“We found that the interval between menarche and age at first live birth is inversely associated with the risk of triple-negative breast cancer,” Dr. Christopher Li said.

Dr. Christopher Li

While relatively uncommon, triple-negative breast cancer is a particularly aggressive subtype of the disease that does not depend on hormones such as estrogen to grow and spread. This type of cancer, which accounts for only 10 to 20 percent of all breast cancers, does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or HER2/neu and therefore does not respond to hormone-blocking drugs such as Tamoxifen.

The study also confirmed several previous studies that have suggested that breast-feeding confers a protective effect against triple-negative disease.

“Breast-feeding is emerging as a potentially strong protective factor against one of the most aggressive forms of breast cancer,” Li said.

The mechanism by which breast-feeding and delaying childbirth reduces the risk of this form of breast cancer is unclear, Li said.

The study has particular implications for African-American women, who experience disproportionately high rates of triple-negative disease. While the reason for this remains largely unknown, reproductive characteristics are known to vary by race, and compared to non-Hispanic white women, African-American women are more likely to start having children at a younger age and are less likely to breast-feed, Li said.

“Our observations that delayed childbearing and breast-feeding are protective against triple-negative breast cancer suggest 
that variations in reproductive histories by race may to some 
extent explain the higher rates of triple-negative disease in 
African-American women.”

Li said the findings were based on an observational study, one of the first to focus on premenopausal breast cancer; results require confirmation and should be interpreted with some caution.

When she is here, she likes to chat with the nurses and doctors who have been caring for her for many years. It’s nice to know, she said, that there are people at Fred Hutch who really want her to be better.

Keren Stronach

“It’s nice to come here to get help in 
managing my GVHD. Sure, it would be really nice if I didn’t have it, but I have gotten used to the idea that every day it is likely to be itchy somewhere in my body,” she said of the telltale symptoms of her immune system’s ongoing tug of war with her transplanted cells.

GVHD remains one of the most intractable complications of transplantation, and at Fred Hutch, a major focus of research. In recent years, researchers have made major strides to prevent GVHD and to help reduce or alleviate symptoms in patients such as Keren.

Keren is a two-time transplant survivor. Her battle against cancer, she said, tempered her stamina and professional 
ambitions, but she hasn’t allowed complications such as GVHD to stand in the way of a life well lived.

She was diagnosed with chronic myeloid leukemia in 1993, when she was seeking a master’s degree in health policy. 
Unfortunately, her unrelated donor’s bone marrow failed to engraft and after two months in a hospital without an immune system, she had to undergo a second transplant, this time receiving stem cells from the same donor, in late 1994.

“It was a difficult time, but what I found so helpful was 
talking to patients. I learned not to have any set expectations and to be prepared for what is possible,” she said.

Several years ago, she decided to write a survivor’s guide to bone marrow transplantation to help patients like her. It remains available at the National Bone Marrow Transplant Link website at nbmtlink.org. Most recently, she published a survivorship guide for coping with late effects of transplantation.

Because of her deep interest in health care 
issues, she chose a career in the cancer field, which has allowed her to remain close to people who have been stricken by the disease. For the past 15 years, she has facilitated a support group for young adults with cancer.

“Navigating the health care world is extremely difficult and much more so for people who are dealing with a life-threatening disease. I love to help,” she said.

Keren and her partner, Joshua, have two beautiful children: Talia, a vivacious 9-year-old, and Ben, who just turned 7. Of course, running after them takes a lot of energy, a task that’s a little harder for a transplant patient.

“A lot of us think we’re going to come out of transplant and return to our previous levels of health and stamina. But that’s not the case,” she said. “There are a lot of changes that happen, and adjusting to these changes is very difficult.

“Having a better idea of what to expect makes it easier to handle the changes, which is why we need to tell the stories of different survivors, those who emerge vigorous and healthy as well as those who have lingering long-term chronic 
health issues.

“This way, patients can go into the transplant with a more complete picture of the possibilities and are better prepared to deal with what is to come,” she said.

“What did this experience with cancer do for me? It made me know on a deep, visceral level that I am mortal and that things may change in a flash,” Keren said. “So, since those 
precarious days in the transplant unit, I have committed myself to doing something nice for myself each day. I wanted to have 
a moment of light, a moment of goodness.”

The study, which has followed the health of more than 160,000 postmenopausal female volunteers, was possible 
thanks to the perseverance and commitment of Fred Hutch’s researchers, including Dr. Ross Prentice and the late 
Dr. Maureen Henderson.

For many years, they and colleagues from around the country sought to rectify disparities in research that focused largely on men’s health, extrapolating these findings to women. And thanks to their perseverance, the National 
Institutes of Health chose Fred Hutch to start and coordinate the WHI, which remains the largest study of women’s health ever undertaken in the U.S.

