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Study Suggests More People with Kidney Cancer Should Be Screened for Hereditary Cancer Genes

Source: Memorial Sloan Kettering - On Cancer
Date: 09/06/2018
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Kidney cancer, also called renal cell carcinoma (RCC), is a relatively common cancer. It’s diagnosed in nearly 65,000 people in the United States every year. Yet despite its frequency, very little is known about what causes it, beyond two broad factors linked to many common cancers: smoking and obesity.

That’s now starting to change for one advanced form of the disease, called non-clear cell RCC. Recent research from a collaborative team at Memorial Sloan Kettering found that more than 20% of people with this type of RCC have disease that is driven by inherited cancer mutations. Many of the types of mutations that were found indicated that the tumors might respond to targeted therapies that would not otherwise be prescribed for kidney cancer.

“These findings suggest that everyone with advanced non-clear cell RCC should be referred for genetic counseling,” says medical oncologist Robert Motzer, one of the authors of the study, published in July in JAMA Oncology. “Beyond a rare inherited condition called von Hippel-Lindau syndrome, as well as a few other uncommon disorders, we haven’t previously known that kidney cancer had this strong hereditary component.”

Non-clear cell RCC makes up about one-quarter of RCC cases. For clear cell RCC, the more common type, the study found that only about 2% of tumors were caused by inherited cancer genes. Before this study, the rate for all kidney cancers was expected to be about 5%.

A Surprising Finding about a Diverse Group of Cancers

Over the past decade, a number of targeted drugs and immunotherapies have changed the outlook for many people with clear cell RCC. Dr. Motzer and his team have led many of the clinical trials that have resulted in US Food and Drug Administration approval for these drugs, including sunitinib (Sutent®), sorafenib (Nexavar®), axitinib (Inlyta®), and nivolumab (Opdivo®). Thanks to these new drugs, even people with advanced kidney cancer can live for many years, often with very few side effects from their treatments.

Non-clear cell RCC has been a different story. Many of the drugs approved to treat clear cell RCC do not have the same efficacy against non-clear cell tumors. “Non-clear cell” is a catch-all term that applies to several types of cancer including papillary, chromophobe, and collecting-duct tumors.

In this current research, investigators looked at 254 people who had been treated for advanced RCC at MSK. Each person had undergone MSK-IMPACT™ testing to look for mutations in their cancer. As part of this test, both normal tissue and tumor cells are analyzed. This enables doctors to detect cancer-related mutations that someone may have inherited.

Unexpectedly, about 20% of people with non-clear cell RCC carried inherited mutations. The study found the most frequently inherited mutation in people with non-clear cell RCC was in a gene called CHEK2. Mutations in this gene have previously been connected to an increased risk of breast and colon cancer, but the link to RCC was not known. The researchers found mutations in other cancer-linked genes not previously known to play a role in kidney cancer as well.

The team also found several people with non-clear cell RCC who had inherited mutations in a gene called FH. Mutations in FH have already been linked to a condition called hereditary leiomyomatosis and renal cell cancer. But they were more common than what would have been expected in a group of people with RCC.

“Once we know that someone has one of these hereditary gene mutations, we can help make sure they get the right treatment,” says Maria Carlo, a clinical geneticist and medical oncologist on the Genitourinary Service and first author of the study. “In addition, we can offer them screening tests for other cancers that may be linked to the same mutation.”

Discoveries Lead to Changes in the Clinic

At the American Society of Clinical Oncology (ASCO) meeting in June, Dr. Carlo presented similar findings from people being treated for advanced bladder cancer at MSK. About 16% were found to have inherited mutations. Some of these mutations suggested that they might benefit from targeted therapies that are not usually given for bladder cancer.

Learning that someone has an inherited cancer gene has important implications for his or her close relatives as well. MSK’s genetic counselors are able to offer them genetic tests. If any of them are found to have the same mutation, they can participate in screening programs for cancer as well.

In fact, due in large part to the findings reported in the JAMA Oncology and ASCO studies, Dr. Carlo is now leading a Genitourinary Cancer Genetics Program within MSK’s Clinical Genetics Service. The program offers genetic testing and screening services to people with hereditary prostate, kidney, and bladder cancers and their families.

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How Acute Myeloid Leukemia Is Treated at MSK: An Interview with Martin Tallman

Source: Memorial Sloan Kettering - On Cancer
Date: 09/11/2018
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Acute myeloid leukemia (AML) is one of the most common types of blood cancer. The word “acute” means that the cancer can advance quickly and needs to be treated right away. The word “myeloid” refers to the type of cells that are cancerous.

Myeloid cells are blood cells that develop into many different kinds of immune cells. They also develop into platelets, which are responsible for blood clotting. This explains why excessive bruising and bleeding are symptoms of AML.

We recently spoke with Martin Tallman, Chief of Memorial Sloan Kettering’s Leukemia Service. He reviewed the latest advances in treatment for AML and how people can benefit from receiving their treatment at MSK.

How common is AML?

About 20,000 people in the United States are diagnosed with AML every year. The average age at the time of diagnosis is 72, but it can develop at any age.

We know that AML is becoming more common, but we’re not sure why. For most adults, the cause is not known. But there has been speculation that more people are developing AML because they have been treated with chemotherapy and radiation for other types of cancer. As a result of advances in cancer care, more people are surviving long enough to develop these secondary cancers.

In children and young adults, however, past treatment with chemotherapy and radiation is a common cause of AML.

How is treatment for AML changing?

