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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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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.”

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First Targeted Cancer Drug Approved Based on Mutation Rather than Tumor Type

Source: Memorial Sloan Kettering - On Cancer
Date: 11/26/2018
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The US Food and Drug Administration has approved the drug larotrectinib (Vitrakvi®; LOXO-101) for cancers caused by a genetic mutation called a TRK fusion. This groundbreaking targeted therapy is the first to be developed and approved based solely on its effect on a specific genetic change in a tumor, regardless of where in the body the tumor originated.

The drug was approved for tumors that have spread to other parts of the body or that cannot be surgically removed. It is also approved for patients who have no other treatment options or whose cancers have progressed following other treatments.

“With this drug, we are seeing the true potential of precision oncology come to life,” says David Hyman, Chief of the Early Drug Development Service at Memorial Sloan Kettering. Dr. Hyman is the senior author of a study published in the New England Journal of Medicine (NEJM) in February on the effectiveness of the drug.

A Big Step Forward for Precision Medicine

The idea behind precision oncology is that people can be given drugs that target specific mutations driving their cancer’s growth. In other words, the same drug may work against many tumor types.

Until now, investigators have found that the effectiveness of a particular therapy can vary greatly depending on where the cancer started. This is true even in people whose cancers share the same mutation. Individuals with lung cancer may respond to a targeted treatment that has little effect for those with colorectal cancer, even if the tumors have the same genetic change.

This is what makes larotrectinib so exciting.

“In our research, we have not noticed a meaningful difference in response to larotrectinib with one tumor type versus another,” notes MSK medical oncologist Alexander Drilon, the first author of the NEJM paper. “In addition, it has seemed to work equally well in all age groups.”

The fact that the drug was tested in adults and children at the same time is significant. “Cancers driven by TRK fusion mutations are rare,” says Neerav (Neal) Shukla, who led the pediatric trial at MSK. “But because we sequence the tumor genomes of all of our pediatric patients, we are able to identify everyone who might benefit from this drug.”

A Lasting Response

In the NEJM article, Drs. Hyman and Drilon and their collaborators reported that the overall response rate to larotrectinib was 75%. At one year, 71% of the responses were ongoing, with 55% of people in the study remaining progression free, meaning that their disease had not advanced.

The paper combined three studies that involved 55 people in total. Within the group, there were 17 different types of advanced or metastatic tumors — including colon, lung, pancreatic, thyroid, and salivary cancers as well as melanoma and sarcoma — that had TRK fusion mutations. Patients ranged in age from four months to 76 years.

The most common side effects of the treatment were fatigue, dizziness, anemia, and shortness of breath, and they were not severe. The more serious side effects, which were much less common, included fever, diarrhea, sepsis, abdominal pain, dehydration, skin infections, and vomiting.

TRK fusions occur when one of three genes called the NTRK (pronounced “en-track”) genes becomes mistakenly connected to an unrelated gene. This error can lead to uncontrolled cell growth. Although the fusions are rare within most individual cancers, they do affect thousands of people each year.

Analysis with MSK-IMPACT™ can identify which tumors carry TRK fusions. Other similar tumor analysis tests can find these genetic changes as well.

A Milestone in Pediatric Cancer Care

Some of the rare cancers treated with larotrectinib in the study included pediatric diseases, such as infantile fibrosarcoma (a soft tissue tumor found in babies) and secretory breast carcinoma (a type of breast cancer sometimes found in children).

Developing more clinical trials for childhood cancers is the focus of MSK’s Pediatric Translational Medicine Program. This effort aims to build a wealth of early-stage trials focused on taking discoveries made in the lab and bringing them to patients. Working closely with the Early Drug Development Service, the experts in MSK’s Department of Pediatrics are seeking to take full advantage of the latest discoveries in molecular oncology.

