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Nov 2, 2017 · Targeting a Molecular Abnormality

Microsatellite instability (MSI) might sound like something a NASA engineer would study. But it’s actually a molecular abnormality found in 15 percent of colorectal cancers, explains Mayo Clinic medical oncologist and gastroenterologist Frank A. Sinicrope, M.D., who is testing an immunotherapy drug that could help patients with this subtype of colorectal cancer.

Just recently, researchers discovered why colorectal cancer with MSI can evade the body’s immune system, grow and become lethal: checkpoint proteins present on MSI tumors allow the cancer to manipulate the body’s defenses.

Armed with this knowledge, Dr. Sinicrope and his team will conduct a national clinical trial to test whether a drug called an immune checkpoint inhibitor can prevent the cancer from dodging death. The trial will enroll patients with stage III colon cancer with MSI who have already had surgery to treat the cancer.

“There is a great deal of interest in the trial and a lot of optimism based upon remarkable results seen for immune checkpoint inhibitors in patients with metastatic colorectal cancers,” Dr. Sinicrope says.

Escaping Attack

Colorectal cancer with MSI is typically diagnosed at an earlier stage, and patients do better than those without the molecular abnormality. But the survival advantage is lost once the cancer spreads to other sites in the body.

MSI has a genetic basis. It results from the loss of function in one of the genes that repair errors in the DNA sequence when DNA is replicated. Tumors with MSI mutate rapidly, acquiring hundreds to thousands of mutations. This causes the immune system to kick into high gear. It recognizes the tumor and dispatches an army of T cells to attack. Yet the cancer has developed ways to escape this attack. Researchers observed this for many years and didn’t understand how it was possible.

Colorectal cancer with microsatellite instability (MSI) has specific features, including a tendency for tumors to be on the right side of the colon. MSI tumors mutate rapidly and grow to a large size.

Researchers now know that colorectal cancer with MSI can tap into checkpoints, an immune system pathway used to distinguish foreign cells from normal cells and signal whether or not to attack cells. Checkpoint proteins present on MSI tumors bind to receptors on T cells so those T cells can’t be activated in an attack. By exploiting the immune system’s checkpoints, MSI tumors can fly under the radar.

Immunotherapy prompts the immune system to refocus on fighting cancer. Immunotherapy drugs are new, but the idea of immunotherapy is not. Some of the foundational discoveries in checkpoints were made two decades ago in a series of experiments performed by Mayo Clinic researchers.

An immunotherapy drug called an immune checkpoint inhibitor is an antibody that blocks the cancer from evading attack and boosts immune response against the cancer. Such drugs have shown promise in clinical trials on metastatic colorectal cancer with MSI — when the cancer has spread to other sites in the body and is often fatal. The U.S. Food and Drug Administration approved in May 2017 the use of one immune checkpoint inhibitor for patients with this kind of cancer who have no other options for treatment.

Determined to change patient care, Dr. Sinicrope will test a checkpoint inhibitor called atezolizumab in a phase III trial, the only one to date focused on colon cancer before it metastasizes and turns lethal.

“We never had drugs before that could effectively modulate the immune system in order to achieve the outcomes that are being observed in certain tumor types,” Dr. Sinicrope says. In the trial, the checkpoint inhibitor will target micrometastases, tiny tumor cells left behind after surgery. These cells can’t be detected with conventional tests and are responsible for the return of the cancer.

The trial will enroll 700 patients at Mayo Clinic campuses in Rochester, Minnesota; Jacksonville, Florida; Scottsdale, Arizona; and at multiple other sites across the U.S. through the Alliance for Clinical Trials in Oncology. Some patients will receive the checkpoint inhibitor in addition to chemotherapy, and others will receive only chemotherapy. After treatment, which could last up to one year, doctors will monitor patients for recurrence and survival for three years.

Predicting treatment

In addition to seeking better therapies for patients, Dr. Sinicrope’s research focuses on cancer biomarkers.

Biomarkers are molecular substances found in body fluids or tissues that can alert doctors to disease. They are used increasingly in screening for the early detection of cancer. Biomarkers can also predict the likelihood of the recurrence or spread of cancer. And they can indicate whether treatment, like immunotherapy, may work in certain patients.