Until recently, there had been no new continually approved drugs for treating AML since 1973. Then in 2017, four new drugs were approved by the US Food and Drug Administration. One more has been approved so far in 2018, and there are three or four others that are poised to be approved within the next year or so.

One of the new drugs, liposomal daunorubicin-cytarabine (VyxeosTM), is a new formulation of a standard leukemia drug. Another, gemtuzumab ozogamicin (MylotargTM), is made from an antibody linked to a potent toxin. Midostaurin (Rydapt®) is a drug that targets a mutated protein called FLT3.

Enasidenib (Idhifa®) was approved to treat AML that carries a mutation in a gene called IDH2. Ivosidenib (Tibsovo®) targets cancers with a mutation in the related gene IDH1. Both enasidenib and ivosidenib work by converting cancer cells back into normal cells rather than killing them. MSK’s Leukemia Service led the trials that resulted in both of these drugs being approved.

In addition to new chemotherapy and targeted drugs currently being studied, there are clinical trials looking at chimeric antigen receptor (CAR) T therapy and other types of immunotherapy for AML. We are also looking at new combinations of drugs.

We’ve been able to develop all these new treatments because — thanks to research in both the lab and the clinic — we now have a much better understanding of what drives this disease. This knowledge leads to more-effective ways to target malignant cells. It’s an amazing, exciting time to be doing leukemia research.

How often are stem cell or bone marrow transplants used to treat AML?

Blood or marrow stem cell transplants are recommended for many, but not all, people with AML. For those who are able to find a donor and are able to safely tolerate the transplant process, this treatment may offer the best chance for a cure.

For people whose disease is considered low risk because of its molecular characteristics, a transplant is usually not recommended. These people usually do well without that procedure.

For others, especially those who have serious, unrelated health problems, a transplant may not be recommended. That’s why it’s so important that we have all these new treatments. They offer a good alternative to transplants.

What does MSK offer people with AML that most other hospitals don’t?

We recently conducted a pilot project in which people were able to receive their consolidation chemotherapy — the second part of their treatment — as outpatients. In consolidation therapy, chemotherapy is given on alternating days throughout the week. This is done every week for a month.

Under our new procedure, the way it works is that patients come in on a Monday and get their first treatment. During that appointment, their chemotherapy for Wednesday and Friday is loaded into an electronic pump. At the end of their treatment on Monday, they can go home. Then on Wednesday and Friday, they use telemedicine to communicate with their nurse, who can then activate the pump remotely for the next two doses.

Historically, induction chemotherapy — the first part of the treatment — has always been done on an inpatient basis. People have to stay in the hospital for at least a month. This is difficult for them and their families. With new developments in technology, a study will soon start for people to receive their induction treatments mostly at home.

The only strict requirement for receiving treatment this way is that patients have to live a reasonable distance from one of our locations, within an hour or two, in case they need to come back in.

What else is special about the way MSK treats AML?

There are 22 doctors on our service who are completely focused on leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms. We also have nurses and nurse practitioners with fantastic expertise in caring for people with acute leukemia. Some of them have many years of experience.

We have a team of clinical pharmacists who are dedicated to working with the Leukemia Service. They are vital for understanding all the new drugs that are being given to patients, whether as part of standard care or a clinical trial. And they’re very good at educating patients about what they need to know when taking these drugs.

We also have wonderful colleagues on the Infectious Disease Service. They focus on the prevention and treatment of the infections that are common in people receiving leukemia therapy. They closely monitor our patients for signs of trouble. They also perform clinical and laboratory-based research that’s leading to better treatment for all people with cancer.

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Putting the STING in Immunotherapy: Research Focuses on Ways to Improve Cancer Treatments

Source: Memorial Sloan Kettering - On Cancer
Date: 09/19/2018
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Drugs called immune checkpoint inhibitors have made a significant difference for some people with cancer. They work by taking the brakes off the immune system, allowing white blood cells called T cells to attack a tumor.

For this approach to work, however, the T cells need to be able to see the tumor and recognize it as something that doesn’t belong in the body. Often, they cannot. That explains why, for most people, these drugs are not effective. Finding new tactics for making tumors more noticeable to the immune system is an important area of research.

Tumors are sometimes described as “hot” if they show signs of inflammation, with lots of immune activity around them. “We’re looking for ways to turn a cold tumor into a hot tumor,” says Memorial Sloan Kettering physician-scientist Liang Deng. “If you can bring the tumor out of hiding and make it more visible, it will help to really ramp up the immune response.”

Finding Ways to Trick Cancer Cells

One approach that many investigators around the world are studying is the potential to harness the cGAS/STING pathway. (The abbreviation cGAS/STING is a much shorter way of saying “cyclic GMP-AMP synthase/stimulator of interferon genes.”)  

In particular, cGAS/STING works by detecting bits of DNA from bacteria or viruses that have infected a cell. The detection fires up the innate immune pathway, the system of immune defenses that are present from birth and are always active. Innate immune cells produce chemicals that alert other parts of the immune system to the presence of the intruders. In 2013, Sloan Kettering Institute structural biologist Dinshaw Patel published two papers in Cellshowing some of these complex structures for the first time.

Now, some pharmaceutical companies are starting to develop drugs called STING agonists. These are small molecules designed to activate the STING pathway after being injected into a tumor, which sends out a beacon for immune cells to follow. The idea is to use these new drugs in combination with checkpoint inhibitors.