“For decades, our pediatric patients have had access to the best care anywhere,” Dr. Shukla says. “Now, with the advances in genetic sequencing, we are coming into an age where we are finding similarities across different kinds of pediatric cancers. For example, we may find that the same mutation is driving both a leukemia and a brain tumor. In addition, because we treat all cancers in all age groups, we are poised to take advantage of these discoveries made in both adults and children.”

MSK’s Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) has also allowed MSK to take a leadership role in developing trials for pediatric cancers. The goal of POETIC, led by hematologic oncologist Tanya Trippett, is to promote the early clinical development of promising therapies for the treatment of children, adolescents, and young adults with cancer and related disorders. This includes basket trials for new targeted agents as well as new drug combinations.

New Opportunities for People with Rare Cancers

The development of larotrectinib was based on the concept of basket trials. These studies test therapies that act against tumors based on their mutations, regardless of where they develop. In addition to having a benefit for many people with common cancers, these kinds of studies also provide an important opportunity to test therapies for rare cancers, which are often underrepresented in clinical trials.

Although many of the studies’ participants had long-lasting responses to larotrectinib, a few became resistant over time when their tumors developed another mutation. The company that makes the drug, Loxo Oncology, has already designed a second drug called LOXO-195 to target this additional alteration. The company is working with investigators at MSK and other institutions to test this drug in people who have stopped responding to larotrectinib. A clinical trial is now open at MSK and is being co-led by Drs. Drilon and Hyman for adult patients. A trial for pediatric patients is being led by Dr. Shukla.

“As we develop more precisely targeted drugs, a large and diverse clinical trials program such as ours, with an integrated effort to characterize patients’ tumors in advance, is key. It allows us to identify an often small group of people for whom a striking benefit may be seen, as in the larotrectinib story,” says Paul Sabbatini, MSK’s Deputy Physician-in-Chief for Clinical Research.

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Personalized Medicine 2.0: MSK Leads the Way in the Study of Drug Resistance in Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2018
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Lung cancer was one of the first cancers that could be targeted by drugs aimed at specific mutations in tumors. Advances in genomic medicine and the molecular analysis of tumors can largely take the credit for this early progress. Unfortunately, that also means that people with lung cancer who were treated with these drugs were among the first to develop resistance. When a treatment that initially works stops working, it is called acquired resistance. Overcoming acquired resistance is one of the most critical challenges in cancer research today.

Memorial Sloan Kettering investigators are at the forefront of studying this problem. They are looking for ways to address acquired resistance. The methods they are considering include combination therapies that attack cancer on multiple fronts at the same time.

“We’re taking personalized medicine to the next level — version 2.0,” says MSK medical oncologist Helena Yu. “It’s not enough anymore to just look for a mutation and give everyone who has the mutation the exact same treatment. Many factors influence how people respond to therapy, and we’re trying to direct treatment in a much more specialized way.”

Is Treatment Resistance Inevitable?

About 20% of lung adenocarcinomas, the most common lung cancer in the United States, are driven by mutations in a gene called EGFR. This type of cancer is often found in people who have never smoked. The first targeted therapy to treat EGFR-driven cancer, called gefitinib (Iressa®), was approved by the US Food and Drug Administration in 2003. Since then, these drugs have become a conventional treatment. As a result, testing for EGFR mutations has become a standard part of diagnosis for advanced lung cancer.

Most people who take these drugs benefit greatly from them. Their tumors shrink measurably, leading to an improvement in some cancer symptoms, such as pain and shortness of breath. In addition, EGFR inhibitors are taken at home as pills and have few side effects compared with chemotherapy.

But the effectiveness of EGFR inhibitors is not long lasting. Although some people respond for years, the average time until the drugs stop working is 12 to 18 months. In some people, the drugs work for only a few months or not at all.

“Not all of the cells within a tumor are the same,” Dr. Yu says. “Even if 99% of the cells respond to an EGFR inhibitor and die off, the ones that don’t die will eventually become dominant and start to take over. Also, because cancer is a living thing, it has the ability to evolve and adapt while being exposed to treatment.”

