able to develop a way to block the altered RNA splicing caused by the mutated splicing factor. Instead of using a drug, they used a small piece of DNA called an antisense oligonucleotide. Oligonucleotide therapy is a relatively new form of treatment: A handful of oligonucleotide-based drugs have been FDA approved, mostly for genetic neurologic diseases.

Dr. Abdel-Wahab and his colleagues tested the antisense oligonucleotide in cultures of cells with SF3B1 mutations and found that it blocked the growth of cancer cells. They then tested the therapy in mice that were implanted with material from patient samples of uveal melanoma. The treatment reduced the size of the tumors in the mice.

“We would like to work to develop this antisense oligonucleotide as a treatment, so that we can eventually start a clinical trial,” Dr. Abdel-Wahab says. “It’s a challenging undertaking because of the way these oligonucleotides behave in the body. But we think it’s a promising approach.”

The October 2 Nature paper was funded by the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Leukemia and Lymphoma Society, a Japan Society for the Promotion of Science Overseas Research Fellowship, a Bloodwise Clinician Scientist Fellowship, the Oglesby Charitable Trust, National Institutes of Health grants (K99 CA218896 and R01 HL128239), an American Society of Hematology Scholar Award, Cancer Research UK, the Cancer Prevention and Research Institute of Texas, the Welch Foundation, a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-16-1-0059), the Starr Foundation, the Henry and Marilyn Taub Foundation, the Edward P. Evans Foundation, the Josie Robertson Investigators Program, and the Pershing Square Sohn Cancer Research Alliance.

The October 9 Nature paper was funded by the Leukemia and Lymphoma Society, the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Conquer Cancer Foundation, an American Society of Clinical Oncology Young Investigator Award, an American Association for Cancer Research Lymphoma Research Fellowship, a Mahan Fellowship from the Fred Hutchinson Cancer Research Center, the Pershing Square Sohn Cancer Research Alliance, the Henry and Marilyn Taub Foundation, the Starr Cancer Consortium, National Institutes of Health grants (R01 DK103854 and R01 HL128239), the Evans MDS initiative, and the Department of Defense Bone Marrow Failure Research Program.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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Genetic Variations Help Explain Why Immunotherapy Works Differently in Different People

Source: Memorial Sloan Kettering - On Cancer
Date: 11/07/2019
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Since 2011, the immunotherapy drugs called checkpoint inhibitors have become an increasingly important treatment for certain cancers. This is especially true for people with melanoma and lung cancer.

Early on, investigators observed that these drugs are extremely effective for some people, even eliminating their cancer entirely. Unfortunately, they don’t work at all for many others. Considerable research has tried to understand why this is the case and exactly how these drugs work.

Memorial Sloan Kettering physician-scientist Timothy Chan has focused on these efforts. He is one of the corresponding authors of a study published November 7, in Nature Medicine that reports a new way to determine who is most likely to benefit from immunotherapy. The findings may help explain why immunotherapy works differently in people around the world.

“Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs,” says Dr. Chan, who leads the Immunogenomics and Precision Oncology Platform at MSK. “It’s important that future clinical trials of immune checkpoint drugs take our discovery into account. This is especially important for international phase III trials.”

Looking to Evolution and Population Diversity for Answers

For decades, the human leukocyte antigen (HLA) genes have been known to govern how the immune system responds to foreign substances in the body. Over thousands of generations, as early humans migrated out of Africa and around the planet, they evolved variations in their HLA genes. These changes protected them from infectious organisms that were found in different parts of the world.

“The classic battle between pathogens and the human immune system plays out in the HLA genes,” Dr. Chan says. A 2017 study from Dr. Chan was the first to show that HLA genes are important for the body’s ability to see cancer after immunotherapy as well. That study reported that people who had a greater number of different copies, or alleles, in their HLA-1 genes responded better to immunotherapy compared with those whose HLA-1 genes had fewer alleles. The new study builds on this previous work.

To quantify how efficient the immune system is at detecting cancer, the researchers looked at the HLA genes from more than 1,500 people who had received immune checkpoint drugs as part of clinical trials at MSK and other hospitals. Most of those included in the study had melanoma or non-small cell lung cancer, but other kinds of cancer were also represented.

People inherit one copy of HLA-1 from each parent. For each person analyzed, the team found that the more molecularly diverse, or different from each other, the two copies of each of their HLA-1 genes were, the more likely someone was to respond to treatment and survive their cancer. The investigators developed a novel way to measure this difference, which they call HLA evolutionary diversity (HED).

Dr. Chan’s co-corresponding author on the Nature Medicine paper, Tobias Lenz of the Max Planck Institute for Evolutionary Biology in Germany, is an expert in the evolution of the human immune system and the HLA genes. Research fellow Diego Chowell and graduate student Chirag Krishna from Dr. Chan’s lab and graduate student Federica Pierini from Dr. Lenz’s lab were the co-first authors.

Recognizing Tumors as Foreign

Dr. Chan has also looked at other factors that make immune checkpoint drugs more effective. In 2014, he led the first studies finding that patients who responded to these drugs tended to have a large number of gene mutations in their tumors. This is known as having a high tumor mutational burden (TMB). When tumors have a greater number of mutations, it is more likely that they will produce proteins that the immune system hasn’t seen before.

“For checkpoint inhibitor drugs to be effective, the immune system needs to be able to recognize cancer cells as foreign,” Dr. Chan says. “High TMB and diverse HLA genes are two sides of the same coin. Both make it more likely that the immune system will see the cancer.”

The researchers note in their study that high TMB and high HED are independent of each other, but the combined outcome of the two led to benefits from immunotherapy drugs that were greater than either of these effects on their own. “These are the yin and yang of T cell–based immune checkpoint treatment,” Dr. Chan says. “High TMB is less useful if a person is unable to present the mutations to the immune system. Having a high HED allows that to happen.”

Finding New Ways to Measure Genetic Diversity

Recent immunotherapy clinical trials have begun to include TMB in their evaluation of how effective checkpoint inhibitors are, Dr. Chan notes. “But among different trials, there is great variation in the role that TMB plays. No one has been able to figure out what’s going on,” he says. “It turns out, we should also be looking at HLA diversity. This finding may account for the unexplained variation that’s seen in the role of TMB in immunotherapy trials.”

He adds that it may also account for the different response rates that have been observed in different parts of the world. HED can vary dramatically depending on where someone lives.

The investigators are now working to develop a standardized way to report HED, so that it can be incorporated into future clinical studies. Dr. Chan’s team is in the process of evaluating HED with industry partners using global phase III trial data. They hope that this measure can eventually become a regular part of cancer diagnosis and be used to match people with cancer with the most personalized treatments.

This research was funded by National Institutes of Health grants (R35 CA232097, RO1 CA205426, and P30 CA008748), the PaineWebber Chair in Cancer Genetics at MSK, and a German Research Foundation grant.

Dr. Chan has filed for a patent related to HED. Additionally, he is an inventor on a patent application filed by MSK relating to the use of TMB in cancer immunotherapy. MSK and the inventors may receive a share of revenue from license agreements relating to these patent applications. Dr. Chan is also a co-founder of Gritstone Oncology and holds equity. He acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, and he has served as an adviser for Bristol-Myers Squibb, Illumina, Eisai, and An2H.