“STING agonists are based on the hypothesis that you can trick immune cells into thinking that the tumor cells are infected with a virus,” says MSK physician-scientist Samuel Bakhoum. “Then the immune cells will come in and basically clear the cancer away.”

Seeing the Full Immune Picture

More recently, however, investigators have learned that in some cases the STING pathway plays a role in helping cancers thrive, making this approach more complicated. “It turns out that many cancer cells also have DNA where it doesn’t belong. Rather than being only inside the nucleus where it normally resides, it’s also floating around inside the cytosol [fluid] of the cell. This is caused by a phenomenon called chromosomal instability — a widespread feature of human cancer,” Dr. Bakhoum says.

“Chromosomally unstable cancer cells have found ways to adapt to that floating DNA. They avoid the harmful consequences of cGAS/STING activation while using this pathway to their advantage,” he adds. “Alternatively, a small number of tumors lose cGAS and STING altogether. This adaptation to DNA in the cytosol may actually help them spread to other parts of the body.” In January 2018, Dr. Bakhoum was the first author of a paper in Naturethat reported this phenomenon.

Along with researcher Lewis Cantley of Weill Cornell Medicine, Dr. Bakhoum recently published a review article in Cell on the ways that cells with unstable chromosomes use STING to their advantage to evolve and become more aggressive. It turns out that chronic activation of this pathway might suppress the immune system rather than trigger it to fight the cancer. “It suggests that we need to be very careful in determining which people could benefit from treatment with STING agonists,” Dr. Bakhoum says. “Patient selection will be a critical contributor toward the success of this therapy.”

Another Approach to Heating Up Tumors

Dr. Deng’s lab is taking a different tack for activating innate immunity in tumors: injecting them with a virus. This is another way to flag tumors and make them more visible to the immune system.

She’s working with modified vaccinia virus Ankara (MVA). This engineered virus has been safely used as a vaccine against smallpox. In 2017, her laboratory published a paper in Science Immunology demonstrating that injecting inactivated MVA into tumors in mice stimulates the immune response against the tumors. The findings showed that the response was boosted by checkpoint inhibitor drugs.

Now her laboratory is working on engineering MVA to make it more potent for immunotherapy. Dr. Deng explains that using the engineered MVA has several potential advantages over drugs designed only to fire up STING. For one thing, the virus is larger than a drug molecule, allowing it to remain in the tumor tissue for a longer time. In addition, the virus can be engineered to do much more than draw attention to the tumor.

The engineered MVA activates STING not only in tumors but T cells too. It also carries a growth factor for immune cells called dendritic cells. “We know based on previous work that dendritic cells are an important part of the immune response to cancer,” she says. “Injecting engineered MVA into tumors creates an in situ vaccination effect, which teaches T cells to recognize tumors.”

Dr. Deng and her MSK colleagues Jedd Wolchok, Taha Merghoub, and Stewart Shuman recently co-founded a start-up company called IMVAQ Therapeutics. The company is developing the virus so that an application can be submitted to the US Food and Drug Administration to begin clinical trials. IMVAQ is planning tests in a number of solid tumors, either alone or in combination with checkpoint inhibitors. “We hope this approach will be particularly successful in tumors that don’t usually respond to checkpoint inhibitor drugs, like breast and prostate cancers,” she notes. “We also believe this virus will be very safe because it doesn’t replicate in human cells.”

MVA is not the only virus being studied for this purpose. MSK already has other trials underway that use this immunotherapy approach as well. A phase III trial using a virus called T-VEC (talimogene laherparepvec) is being studied in combination with the checkpoint inhibitor pembrolizumab (Keytruda®) for advanced melanoma, for example.

“All of the research that’s been done over the past 20 years on the basic science of the innate immune system, including a lot of work done at MSK, has made these kinds of studies possible today,” Dr. Deng concludes.

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Proof that Fecal Transplants Can Restore a Gut’s Natural Balance of Microbes

Source: Memorial Sloan Kettering - On Cancer
Date: 09/26/2018
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Fecal microbiota transplants (FMTs) are also known as stool transplants. The process involves collecting feces from a healthy donor, processing it, and then delivering it into the colon of the recipient. Just a decade ago, FMTs were unconventional. But they are becoming accepted by the medical establishment. The procedure is primarily used to treat intestinal infections from a bacterium called Clostridium difficile (C. diff), but it’s being studied for other conditions as well. 

FMTs are not formally approved by the US Food and Drug Administration. But in 2013, the FDA said that doctors could use them to treat chronic C. diff infections that have not responded to other treatments, opening the door for more controlled clinical studies.

A clinical trial at Memorial Sloan Kettering is now showing for the first time that FMTs can reestablish the health-promoting bacteria that are often lost in people who have stem cell or bone marrow transplants for blood cancer. The trial involves collecting and storing a person’s own stool prior to the procedure. After the stem cell or bone marrow transplant, the FMT is given to the patient. Because the FMT comes from a person’s own body, it is called an autologous FMT. The results are being published today in Science Translational Medicine.

“When we started this trial three years ago, we knew much less about FMTs than we know today,” says MSK infectious diseases specialist Ying Taur, the study’s first author. “This study is really a milestone. It removes whatever trepidation there may have been about exploring this procedure in people who have recently undergone cancer treatment.” 

Addressing Serious Complications from Bone Marrow Transplant

People who have stem cell or bone marrow transplants to treat blood cancer face a number of challenges. These complications especially affect those whose transplanted blood cells come from a donor, called an allogeneic transplant. In order for the body to accept the donor’s cells, the recipient’s own blood cells are wiped out with high doses of chemotherapy. During the time when the new blood cells are growing, recipients are prone to infections and require high doses of antibiotics. But those antibiotics can, in turn, destroy the healthy microorganisms that live in the body and allow more dangerous microbes to take over.