Finding Genetic Markers for Resistance to Targeted Drugs

When people with lung cancer stop responding to an EGFR inhibitor, their MSK doctors are ready with an arsenal of other treatments. Many patients have a second biopsy. The resistant tumor is then analyzed with MSK-IMPACT™, a test that looks for more than 400 mutations that are known to play a role in cancer.

“Sometimes we find a mutation that wasn’t there the first time we analyzed the tumor. That may suggest that there are other targeted drugs to try,” Dr. Yu says. But other acquired changes, such as changes that don’t affect genes’ sequences, are not detected with MSK-IMPACT.

“Genomic sequencing of tumor tissue is part of the story, but not the whole story,” she adds. “We’re working on additional tests that can detect other kinds of molecular changes.”

MSK investigators are also developing liquid biopsies. These tests could allow doctors to analyze the molecular changes in a tumor with a blood test rather than having to take samples of the tumor from the lung.

Combining Targeted Therapies for a One-Two Punch

MSK already has clinical trials underway to address some of the acquired mutations commonly seen in lung cancer. One clinical trial combines a newerEGFR inhibitor called osimertinib (Tagrisso®) with an experimental drug called AZD6094. This second drug targets a mutation in the gene Met. About 20% of people treated with osimertinib eventually develop a Met mutation.

Another trial is looking at the combination of osimertinib and bevacizumab (Avastin®). Bevacizumab blocks the growth of a tumor’s blood vessels. Earlier research suggested that it is sometimes effective in combination with EGFR inhibitors.

Researchers have found thatEGFR inhibitors can drive some adenocarcinomas to transform into small cell lung cancer, a type of lung cancer that is treated with different drugs. And so another trial is testing osimertinib in combination with the chemotherapy drugs typically used to treat small cell lung cancer. This trial is open to people whose tumors carry genetic mutations that make their cancer more likely to transform. “We’re always trying to stay ahead of the curve,” Dr. Yu says.

Most people with EGFR mutations don’t initially respond to immunotherapy, but they may respond if the cancer develops additional mutations.

Dr. Yu emphasizes that combination treatments have more side effects than using EGFR inhibitors on their own. That is why it is important to carefully identify who is likely to benefit from these more aggressive drugs.

“Unfortunately, we can’t cure stage IV lung cancer as of yet, but the longer we can maintain people on treatments that are effective and have minimal side effects, the better,” she concludes. “We want to be able to stretch out the benefit for each treatment as long as possible while, at the same time, always having more options in our back pocket when we need them.”

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Gut Microbes May Protect People Having Bone Marrow Transplants

Source: Memorial Sloan Kettering - On Cancer
Date: 12/02/2018
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One of the most serious complications of blood stem cell or bone marrow transplants (BMTs), which are used to treat many types of blood cancer, is graft-versus-host disease (GVHD). In this condition, a donor’s immune cells attack the vital organs of a transplant recipient. It can cause death in some cases.

In the past few years, researchers from Memorial Sloan Kettering and other institutions have found that a transplant recipient’s microbiota plays an important role in their survival after a BMT. (The microbiota is the community of organisms, or flora, that live in the body, especially in the gut.) Now, for the first time, investigators have found an association between the health of the microbiota before a transplant and a person’s survival afterward. The findings were presented December 2, 2018, at the annual meeting of the American Society of Hematology (ASH).

“Patients who went into the BMT process with a gut flora that was already disrupted had a higher risk of death after the transplant,” says the study’s senior author, Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “The thing that we keep coming back to is that preserving the commensal flora in the microbiome is good for transplant patients.” Commensal flora are microbes that live in the body without causing disease. In some people, they may be beneficial.

The Forgotten Organ

Many of those who study the gut microbiota refer to it as the “forgotten organ.” It can have a huge impact on someone’s health. But scientists are still learning what makes it healthy or damaged, and what can be done to correct that damage.