As you will read in this issue of Quest, our researchers, through the WHI, have made a major impact on our understanding and prevention of breast cancer and other major diseases. In 2002, the WHI reported its first major breakthrough: Combination hormone replacement therapy to alleviate symptoms of menopause dramatically boosted the risk of breast cancer, heart disease and stroke.

Previously, it was assumed by most that hormone replacement therapy reduced the risk of these diseases, so the findings that this combination of hormones were actually cancer-causing was stunning. Yet, the data were so solid and the study done so well that women and physicians quickly altered what was almost routine medical practice.

Millions of women stopped taking the therapy, and within two years of its publication, breast cancer rates in the U.S. started to drop. An estimated 20,000 U.S. women per year since 2002 have been spared from developing breast cancer—with tens of thousands of additional lives spared in other countries as well.

Because the WHI has been so successful, it has been funded through 2015, focusing on aging, cardiovascular 
diseases and cancer survivorship. Fred Hutch remains a committed leader of the WHI, seeking answers to difficult 
medical questions.

The WHI has taught us other lessons. Complex research requires funding—a concerted effort and the resolve 
of many people to push us into breakthroughs that will expand our knowledge of cancer and other diseases. 
It’s increasingly clear that we will have to rely more heavily on private donations, since federal funding for research 
is declining.

A friend of Fred Hutch, longtime Seattle businessman Stuart Sloan, puts it best: “If you want to make a difference 
in the fight against cancer, giving to research is the best investment you can make.”

That’s why Stuart is helping Fred Hutch start a new event to help fund our cancer research: Obliteride. The 
community-based bicycle event is designed to involve all of us.

Obliteride will be held Aug. 9-11. So, don’t forget to visit our website and join Stuart and me in this incredible effort to raise money to accelerate research and save lives faster.

Dr. Larry Corey
President and Director

Reporting the results of a first-of-its-kind phase 1 clinical trial to test the effectiveness of a new class of drugs to augment standard chemotherapy, a team led by Fred Hutch researchers found that giving patients high doses of Vorinostat (suberoylanilide hydroxamic acid) in combination with another round of commonly used second-line drugs resulted in a 70 percent response rate, including several patients whose lymphoma cells disappeared entirely.

According to Fred Hutch’s Dr. Ajay Gopal, a corresponding author of the paper published online in the British Journal of Haematology, the study results open the way to potentially solve the dilemma of how to effectively treat patients when modern cancer drugs fail after the first try.

And, he said, it sets the stage for using a new class of drugs called histone-deacetylase inhibitors (HDAC), such as Vorinostat, to sensitize tumor cells to the cancer-killing effects of chemotherapy.

Patients treated in the trial had several types of lymphoma, however the best responses were seen in those who had Hodgkin and diffuse large B-cell lymphomas, two of the most aggressive types that typically require a stem cell transplant to cure if they are not cured after the first line of treatment. Knocking back the cancer raises the likelihood for a successful transplant.

“The better the response, the better the outcome will be when patients proceed to a stem cell transplant designed to cure them of their disease,” said Fred Hutch’s Dr. Elizabeth Budde, first author of the study.

The goal of the Fred Hutch and GlaxoSmithKline PLC effort is to develop a small-molecule-based medicine to potentially reverse facioscapulohumeral muscular dystrophy, or FSHD, by inhibiting the activity of a protein that is incorrectly expressed by the DUX4 gene in people with the disease.

The protein activity damages muscle cells and leads to progressive muscle weakness and atrophy in FSHD patients.

Dr. Stephen Tapscott

The genetic and disease mechanisms of FSHD were discovered by an international team of scientists led by Dr. Stephen Tapscott, a member of the Fred Hutch Human Biology Division, in a series of studies published between 2010 and early 2012. Tapscott will lead Fred Hutch’s work in the GSK collaboration.

FSHD affects about one in 20,000 individuals and usually begins in late adolescence. The effects start around the facial and upper-extremity muscles and eventually progress to muscles in the lower extremity. People with more severe FSHD become wheelchair bound and their life spans are often shortened.

The team’s discoveries have implications for developing cancer immunotherapies because researchers discovered that DUX4 regulates cancer/testis antigens.

Cancer/testis antigens are abnormally expressed in various tumor types, including melanoma and carcinomas of the bladder, lung and liver. This knowledge gives researchers a way to manipulate the expression of cancer/testis antigens, potentially opening the opportunity to use these antigens in a cancer vaccine.

In an era of flat federal research funding, this collaboration signals an increasing interest on the part of Fred Hutch to develop partnerships that further its lifesaving and innovative research.