This is where an FMT comes in: The procedure helps restore a balance of healthy bacteria in the gut.

In earlier work, MSK physician-scientists Eric Pamer and Marcel van den Brink found that out-of-balance intestinal microbes can contribute to serious side effects. This disparity can affect outcomes after stem cell transplants. In particular, when harmful bacteria like C. diff dominate in the intestine, people are more likely to suffer complications from graft-versus-host disease. This potentially fatal side effect occurs when immune cells from the donor attack healthy tissues in the recipient, especially the intestinal lining. Dr. Pamer is one of the senior authors on the new paper; Dr. van den Brink is a coauthor.

Restoring the Balance of Microorganisms after Transplant

In the current study, participants’ own fecal material is collected before beginning the stem cell transplant process. Using their own feces helps ensure that the transplant won’t expose them to any unfamiliar flora. Any new bacteria could cause problems after the FMT. The collected stool is frozen to preserve the healthy microbe balance when the processed fecal material is reintroduced after the stem cell transplant.

The paper reports the results from the first 25 people in the study, 14 of whom received a transplant of their own fecal material and 11 controls, who did not.

The investigators looked at a number of measures. They considered levels of beneficial microbes as well as potentially harmful microbes. The mixture of microorganisms that came from the stored fecal material was able to reestablish itself after transplant. This resulted in more diverse, balanced microbiota.

“The important message here is that we showed we could bring the microbiota back to a level that was much closer to what people came in with before their stem cell transplant,” says Dr. Pamer, who heads a lab in the Sloan Kettering Institute’s Immunology Program.

Wide-Ranging Implications for the Health of People with Cancer

Another study from MSK researchers reported that having higher numbers of certain healthy bacteria in the intestinal tract contributed to fewer viral infections in the lungs after a stem cell transplant. Respiratory infections are another major complication in people who have stem cell transplants. This study points to the importance of maintaining healthy microbiota for overall recovery, not just for the health of the intestinal tract. The results were published online in April in the journal Blood.

Drs. Pamer and Taur say that since assembling the results in the current report, they have brought the total number of people in the FMT trial to 59. The MSK team is continuing to follow them, with the goal of determining whether autologous FMT can affect overall clinical outcomes and improve survival. They expect those results to be available next year.

Investigators plan to study using fecal material from healthy donors rather than a patient’s own stool for the transplant.

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HPV Vaccine and Cancer Risk: Frequently Asked Questions

Source: Memorial Sloan Kettering - On Cancer
Date: 09/27/2018
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According to a recent report from the Centers for Disease Control and Prevention (CDC), the number of cancers caused by the human papilloma virus (HPV) has risen significantly in recent years. There were slightly more than 30,000 cases in the United States in 1999 and more than 43,000 in 2015. This includes not only cervical cancer but also cancers of the vagina, vulva, anus, penis, and oropharynx (the middle portion of the throat, beginning at the back of the mouth and including the base of the tongue, the tonsils, and the soft palate).

The first HPV vaccine was approved by the US Food and Drug Administration in 2006. Vaccination is given as a series of two or three shots. It is currently recommended for both girls and boys beginning at age 11 or 12. The vaccine can be given to children as young as nine, and it’s recommended for women through age 26 and men through age 21 if they didn’t get it when they were younger. For men who have sex with men, people who are transgender, and those who are immunocompromised, the vaccine is recommended through age 26. 

According to another CDC report released last month, 66% of adolescents between the ages of 13 and 17 have had one dose and only 49% have received the full series of shots. We recently spoke with Memorial Sloan Kettering gynecologic oncologist Chrisann Kyi about why it’s so important for young people to get vaccinated. We also asked her to dispel some common myths about the vaccine.

What is HPV, and how is it spread?

HPV is a type of virus that lives on the surface of the skin. There are actually more than 100 different varieties. Many of them cause warts, like those found on the hands and feet. About 40 kinds of HPV live on the genitals and anus, and inside the mouth and throat. Those types are transmitted through sexual activity.

The highest-risk strains for cancer in the genital and throat areas are HPV 16 and 18. HPV 6 and 11 are associated with most genital warts. The newest HPV vaccine, Gardasil® 9, protects against all four of those plus five other cancer-causing strains. Altogether, the viruses covered in the vaccine contribute to more than 90% of cervical adenocarcinomas and genital warts.

How effective are HPV vaccines?

HPV vaccines are very effective. In the trials that led to the vaccines’ approvals, they were found to be nearly 100% protective against persistent cervical infection with HPV types 16 and 18. They also protected against the changes to the cervical tissue that these persistent infections can cause.

Two studies showed that protection against the HPV types that are included in the original Gardasil, the first vaccine approved, has been found to last for at least ten years, and the data is still being collected. Long-term studies of vaccine efficacy are in progress. As more time passes from when Gardasil first came out, we are going to better understand the total duration of protection.

HPV infections are very common in both men and women. Most people have had an infection at some point in their lives without even knowing it, and most of them are clear of the virus within a few months. The virus becomes a problem only when it doesn’t go away — after remaining in the body for ten or 20 years it can begin to drive the formation of cancer.