“There are as many bacterial cells as there are human cells in our bodies,” says first author Jonathan Peled, an MSK medical oncologist who specializes in BMTs. “In addition, these bacteria are really important for the way our bodies function.”

“Before someone has a BMT to treat their cancer, we do a lot of screening tests to make sure they are otherwise healthy. We look at things like their heart, lung, and kidney function,” says Dr. van den Brink, who runs a lab in the Sloan Kettering Institute’s Immunology Program. “This study suggests that we should also screen the microbiota. If we find out that it’s in bad shape, we could do something to repair it.”

Dr. Peled adds, “This study opens the door to repairing the microbiota in the pretransplant period. Because this is a time when we’re usually not in a rush to move forward with treatment, it’s also a good time to look for ways to do this before continuing the transplant.” Interventions that could improve the health of the microbiota include changes to diet, using or avoiding certain antibiotics, and fecal transplants of healthy gut microbes.

MSK doctors are already conducting research on fecal transplants that make use of a patient’s own stool. The stool is preserved before the BMT and given back to the patient after the process. A recent study led by MSK physician-scientists Eric Pamer and Ying Taur found that fecal transplants are effective in restoring the balance of healthy microbes that is lost during a BMT. Researchers also plan to study the safety of providing fecal transplants with material from a healthy donor. Donor stool may ultimately prove to be a better option for people who come to a BMT with a microbiota that’s damaged.

Throwing Off the Healthy Balance of the Gut

In the analysis presented at ASH, the researchers studied 1,922 stool samples from 991 people having allogeneic BMTs. “Allogeneic” means the blood or marrow stem cells come from a donor. (In the other type of transplant, an autologous procedure, a patient’s own blood cells are stored before treatment and later infused back into the body.) The people were treated at MSK and three other hospitals. The samples were evaluated for a range of bacteria types, including commensal strains and those that are known to cause disease.

The investigators found that, on average, the people about to have BMTs had decreased diversity of bacteria in their guts. They also found that different strains were dominant, compared with healthy volunteers. This was a new finding, but it was not surprising. Most people with blood cancer who need transplants have gone through months or years of treatment with chemotherapy drugs and antibiotics that throw off the normal, healthy balance.

Diversity in the microbiota is important because commensal bacteria help keep more dangerous strains in check. Previous studies have also shown that certain commensal strains actually provide specific benefits for people having transplants. Some strains release substances that protect the walls of the intestines, for example.

In the current study, only 10 to 30% of patients had what researchers considered a balanced gut flora before their transplant. The more the ecology of the microbiota was disrupted, the more likely it was that patients had fatal complications from GVHD. However, the researchers emphasize that this study showed only an association, not direct causation.

A Study with a Broad Geographic Scope

Investigators at three other transplant centers also participated in the research and contributed patient samples: Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Different locations were included because other research has shown that microbiotas across geographic regions vary widely. Factors like environment and diet are thought to play a role.

All of the samples were analyzed in MSK labs, Dr. Peled says, improving the validity of the results across the sites.

“One of the main findings of this study was that the injury patterns that we saw in people’s microbiotas were comparable across geography,” he concludes. “This suggests that if we find interventions to correct these imbalances at one center, they will also apply to people being treated in other parts of the world.”

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Sessions at Annual Breast Cancer Conference Focus on Prevention and Treatment of Lymphedema

Source: Memorial Sloan Kettering - On Cancer
Date: 12/07/2018
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Cancer-related lymphedema is one of the most challenging long-term side effects that can occur after cancer surgery. This chronic, sometimes severe swelling in an arm or leg can greatly impact a person’s quality of life. It often leads to pain as well as difficulty using the affected limb.

At the annual San Antonio Breast Cancer Symposium, held December 4 to 8, two educational sessions focused on the prevention and treatment of lymphedema. Both talks featured investigators from Memorial Sloan Kettering.