Frank A. Sinicrope, M.D.

MSI is considered a predictive biomarker for treatment with checkpoint inhibitors, Dr. Sinicrope says. Testing for MSI at the time of a colorectal cancer diagnosis is increasing around the U.S. and now is recommended for all newly diagnosed patients. MSI is seen in a range of other cancers as well, including endometrial cancer.

Discovering biomarkers like MSI and categorizing the immune composition of tumors can help transform patient care, Dr. Sinicrope explains. In the case of MSI tumors, the evolving perspective is to treat the molecular abnormality — not necessarily the tumor type, he says.

“This is the exciting area of precision oncology.”

This story originally appeared in the 2017 print edition of Forefront magazine.

Oct 26, 2017 · New Issue of Forefront Magazine

Forefront is the complimentary magazine of the Mayo Clinic Cancer Center. Published in print and online magazine editions annually and in email and online newsletter editions quarterly, Forefront highlights Mayo Clinic’s cutting-edge cancer research and the latest Cancer Center news.

View the online edition.

View the email newsletter.

Subscribe.

Oct 19, 2017 · Cycling Through Multiple Myeloma

Meet Andy Gordon, a health care litigator, dad, husband, cyclist, philanthropist and one in 14 million.

It was Labor Day 2009 when Andy received the same diagnosis his wife had heard 12 years earlier — a one in 14 million possibility. Andy’s wife Sue was diagnosed on April 11, 1997, with multiple myeloma, and she died on May 1. She never came out of the hospital. Their kids were 12 and 14 at the time.

Multiple myeloma is a blood cancer that forms in a type of white blood cell called a plasma cell. Plasma cells help you fight infections by making antibodies that recognize and attack germs. Multiple myeloma causes cancer cells to accumulate in the bone marrow, where they crowd out healthy blood cells.

“I was living in Washington, D.C., and riding my bike a fair amount when I started to have back pain,” recalls Andy. “I thought it was just middle-aged stuff.” The pain became unbearable while he was in Guantanamo Bay, Cuba, working for the U.S. Department of Homeland Security. In and out of planes and boats, he chalked it up to his activity, but he scheduled an appointment when he returned to the states just to make sure.

When the doctor couldn’t figure out the source of the pain, she sent Andy for a CAT scan. “I could tell just from the look on her face this is not going to be terrific news,” Andy says.

The doctor told Andy he needed to be hospitalized immediately. Andy had just turned 60 when an oncologist in the Washington, D.C., area confirmed he had multiple myeloma.

Andy began chemotherapy right away. “I knew the most important thing for me was for my kids to know that what happened to their mom was not going to happen to me,” Andy declares.

The Journey for Treatment

Three months before his diagnosis Andy married Patti Evans, a friend he had known for years. “If you get sick, you want Patti on your team,” he says. Patti was caring for her ailing father in Phoenix and was unable to fly to Washington while Andy was undergoing chemotherapy, so instead she secretly called friends and asked them to visit him. “Patti’s just one of those people who is a problem solver. When you’re facing a cancer for which there’s no cure, that’s particularly important,” Andy says.

The chemotherapy was working, and Andy’s cancer was decreasing enough to make him a candidate for a stem cell transplant. On the advice of his physician in Washington, Patti and Andy began to look for a medical center where he would get the transplant. They had consultations with several top medical centers in the U.S., but found their reputations to be different than what he experienced as a patient.

“I can close my eyes and actually see our first visit to Mayo Clinic and my initial interview with Joe — the sense was completely different than what I’d gotten from some of these other places,” Andy emotionally recalls. Joseph R. Mikhael, M.D., is a hematologist at Mayo Clinic in Arizona. He has conducted extensive research on multiple myeloma and is one of the world’s foremost leaders on the disease.

Changing the Outcome

The revolution in multiple myeloma over the past two decades means patients today like Andy are living healthier lives.

Multiple myeloma research has evolved incredibly over the last 10 to 15 years. Today there are new approaches, drugs and transplants that can be used to bring multiple myeloma into remission. In 1997, when Sue Gordon was diagnosed, the use of combining chemotherapy drugs was just in the  experimental stages.