The assumption is that by the time someone is in their 20s, they have already been exposed to the virus through sexual activity. At that point, they will no longer benefit from vaccination. This is why it’s important to provide the vaccine early, before someone becomes sexually active.

Some studies conducted by Merck, the company that makes Gardasil, have suggested that women up to age 45 may benefit from the vaccine. If you are above the recommended age and think the vaccine might help you, you should discuss it with your doctor. However, it’s likely that insurance won’t cover it for people who are older than 26.

What concerns have you heard about the HPV vaccine?

A lot of people have hesitation about the vaccine because they think they might contract the virus from it and develop cancer. It is similar to when people are convinced they have contracted the flu from a flu vaccine.

But that’s a big misconception. The HPV vaccine doesn’t contain the complete virus. It contains a protein that’s present in the outer coat of the virus. Vaccination works by exposing someone’s immune system to this protein, so they are able to develop antibodies that recognize the protein. Then if they do contract the virus in the future, antibodies that remember the protein and can fight the virus are already present in the body, like soldiers ready to go to battle.

What about people who don’t want their kids vaccinated because they don’t think the HPV vaccine has undergone enough safety testing?

Clinical trials that were conducted for the vaccine, as well as follow-up studies since it was approved, have shown that it’s very safe. The side effects of the shots are minimal — they are mainly related to soreness at the injection site or flulike symptoms that may develop while your immune system is responding to the vaccine. You hear some anecdotal stories about other side effects, but those are not based on any science that I know of.

In fact, I know of no long-term consequences related to the HPV vaccine.

Are there other reasons that vaccination rates are not higher?

Some women think that if they’re already getting regular checkups from their gynecologist and undergoing recommended HPV screening tests and Pap smears, they don’t need the vaccine. But actually, it should be the other way around. Because we know it works so well, the vaccine should be the driving measure for cancer prevention. Pap smears and other tests can be that extra layer of support.

Why is it so important to bring immunization rates up?

The numbers are definitely not as high as we would like them to be. A rate of 60% or so is not going to be able to provide herd immunity, which is when a high enough proportion of a population has immunity that it becomes difficult for an infection to spread. 

To get to a level that is considered good for public health from an epidemiological standpoint, we’d like to see rates that are closer to 80%. And rates need to be that high in both men and women. When more men are vaccinated, it lowers the overall prevalence of cervical cancer in women, as well as protects the men from other HPV-associated cancers and genital warts.

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New Study Shows Immunotherapy and Chemo Combination Extends Survival for People with Hard-to-Treat Breast Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 10/20/2018
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Today at the annual meeting of the European Society for Medical Oncology, an international team of breast cancer experts reported findings from a large clinical trial. They had tested a combination of immunotherapy and chemotherapy in people with advanced triple-negative breast cancer. The investigators found that many people in the study who had the immunotherapy combination therapy lived longer compared with chemotherapy alone.

Memorial Sloan Kettering medical oncologists Elizabeth Comen and Christopher Klebanoff, both experts in breast cancer immunotherapy, offer their perspective about these findings and the potential impact on the field. Neither Dr. Comen nor Dr. Klebanoff were part of the study, which is being published in the New England Journal of Medicine.

“Immunotherapy works best on solid tumors that have large numbers of mutations because mutations put up flags that make the tumors visible to the immune system,” explained Dr. Comen. “It’s long been thought that triple-negative breast cancers might be susceptible to immunotherapy because they tend to have a lot more mutations that the immune system can recognize.”

The trial included 902 people who were treated at 246 hospitals in 41 countries. All of them had locally advanced or metastatic triple-negative breast cancer. The people in this study were given either a standard chemotherapy drug for this type of breast cancer called nab-paclitaxel (Abraxane®); an immunotherapy drug already approved for other cancers called atezolizumab (Tecentriq®), which works against the protein PD-L1; or a combination of the two.

The researchers reported that people with tumors that expressed the PD-L1 protein who received the combination therapy lived 9.5 months longer. About 41% of people in the trial had this protein on their tumors. “This is not a cure, and at every step of the way we’re always looking for that,” Dr. Comen says. “But any incremental benefit to patients’ lives can be significant, and this is a significant benefit.”

“There is a tremendous unmet medical need in this breast cancer subtype,” Dr. Klebanoff says. “We’ve made great progress in recent years in treating other types of breast cancer, but triple-negative breast cancer has not benefitted from many advances. This study dispels the myth that immunotherapy cannot work for breast cancer. As we learn more about this approach, we expect to see more and better treatment options for many breast cancer patients.”

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What Women Should Know about Breast Density and Cancer Risk

Source: Memorial Sloan Kettering - On Cancer
Date: 10/26/2018
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In 2009, Connecticut was the first state to pass a law that requires radiologists to notify women who have had screening mammograms if they have dense breasts. Since then, more than 30 states have followed suit. Having dense breasts is a risk factor for breast cancer.

Breast density has to do with the amount of fibrous and glandular tissue that a woman has in her breasts compared with the amount of fat.

  • About 10% of women have extremely dense breasts.
  • Around 40% have heterogeneous density, which means their breasts are mostly dense with some areas of fat.
  • Another 40% have scattered density, which means they have some areas of density but most areas are not dense.
  • Only about 10% of women have breasts that are mostly fatty, with little or no fibrous and glandular tissue.

We spoke with Sandra Brennan, Director of Radiology at MSK Westchester, about what doctors know about breast density and what steps women with dense breasts can take to increase the likelihood that any cancer they may develop is detected early.

What does it mean when a woman is told that she has dense breasts?