But this spring, there’s a heightened sense of urgency 
among many riders. Just ask longtime Seattle businessman Stuart Sloan, who’s been hitting the road with a single purpose in mind: use bicycling to galvanize a movement in support of cancer research at Fred Hutch.

“Cancer is the health issue of our generation,” Sloan said, “and in Seattle, we’re truly blessed to have one of the leading cancer research centers in the world. Fred Hutch pioneered bone marrow transplantation, and that’s just the start of its contributions.”

“There’s no one who has not been touched by cancer. Shouldn’t we support a cause like this? A place like Fred Hutch? We have something really special here in our own community.”

This is why Sloan has become one of the anchor sponsors of the inaugural Obliteride, a new bike ride experience that will be quintessentially Northwest. Sloan wants Obliteride, scheduled for Aug. 9-11, to become an annual community-driven effort to accelerate lifesaving cancer research at Fred Hutch.

“This is not a race, although some people could see it as a race against cancer,” Sloan said. “Obliteride is about community, with the bike as the medium. It’s about all of us doing something to obliterate cancer.

“Obliteride is a win win win for everyone involved. Organizations—corporate, community, or otherwise—benefit from deeper connection, individuals enjoy a great weekend of cycling and celebration, and we all benefit from accelerated cancer research,” he said. “With 100 percent of all funds raised going to cancer research, we fund more research to learn more and save lives faster. It’s a win for everyone.”

Sloan saw the power of a community coming together for a big cause when he participated in a similar event. In that Ohio-based event, several thousand riders have raised more than 
$42 million in four years for cancer research.

“The potential of Obliteride is fantastic,” he said.

As a longtime Seattle resident and friend of Fred Hutch, Sloan said he clearly understands the need for the community to donate to causes like cancer research.

Historically, research at Fred Hutch has been funded mostly by federal grants. But that funding has been flat; and in real dollars is declining. Cancer rates, however, continue to grow; the disease affects one in two men and one in three women in this country. Donations from the community are needed more urgently than ever.

“If you want to make a difference in the fight against cancer, giving to research is the best investment you can make,” Sloan said. “By participating in Obliteride, you can help fund Fred Hutch’s lifesaving cancer research. And I really have to emphasize lifesaving, because that’s what they have been doing for 40 years.”

Thanks to supporters like Sloan, the Obliteride organizing team is inspired to think big. They have their sights set on raising millions of dollars this first year by engaging more than 2,500 riders and at least 1,000 volunteers on the inaugural ride.

Amy Lavin, Obliteride’s executive director, said the event’s goals are quite achievable.

“Obliteride is going to be so much more than a phenomenal bike ride,” she said. “It’s going to become a movement of people actively committed to obliterating cancer and saving lives faster.”

And that effect, the study showed, appears to be stronger with regard to more aggressive forms of the disease.

While previous studies have suggested that eating foods made with high-heat cooking methods, such as grilled meats, may increase the risk of prostate cancer, this is the first study to examine the addition of deep-frying to the equation.

“The link between prostate cancer and select deep-fried foods appeared to be limited to the highest level of consumption—defined in our study as more than once a week—which suggests that regular consumption of deep-fried foods confers particular risk for developing prostate cancer,” said Dr. Janet Stanford, a corresponding author of the study.

Dr. Janet Stanford

Stanford, co-director of the Hutchinson Center’s Program in Prostate Cancer Research, and colleagues found that men who reported eating French fries, fried chicken, fried fish or doughnuts at least once a week were at an increased risk of prostate cancer as compared to men who said they ate such foods less than once 
a month.

In particular, men who ate one or more of these foods at least weekly had an increased risk of prostate cancer that ranged from 
30 to 37 percent. Weekly consumption of these foods was associated also with a slightly greater risk of more aggressive prostate cancer. The researchers controlled for factors such as age, race, family history of prostate cancer, body-mass index and PSA screening history when calculating the association between eating deep-fried foods and prostate cancer risk.

Possible mechanisms behind the increased cancer risk, Stanford hypothesizes, include the fact that when oil is heated to temperatures suitable for deep frying, potentially carcinogenic compounds can form in the fried food.

They include acrylamide (found in carbohydrate-rich foods such as French fries), heterocyclic amines and polycyclic aromatic hydrocarbons (chemicals formed when meat is cooked at high temperatures), aldehyde (an organic compound found in perfume) and acrolein (a chemical found in herbicides). These toxic compounds are increased with re-use of oil and increased length of frying time.

“To the best of our knowledge, this is the first study to look at the association between intake of deep-fried food and risk of prostate cancer,” Stanford said. However, deep-fried foods have previously been linked to cancers of the breast, lung, pancreas, head and neck, and esophagus.