The revolution in multiple myeloma over the past two decades has been fueled by giant leaps in the understanding of its pathogenesis and the development of several novel agents. Today, patients like Andy are living healthier lives, and overall survival has doubled.

Because multiple myeloma is a complex and wide-ranging disorder, it must be managed individually based on multiple interacting disease- and patient-related factors. Mayo Clinic was instrumental in the development of carfilzomib and pomalidomide, two new drugs approved by the U.S. Food and Drug Administration for multiple myeloma in 2012. The last time the federal agency approved a novel myeloma therapy was in 2006. This approval was based primarily on the results of a large Mayo-led clinical trial that took place at multiple centers across the U.S.

Back on the Bike

Andy underwent a combination of high-dose chemotherapy and an autologous stem cell transplant, which means his own stem cells were used. Andy stayed in remission for more than four years.

“I got on with my life. I went back to work and back to riding. I wanted to do something to help find a cure for blood cancers. That’s why I got involved in the Arizona Chapter of the Leukemia and Lymphoma Society,” Andy says. He raised more than $150,000 through cycling fundraisers. Mayo Clinic’s Arizona campus has received grant funds from the Leukemia and Lymphoma Society, which provides research funds to organizations to find cures for blood cancer.

During those four years, multiple myeloma treatments continued to improve. Dr. Mikhael relied on a similar chemotherapy treatment and a second autologous stem cell transplant, putting Andy into a deep remission.

One year after the second transplant, Andy got back on his bike and completed a 100-mile ride around Lake Tahoe. And he’s back to working as an attorney and professor at Arizona State University Sandra Day O’Connor College of Law.

Andy’s children are now 32 and 34. “My greatest joy,” says Andy, as he wipes a tear, “is that I’ve gotten to see our first two grandchildren and will hopefully see many more grandchildren.”

This story originally appeared in the 2017 print edition of Forefront magazine.

Sep 21, 2017 · Game Changers: Five Innovative Tests for Cancer Detection

Finding cancer as early as possible is critical to saving lives. Mayo Clinic is creating a new era in health care with tests that make early and accurate detection of common cancers easy. Many are minimally invasive, convenient, cost-effective and widely available, removing the barriers that prevent people from getting treatment.

  1. Breast cancer can’t hide in dense tissue

Deborah J. Rhodes, M.D., Carrie B. Hruska, Ph.D., Katie N. Hunt, M.D., and Michael K. O’Connor, Ph.D.

Mammography may not be enough to spot breast cancer for about half of all women who are screened. These women have dense breast tissue. They can be helped by a breast imaging technique pioneered at Mayo Clinic that nearly quadruples detection rates of invasive breast cancers in dense breast tissue.

On a mammogram, both dense tissue and tumors appear white. Spotting a tumor in dense tissue is like looking through a frosted glass window. Molecular breast imaging, or MBI, provides a clearer picture.

“MBI can uncover the reservoir of cancers that remain undetected on screening mammography because of masking by dense breast tissue,” says Deborah J. Rhodes, M.D., a Mayo Clinic Breast Clinic physician and a member of the team that developed the supplemental test.

In MBI, a short-lived radioactive tracer is injected into the vein. If tumor cells are present, they absorb the tracer like a sponge and illuminate on the image.

A Mayo Clinic team of physicists, radiologists and internists has spent nearly 15 years developing and evaluating MBI, including three clinical trials with over 5,000 women.

  1. Recurrent prostate cancer lights up

Eugene D. Kwon, M.D., and Val J. Lowe, M.D.

Recurrent prostate cancer lights up Prostate cancer is the most common cancer among men, and about 30 percent of those diagnosed will experience a recurrence. These recurrences can often be difficult for physicians to find.

A Mayo Clinic research team developed an imaging method known as Choline C-11 positron emission tomography, or PET, scan that can find recurrent prostate cancer earlier than other tests.

“It’s a way of looking at the body three-dimensionally so you can see through the body and around the body to find cancer,” says Mayo Clinic radiologist Val J. Lowe, M.D., who helped create the new technology.

Choline C-11 uses a radioactive form of the vitamin choline, which is readily absorbed by cancer cells. The drug is injected into the patient who then has a PET scan.