Having dense breasts makes it more difficult for cancer to be picked up by a mammogram. The dense tissue looks white on the image, and that can obscure cancerous masses.

Women with dense breasts also have an elevated risk of breast cancer. The 10% who have the most dense tissue have a risk that’s four to six times higher compared with those whose breasts are the least dense. This is because glandular tissue is more likely to become cancerous. But even women with breasts that are mostly fatty can develop breast cancer.

What causes dense breasts?

Mostly it’s just part of the natural makeup of your body. Density is affected by age and hormones. Taking hormone replacement therapy will increase breast density, and conversely, taking tamoxifen (Nolvadex®), an estrogen-receptor drug used to treat some types of breast cancer, will decrease it. A woman’s breasts may become less dense as she ages. But that doesn’t always happen. Sometimes a woman with dense breasts can keep that density even as she gets older.

Is there anything women can do to reduce their breast density?

It’s not something you can really change. There are no foods or supplements that make a difference. Some women may have changes in the amount of fat in their breasts if they lose or gain weight. Women with a low body mass index tend to have dense breasts.

What are the screening recommendations for women with dense breasts?

We know that 3-D mammography, also known as tomosynthesis, is better at detecting masses in dense breasts than traditional 2-D mammography. This is because it looks at the breasts in visual slices and removes some of the masking effect of the overlying dense tissue. We offer 3-D mammograms as an option for standard screening to all women who get screened at MSK, both in Manhattan and at our regional sites.

Women with dense breasts should discuss with their doctor whether they should have supplemental screening with ultrasound. Screening breast ultrasound can pick up additional cancers that we might not see on a mammogram in women with dense breasts.

For women at a higher risk unrelated to their breast density, we recommend an annual screening with a breast MRI. This may detect small tumors that a mammogram misses. Women at a higher risk include those with inherited mutations in BRCA1 or BRCA2, a history of lobular carcinoma in situ, a previous biopsy that found atypical tissue, or a history of radiation to the chest wall at a young age. Breast MRIs are not routinely recommended for women with an average risk, including those with dense breasts, because the high number of false positives can lead to unnecessary biopsies.

Why are we hearing more about breast density now?

Radiologists have known about breast density since we began doing mammograms. It came to the public’s attention when breast density notification laws were passed. These laws came about largely because of patient activism.

What are some of the screening tests and other services that are available at MSK Westchester?

We offer 2-D and 3-D mammography, screening breast ultrasounds, and breast MRIs. Breast cancer screening services are available to MSK employees and their family members, MSK patients, and women in the community. Any woman who needs a screening mammogram can make an appointment to get one at MSK. We accept outside prescriptions for screening mammography and breast ultrasounds.

For those who need a breast biopsy, we perform a number of nonsurgical procedures at MSK Westchester. These include percutaneous ultrasound-guided core biopsies, fine-needle aspirations, stereotactic breast biopsies, and MRI-guided biopsies. People who are having surgery at Memorial Hospital in Manhattan can have their preoperative seed localizations and sentinel node injections done at MSK Westchester.

We are excited that we’ll soon be able to offer contrast-enhanced mammography at MSK Westchester. This technique, which gives us a vascular map of the breast, similar to an MRI, was first piloted at MSK’s Evelyn H. Lauder Breast Center in Manhattan. We are glad to expand that service to the regional sites, including MSK Westchester and MSK Commack. It’s a very specialized procedure that, to the best of my knowledge, is not available anywhere else in Westchester County.

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New Framework for Categorizing Inherited Cancer Genes Will Have Wide-Ranging Impact

Source: Memorial Sloan Kettering - On Cancer
Date: 11/01/2018
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Every gene is made up of thousands of As, Cs, Gs, and Ts, which spell out the instructions for making all the proteins in our cells. Errors in those instructions — known as mutations or variants — can occur anywhere in these long strings of code.

For genes linked to diseases, including cancer, researchers are focused on determining which mutations matter. Some don’t affect risk, but others actually change the functions of proteins and could have a negative effect in the body.

“Understanding the significance of the variants we find in cancer genes is important,” says Memorial Sloan Kettering clinical geneticist Michael Walsh. “We need to know if they are harmless or harmful, so when we learn that someone has inherited one of them, we can tell them what it means. Should they have more frequent cancer screenings? Should their family members get tested as well?” In addition, for those who already have cancer, inherited gene variants may influence what treatments they are given.

The Tremendous Task of Finding Meaning in Gene Variants

The field of cancer genomics took off in the early 1990s. At that time, scientists, including geneticists Mary-Claire King and MSK’s Kenneth Offit, began to report details on some of the first genes connected to cancer. These genes, BRCA1 and BRCA2, are associated with an increased chance of developing certain cancers, especially breast cancer and ovarian cancer. But what predisposes people to cancer are specific alterations in the genes. These changes can cause the proteins to malfunction in such a way that cancer may develop.

As genomic sequencing has become easier and less expensive, it has become much more commonplace. Huge amounts of data are now being generated. New cancer genes and variants are frequently being discovered. When the dozens of variants in hundreds of genes linked to cancer are taken into account, the task of determining which variants are significant may seem Sisyphean.

To help address that challenge, a few years ago the American College of Medical Genetics and Genomics (ACMG) released recommendations on how to classify the variants found in inherited cancer genes. Variants found in any gene may be classified in one of five categories: benign, likely benign, uncertain, likely pathogenic, or pathogenic. What remains a problem are the many variants that fall under the “uncertain” grouping, also called “variant of unknown significance.”