A Distressing but Common Complication

Lymphedema often strikes after lymph nodes are removed during cancer surgery. About one-third of women treated for breast cancer who have all of the lymph nodes in their armpit removed — an operation called complete axillary dissection — will experience some degree of lymphedema in the affected arm. Lymphedema of the leg can occur in people treated for cancer in the abdominal area who have lymph nodes in the groin removed.

Monica Morrow, Chief of the Breast Service in MSK’s Department of Surgery, moderated a session with experts from MSK and two other institutions on the best ways to manage the treatment of underarm lymph nodes in people being treated for breast cancer.

“It’s important to focus on ways to reduce the risk that patients will later develop lymphedema,” Dr. Morrow says. “At the same time, removing the cancer and making sure that it doesn’t come back remains our primary focus.”

Evolving Treatment Approaches

For decades, people undergoing surgery for breast cancer had all the armpit lymph nodes on the affected side of the body removed. That’s because these lymph nodes were one of the first places that cancer cells traveled when they left the breast, and that removal would impede further spread.

In the 1990s, experts began to use a technique called sentinel lymph node biopsy. Surgeons at MSK, led by Hiram Cody, played a key role in establishing the clinical utility of this approach. The technique uses a combination of two tracers, which signal where they have traveled in the body. This dual-tracer approach involves injecting both a dye and a radioactive compound into the breast.

Doctors can inject the tracers and follow the natural flow of lymphatic fluid out of the breast. This allows them to see the first few nodes to which the fluid travels — dubbed the sentinel nodes. If the sentinel nodes are clear of cancer, there is no need to remove the remaining lymph nodes. This technique is now standard at hospitals around the world.

In the past several years, advances in chemotherapy, hormone therapy, and targeted drugs have further changed breast surgery. In particular, people with certain subtypes of breast cancer increasingly receive cancer drugs before surgery to shrink the tumor and make it easier to remove. This is called neoadjuvant therapy. These drugs can also knock out cancer in the lymph nodes, reducing the need for complete axillary dissection and, in turn, reducing the risk of lymphedema.

Finding the Sentinel Nodes

The annual conference in San Antonio is attended by researchers and physicians from around the world who want to learn about the latest in diagnosis, prevention, and treatment for breast cancer. MSK surgeon Andrea Barrio conducted an educational session on the latest methods for studying the sentinel nodes in people who have been treated with neoadjuvant chemotherapy and determining whether additional nodes need to be removed.

She presented research that looked at patients who had cancer in their lymph nodes before neoadjuvant therapy who had a sentinel lymph node biopsy after receiving drug treatment. The study found that when three or more sentinel nodes were able to be identified and were found to be clear of cancer, these people no longer needed to have the rest of their lymph nodes removed, even though those nodes previously had cancer. (For a complete axillary node dissection, usually between 20 and 40 nodes are removed.)

“It’s important to remove at least three sentinel nodes that have been identified with two different tracers,” she says. “Otherwise, some cancers may be missed.”

She stressed the importance of using established processes for identifying sentinel nodes because imaging techniques like ultrasound and MRI are not reliable in determining whether nodes are cancerous.

“The good news is that lymph nodes do respond to neoadjuvant chemotherapy, reducing the need for more extensive surgery in many people,” she says.

Treatments Based on Underlying Mechanisms

In another session, Babak Mehrara discussed the latest research on treating lymphedema in cases where removal of all of the lymph nodes is necessary to control the cancer.

Dr. Mehrara, Chief of MSK’s Plastic and Reconstructive Surgical Service, discussed the history of this research, including drug trials that have attempted to reduce lymphedema, as well as what scientists know about the underlying mechanisms of this condition.

He does research in the lab as well as in the clinic, hoping to find the most effective lymphedema treatments. One potential solution involves a topical cream, which appears to reduce the swelling from lymphedema in mice. He hopes to begin clinical trials with this drug soon.

“This is an exciting time for lymphedema research,” Dr. Mehrara concludes. “There have been advances in multiple fronts, thanks to new surgical and medical therapies that are coming together.”