“Choline C-11 lets us pinpoint at a very early interval where the cancer is returning,” says Mayo Clinic urologist Eugene D. Kwon, M.D., who was part of the team that developed the test.  “Based on what we see in the PET scan, we can more intelligently design the patient’s next therapy.”

In about one-third of men, Choline C-11 PET scanning picks up metastatic lesions that aren’t seen with traditional imaging.

  1. Screen for colorectal cancer at home

David A. Ahlquist, M.D., and his research team collaborated with Exact
Sciences Corp. to develop the test.

Colorectal cancer is the second-leading cancer killer in the U.S.

Yet many people who should get screened skip it. Colonoscopy, the most widely used screening method, is expensive and requires bowel prep, sedation and time off work.

Mayo Clinic researchers co-developed a test, now called Cologuard, that screens for colorectal cancer by measuring tumor DNA in stool. Cologuard is mailed to patients at home and requires only a stool sample, with no bowel preparation, medication or dietary restrictions. A patient mails the sample to a lab for analysis, and results are sent to the prescribing physician. In published studies from the screening setting, this noninvasive, inexpensive test detected 94-100 percent of early, curable-stage colorectal cancers.

Mayo Clinic became the first health care organization to offer Cologuard. Mayo Clinic gastroenterologist David A. Ahlquist, M.D., and his research team collaborated with Exact Sciences Corp. to develop Cologuard.

Among the first 100,000 patients to send in tests, 42 percent had never been screened for colorectal cancer by any approach.

“That’s exactly what we were hoping for — improving screening participation rates should lead to more effective cancer detection at the population level,” Dr. Ahlquist says.

Dr. Ahlquist and Mayo Clinic have a financial interest in Cologuard. Neither Mayo Clinic nor Dr. Ahlquist receives royalties for Cologuard tests ordered for Mayo Clinic patients by Mayo Clinic physicians.

  1. Developing a test for esophageal cancer

Prasad G. Iyer, M.D.

Over four decades, esophageal cancer cases have increased 600 percent in the U.S.

“Compared with all other, more common cancers, incidence of esophageal cancer has skyrocketed,” says Mayo Clinic gastroenterologist Prasad G. Iyer, M.D.

The cancer can be very deadly. A sedated endoscopy at a gastroenterology lab is the recommended screening test today.

Dr. Iyer is collaborating with Exact Sciences Corp. and Mayo Clinic gastroenterologist David A. Ahlquist, M.D., to develop a new screening test that scans for DNA biomarkers of precancerous conditions in the esophagus. The biomarkers are picked up on a capsule sponge that a patient swallows. When the gelatin shell of the capsule dissolves, the released sponge is pulled out, providing cellular samples of the esophagus lining.

The sample can be gathered in a primary care office without the expense and side effects of an endoscopy, Dr. Iyer says. It’s sent to a lab for biomarker analysis.

Early data from studies show very high rates of sensitivity and specificity for predicting the presence of Barrett’s esophagus, a precursor for cancer. The capsule sponge was swallowed by over 90 percent of participants and was safe and well-tolerated. A phase II clinical trial is underway now at Mayo Clinic.

When esophageal cancer is caught early, survival is 80–90 percent.

“That tells the story of why early detection is the best. That’s the whole rationale for early screening,” Dr. Iyer says.

  1. Tampon may do double-duty protection

Jamie N. Bakkum-Gamez, M.D.

Soon, women may be using tampons to screen for the most common gynecologic cancer in the U.S.

An increasing number of women are diagnosed each year with endometrial cancer. Mayo Clinic gynecologic oncologist and surgeon Jamie N. Bakkum-Gamez, M.D., is attempting to change that trend.

“When this cancer is detected early, it has a very high cure rate,” Dr. Bakkum-Gamez says. “But when it’s detected at advanced stages, it’s almost always lethal. And we don’t have a screening test.”

In a 2015 study, Dr. Bakkum-Gamez showed it is possible to detect endometrial cancer using tumor DNA picked up by ordinary tampons. Now her team is working to develop the first early-detection test for endometrial cancer using tampons. This would be a prescribed, self-administered mail-in test, similar to Cologuard.

“We’re keeping the patient at the center of this. We want to make sure this is a test that provides wide access to care,” Dr. Bakkum-Gamez says. Her team is working on a commercially available test.