Now the ACMG is releasing an updated framework for classifying inherited variants in cancer genes. It focuses on integrating both tumor data and biomarker data. Dr. Walsh, a member of MSK’s Robert and Kate Niehaus Center for Inherited Cancer Genomics, is the lead author of the new guidelines, which were published November 1, 2018, in the journal Human Mutation.

“In the past, the ACMG has provided guidance for testing labs, saying that people who get their genomes sequenced should be informed about which of their genes harbor variants. But in some ways that was like putting the cart before the horse,” Dr. Walsh says. “We didn’t know enough to determine what many of these variants meant.”

He explains that researchers are starting to make some headway in pulling together all the tumor and biomarker data that’s being collected. There may now be evidence about whether certain previously unknown variants cause harm.

A Rapidly Changing Field with Real Consequences

As the new guidelines are adopted by labs around the country, variants will continue to be reclassified. As a result, earlier genomic screening will need to be revisited on a regular basis.

“As labs begin to apply these new rules, there will be some people who had testing in the past who will need to be contacted with updated results,” Dr. Walsh says.

Even as the guidelines are still being phased in, the issues that they are expected to bring up are already apparent. A recent study from investigators at the University of Texas Southwestern Medical Center in Dallas found that nearly one-quarter of the variants that had originally been classified as being of “unknown significance” were later reclassified as being either likely or unlikely to be associated with cancer. The investigators reviewed the results from 1.45 million people who were screened for cancer genes with a test developed by Myriad Genetic Laboratories.

Dr. Walsh says that people who have had testing in the past should consider contacting the labs and clinics where the testing was performed. The incremental change in rule classification will impact few people overall, so it is important that appropriate channels are established between patients and providers, he adds. MSK encourages people who have been tested here to contact their doctor or genetic counselor at regular intervals to see if there are any updates pertaining to the tests they had.

“Communicating is key and delivery of information needs to be in such a way that the information is useful and not frightening,” Dr. Walsh notes. “These changes in gene classification can have meaningful implications for people’s lives.” Some people who learn that gene variants they carry are linked to cancer will likely want to explore questions surrounding screening guidelines, risk-reducing surgeries, and even family planning. Others who learn that their variants are harmless after months or years of worry may be able to breathe a sigh of relief.

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Something New Under the Sun: Study in Leukemia Finds Role for Helios Protein

Source: Memorial Sloan Kettering - On Cancer
Date: 11/21/2018
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Proteins are one of the fundamental building blocks of life, controlling many of the vital functions carried out by cells. These activities include cell growth, division, and death. Sometimes the same protein can have more than one job, depending on how it interacts with other proteins in a cell.

The latest example of a protein with a dual role is one called Helios. When it’s missing, Helios can contribute to a type of pediatric blood cancer called B-acute lymphoblastic leukemia (B-ALL). But researchers at Memorial Sloan Kettering are now learning that when Helios is abundant, it can actually drive the formation of a different and a more common type of blood cancer called acute myeloid leukemia (AML). The findings were published in Cell Stem Cell.

“There are not a lot of examples of this type of situation,” says senior author Michael Kharas, a cancer biologist in the Molecular Pharmacology Program in the Sloan Kettering Institute. ”Occasionally, there are proteins that have completely different activities in different kinds of cancer. In this study, we figured out the ways in which the protein works and showed how it turns different genes on and off.”

A Protein That Regulates Genes

Helios is the name for the ancient Greek god of the sun. (Genes and proteins are sometimes given whimsical names, and Helios is a member of a family of proteins that are all named after characters from Greek mythology.) The Helios protein acts as an epigenetic regulator, which means it can control which genes get turned on and which genes get turned off. It exerts control by regulating chromatin, the part of the cell that packages DNA. If you imagine DNA as long strands of yarn, chromatin is the spool that the strands wrap around. When DNA is tightly wound, it’s hard for proteins to get made because the machinery that’s needed to start the process can’t make contact with the DNA. But when it’s unwound, the DNA becomes accessible.

In the new study, investigators found that Helios unwraps DNA from chromatin in areas that are important for the survival of leukemia cells. It also winds up the DNA in locations that are important for blood stem cells to turn into specific cell types. This process is called differentiation.

In someone with AML, the bone marrow produces immature white blood cells called myeloblasts rather than healthy, normal blood cells. Myeloblasts are unable to function like normal blood cells. They grow out of control and crowd out healthy cells. High levels of Helios are present in leukemia stem cells, which are essential for leukemia to grow. These cells are also thought to be the cause for relapse. 

“In the case of AML, Helios controls the program that leukemia stem cells use,” Dr. Kharas explains. “In some areas of the genome, it keeps the chromatin open, and in other places, it keeps the chromatin closed. The genes that are important for the cells’ ability to keep growing are left on, and those that would drive normal differentiation are turned off.”

By contrast, in the pediatric blood cancer B-ALL, it’s the absence of Helios that causes trouble. Earlier research found that Helios was lost in about half of people with a type of B-ALL called hypodiploid B-ALL.

In this study, however, investigators found that knocking down, or deleting, Helios can reduce the number of leukemia stem cells. Furthermore, Helios is required for leukemia cells to survive, and when it’s removed, leukemia cells stop growing and differentiating, and ultimately die.

To confirm that Helios contributes to AML development, the investigators also transplanted human leukemia cells into mice models. They found that when Helios was deleted, the mice had a greater reduction in leukemia cells and lived longer.

What’s Next? Targets for Drug Development

Based on the findings, the researchers hope to develop drugs that target Helios as a treatment for AML. Dr. Kharas doesn’t believe there is any danger in causing B-ALL by blocking Helios, since several other mutations are needed to drive the formation of that cancer. In addition, the mice that had Helios blocked in their blood cells didn’t show any signs of other cancers, including B-ALL, and had normal blood stem cell function. But until further research is conducted, investigators won’t know for sure.

Dr. Kharas notes that other researchers have discovered that Helios plays a role in the proper functioning of a type of white blood cell that affects immune response. This suggests that drugs that influence Helios could also be used to boost immune therapies for cancer.

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Four Things Researchers Know — and Some Things They Don’t Know — about Vaping

Source: Memorial Sloan Kettering - On Cancer
Date: 11/23/2018
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More than 10 million people in the United States currently use electronic cigarettes, according to a recent study published in the Annals of Internal Medicine. About half of them are under 35 years old, raising concerns about long-term health consequences.

The US Food and Drug Administration recently announced that it was taking new steps to address vaping among teenagers by preventing access to flavored products. But there has been less discussion about use among adults.

We spoke with clinical psychologist Jamie Ostroff, Director of Memorial Sloan Kettering’s Tobacco Treatment Program, about vaping. Much is still unknown about the health effects of vaping in people of all ages, including those with cancer.

1. Vaping is considered to be safer than smoking traditional cigarettes, but it is still not considered to be safe.

Traditional tobacco products like cigarettes and cigars contain thousands of chemicals, about 70 of which are known to cause cancer. E-cigarettes are battery operated and are not burned, so they don’t emit all the cancer-causing compounds that are released when tobacco is smoked. For this reason, most public health experts consider them to be safer than cigarettes and other smoked tobacco. But e-cigarettes do contain nicotine, which is highly addictive, as well as other chemicals with largely unknown long-term health effects.

E-cigarettes are currently unregulated and manufactured without strict safeguards, and may contain other dangerous substances, such as heavy metals like nickel, tin, and lead. Ultrafine particles contained in the vapor from vaping can cause irritation and inflammation in the lungs. Some of the most harmful substances found in e-cigarettes come from the chemicals that give these products their flavors.

Nicotine itself can be unsafe, especially at high doses. In addition to causing addiction, it can have negative effects on the cardiovascular system.

2. Vaping is especially dangerous for teenagers and young adults.

A study from the US Surgeon General in 2016 reported a 900% increase in the use of e-cigarettes by high school students from 2011 to 2015.

According to the Centers for Disease Control and Prevention, vaping is especially unsafe for kids, teens, and young adults. Nicotine can harm the parts of the developing brain that control attention, learning, mood, and impulse control. Brain development continues until someone is in their mid-20s.

“There’s always been experimentation with tobacco use among adolescents, but vaping doesn’t have the stigma that’s associated with smoking,” Dr. Ostroff says. “There are young people who would never consider smoking cigarettes, but they might consider using e-cigarettes.” She adds that because vaping doesn’t produce odor or smoke, it can be done much more secretively by young people who want to hide it from parents and teachers.

There are also concerns that use of e-cigarettes among young people who previously had never smoked may lead to use of more traditional tobacco products later. On the other hand, e-cigarettes could intercept some who would become smokers.

3. There is not enough evidence to recommend vaping to quit smoking.

“Many adult electronic cigarette users are smokers who report trying to quit smoking, which begs the question about whether they help or hinder quitting efforts,” Dr. Ostroff says.

Findings from rigorously designed clinical trials give healthcare providers guidelines for what works and what doesn’t. “Members of MSK’s Tobacco Treatment Program would tell someone who wants to quit or cut down their smoking to seek behavioral counseling combined with medications that have been found to be safe and effective in helping people to quit in clinical trials,” she adds. There are currently five FDA-approved nicotine replacements, including patches, gum, and inhalers, and two non-nicotine drugs (bupropion and varenicline) that help people reduce symptoms of nicotine withdrawal and successfully quit.

“That said, we know that many adults are using these products as alternate nicotine delivery devices to try to quit smoking, so we have an obligation to discuss the known and unknown risks and benefits,” Dr. Ostroff says. “We take a very individualized approach and work with each patient to develop a tailored quitting plan informed by the latest research findings and patient preferences.”

She explains that one advantage of using FDA-approved nicotine replacements over vaping is in determining how much to use and how often to use it. “There’s so much ambiguity and variation in the nicotine content among electronic cigarettes, so people who use them don’t know how much nicotine they’re getting,” she says. “This makes it hard for doctors to guide smokers trying to quit and make recommendations that will help them manage nicotine withdrawal.”

She notes that many people who vape are dual users who continue to use some traditional tobacco products as well. “We know that dual use is extraordinarily common. But people don’t get the full benefits from quitting smoking unless they quit smoking cigarettes completely.”

4. There are special considerations surrounding vaping in people with cancer.

“When someone has been diagnosed with cancer, there is an urgency for them to quit smoking cigarettes so that it doesn’t interfere with their treatment or negatively affect their cancer outcomes,” Dr. Ostroff says. E-cigarette use is not allowed in healthcare settings, so it especially important that people seek support to quit and medication recommendations from health professionals with expertise in treating tobacco dependence.

“To be sure, it can be challenging to quit smoking in the midst of dealing with a cancer diagnosis,” she concludes. “That’s why it is so important to seek out cessation support services to help patients quit and stay quit.”