“This is an exciting time in women’s health, as we’re on the brink of introducing a life-changing test for cancer.”

This story originally appeared in the 2017 print edition of Forefront magazine.

Jul 27, 2017 · Meet the Investigator: Kristin R. Swanson, Ph.D.

At the Mayo Clinic Cancer Center, hundreds of researchers dedicate their professional lives to reducing the burden of cancer. Each one has a unique story. In this video, Kristin R. Swanson, Ph.D., a brain cancer researcher at Mayo Clinic’s campus in Phoenix, Arizona, discusses her research.

This article originally appeared in Forefront, Mayo Clinic Cancer Center’s research magazine.

Jul 18, 2017 · Check Out the Latest Issue of Forefront Magazine

Forefront is the complimentary magazine of the Mayo Clinic Cancer Center. Published in print and online magazine editions annually and in email and online newsletter editions quarterly, Forefront highlights Mayo Clinic’s cutting-edge cancer research and the latest Cancer Center news.

View the online edition.

View the email newsletter.

Subscribe.

 

May 2, 2017 · Meet the researcher - Alex Adjei, M.D., Ph.D.: The Power of Hope

There’s a reason Mayo Clinic oncologist Alex A. Adjei, M.D., Ph.D., spends so much time in the lab testing molecular solutions to cancer — it gives his patients hope.

When Dr. Adjei started as a lung cancer specialist about 20 years ago, patients with the disease had a dismal prognosis. There was basically one treatment option, and if that didn’t work — and it usually didn’t — there was little else he could do.

“When I started in ’95, of my first 20 lung cancer patients, nobody had any tumor shrinkage,” Dr. Adjei recalls. “All they did was lose hair and lose weight. None lived a year. It was so depressing. But now I have patients with metastatic lung cancer who I’ve been taking care of since 2009 and 2010. Now the vast majority of metastatic lung cancer patients are living 2 years or more.”

Dr. Adjei recently returned to Mayo Clinic (after starting his career here, he spent 9 years at Roswell Park Cancer Institute in Buffalo) to develop even better options for people with cancer. In his new role he’ll help lead the Mayo Clinic Cancer Center’s Early Therapeutics Program.

The program involves first-in-human trials testing new cutting-edge treatments for patients with a variety of cancers for whom no life-prolonging treatments exist. This is a critical step in the development of all new promising treatments for cancer. As medical director of this program, Dr. Adjei will help build an enterprise-wide cohesive program, making these promising treatments available to all Mayo patients with all type of cancers across its centers in Minnesota, Florida and Arizona.
Dr. Adjei says this kind of work gives patients hope, which changes the way they face their disease.

“You may not always change how long they will live with the disease,” he says. “But it’s amazing how people react when they are told we can try something. People feel better that they aren’t just waiting to die, but they are trying something, they are fighting. I strive to not mislead a patient but also not to take away hope. I don’t want to take away hope completely because people don’t do well in that situation.”

And he’s just as hopeful. He talks about one patient who came to him with stage IV lung cancer in 2000. He enrolled her in a clinical trial testing a new drug. The drug failed the trial and was never approved. But for her, and only her, it worked. She’s still alive today.

“That kind of situation is certainly not common,” Dr. Adjei says. “And going in, we know the chances of survival may be really, really small. But they aren’t zero. And that gives patients, and me, hope.”

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This article, part of the “Meet the Researcher” series, originally appeared in Forefront, Mayo Clinic Cancer Center’s magazine.

Investigate some of Mayo Clinic’s available clinical trials online.

Apr 18, 2017 · Attack the Gap--New Immunotherapy May Help the Body Fight Ovarian Cancer

It was only when Kathi Schroeder took to the bone-chilling streets of Cedar Rapids, Iowa, on her bike last January that she noticed something was not right.

“I was having trouble breathing; just taking a deep breath was difficult,” she remembers.

Kathi went to her local doctor’s office and was prescribed a round of antibiotics and steroids to address what the doctor considered a respiratory issue.

“I felt better for a little while — but then by March, I just bloated up and was having increasing difficulty breathing,” she says. “It was terrible. I just thought, something is horribly wrong.”

As the symptoms progressed, Kathi’s concern grew, and on March 18, 2015, she went in for a chest X-ray. Her doctor took one look at the X-ray and sent her directly to the emergency room for a CT scan and additional X-rays.

The news was not what she was expecting. “Right there in the emergency room, they told me, ‘We think you might have ovarian cancer.’ “

A week later Kathi arrived at Mayo Clinic in Rochester, Minnesota, in search of answers. A series of biopsies on the fluid around her lungs confirmed her worst fears. “To be hit at that point with ‘You have stage IV cancer,’ you have to stop and say, ‘Where do I go from here?’“

Attacking the Cancer

Kathi had a general idea of the statistics. Even if she beat the cancer in the first round, upward of 80 percent of women with her diagnosis will have a recurrence of, and ultimately die of, the cancer. A main reason why is because, most of the time, ovarian cancer only presents after it has spread within the abdominal cavity. And since it is constantly bathed in abdominal fluid, the cancer tends to break off and spread before the tumor grows in size.

Unfortunately, the only approved treatments are surgery and chemotherapy.

Oncologist Matthew S. Block, M.D., Ph.D., co-principal investigator of the clinical trial Kathi is participating in.

“The standard options against ovarian cancer are maxed out,” explains Mayo Clinic oncologist Matthew S. Block, M.D., Ph.D. “We have drugs that work and surgery works, but they don’t work perfectly. They are reasonably effective when there’s a known tumor, but they’re not effective to continue throughout the remission. Unfortunately, the majority of my ovarian cancer patients still die of their cancer.”

Kathi didn’t want to accept that finality.

First of Its Kind

One of the trickiest aspects of cancer is its ability to outwit the body’s immune system. For instance, T cells are on the forefront of the immune system. It’s their job to recognize invasive cells and kill them. They do this by detecting proteins — cells with familiar proteins are left alone; cells with foreign proteins are destroyed. But as cancer cells grow, they devise ways to kill the T cells or trick them into leaving the cancer cells alone.

“The idea behind cancer vaccines is to present the tumor to the immune system in such a way that the immune system attacks it as if it were a virus or bacteria,” Dr. Block says. “Essentially, we need to tell the immune system that this is a threat, and we need to attack it.”

To help patients harness the power of their immune systems, Dr. Block and colleagues launched a clinical trial. The phase I trial targets a specific protein, folate receptor alpha, in the cancer cells. It also uses a specific type of T cell, Th17, to trigger an immune response. These T cells not only attack the tumor cells but regulate other T cells that suppress the immune system’s response.

The trial is the first of its kind. “There are plenty of other ovarian cancer vaccines, but to my knowledge, this is the first time something has that goal of attacking T-reg cells via Th17 cells,” Dr. Block says.

When Kathi heard about the study, she knew she wanted to participate. Fortunately, she met the criteria — have stage III or IV cancer, be in remission, and have completed both surgery and chemotherapy.

“I’m always like, This is the next step, this is the next step,” she says. “That’s just my nature. This study has helped a lot because it feels like I’m doing something. It just makes you feel very powerful. I want it to work not only for me but also for other women that are out there in this situation.”

Back on the Bike

Kathi arrives at Mayo Clinic every three weeks for a series of shots and to be tested for recurrence. After the first three months, she will reach the maintenance phase — only coming in every three months for two years. “This is so easy. You get a few little shots, and you’re free to go. It’s just a wonderful study.”

And so far so good.

Kathi is back to riding her bike and is training for RAGBRAI — a nearly 500-mile, seven-day bike ride across Iowa.

“You wonder, how much of my life can I cram into the next year, two years,” she says. “The people that live past five years are what, maybe 20 percent? Where do you go with that when you have a family? You look to your bucket list and say, ‘Let’s just plan it and do it.’

“There’s not a day that goes by that I don’t think about it. I try to keep a positive attitude. I mean, in this case, it feels like I’m doing something — but you still have to live day to day. You can’t just stop living. This study is helping me with that.”

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Read about Mayo Clinic’s work to develop a TH17-inducing dendritic cell vaccine for ovarian cancer.

This article originally appeared in the late 2016 print edition of Forefront, Mayo Clinic Cancer Center’s magazine. Read the whole issue online (pdf).

 

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