In the early 1990s, Fred Hutch was chosen to start and coordinate the Women’s Health Initiative to address the most frequent causes of death, disability and poor quality of life 
in older women. As a member of Fred Hutch’s Public Health 
Sciences Division, Anderson became a central figure in 
the WHI.

Dr. Garnet Anderson

“It was clear to me that no matter what the results, the WHI would be important,” Anderson said. “What is attractive about clinical trials is that you always learn something important.”

And she did—and so did millions of others—as results of the study trickled out. Early data gathered from these women quickly morphed into a tsunami of lifesaving information.

Among the WHI’s many contributions to women’s health, the most prominent was its report in 2002 that combined estrogen-plus-progestin hormone-replacement therapy increases a woman’s risk of breast cancer, stroke and heart disease.

This finding quickly decreased the use of hormone therapy nationwide by about 50 percent, which led to a significant, sustained decline in breast cancer rates starting in 2003.

Anderson continued to play a major role in clinical 
trial design, monitoring and analysis, and in overseeing 
implementation of data management and quality control 
activities for the WHI. She became co-principal investigator 
of the WHI Clinical Coordinating Center with Dr. Ross 
Prentice in 2008 and the sole principal investigator in 2011.

Today, as WHI celebrates its 20th anniversary, Anderson remains one of its most committed investigators. Earlier this year, she earned a new appointment: senior vice president and director of Fred Hutch’s Public Health Sciences Division.

“Through the WHI, Anderson and colleagues have made a major impact on our understanding and prevention of breast cancer and other major diseases,” said Dr. Larry Corey, Fred Hutch president and director, in announcing her appointment.

“The WHI trials led to sweeping changes in clinical 
practice—changes that have led to approximately 20,000 fewer women developing invasive breast cancer each year in the U.S.,” he said. Worldwide, the decreased use of hormone therapy has resulted in additional reductions in breast cancer incidence by tens of thousands of cases per year.

For Anderson, Fred Hutch has been a perfect place to 
conduct her research.

“I jumped with both feet into WHI, where I knew I could have the most impact,” Anderson said. “In the last 20 years, all of us here who worked in the WHI wanted to make sure we produced the highest quality science.”

Renowned for its cancer studies, Fred Hutch is a leader in biostatistics and epidemiology, quantitative sciences critical for WHI efforts.

“We’ve had visionary leadership in these fields,” she said. “And we have been able to attract really great staff—people who want to give back, who want to help others.”

These days, Anderson is focused on lifestyle factors and their relationship to disease.

“For example, what is the relationship between obesity and cancer?” she said. Are some aspects [overall food intake or 
specific types of food, exercise] more directly tied to cancer?

“Obesity and its link to disease is one of the great health problems of our time,” she said. “Getting ahead of these issues will be a major contribution to public health. I really believe we need to make headway on this issue.”

Ruth Ross

Ross didn’t know then that she had become part of an unprecedented research effort that would impact her own immediate health and the health of millions of other women of her generation—and those to come.

The 72-year-old Woodinville, Wash., resident is part of a legion of more than 160,000 postmenopausal women who volunteered for the Women’s Health Initiative, one of the largest women’s health studies ever conducted in the U.S.

Since Ross joined the WHI, many important discoveries have been announced, but none more important than the breast cancer risk finding in 2002. That breakthrough discovery alone shocked the medical community and the public, and it helped save the lives of tens of thousands of women each year in the U.S. and throughout the world.

“It feels very good that there was something I was able to contribute that could help save lives—and now, rather than later,” Ross said.

Headquartered at Fred Hutch, the WHI reaches a major milestone this year—its 20th anniversary.

As WHI researchers at Fred Hutch and throughout the country—and the thousands of women like Ross who continue to participate in WHI studies—pause to celebrate their contributions, one thing remains clear in their minds: WHI’s discoveries over the past 20 years have reduced the risk of breast cancer, heart disease and stroke for women.

Today, the WHI remains a crucial contributor to the understanding of women’s health issues and shows no signs of slowing down. 

A pivotal finding in cancer risk

As WHI researchers uncovered 10 years ago, Ross and millions of other U.S. women were swallowing pills every day which, unbeknownst to them, were increasing their risk for disease.

In July 2002, the WHI released its findings that combination hormone replacement therapy—at the time prescribed to 15 million post-menopausal women in the U.S. to alleviate symptoms of menopause— dramatically increased the risk of heart disease, stroke and breast cancer. This type of therapy was also common in many other countries.

Ross’ doctor had prescribed hormone replacement therapy for its purported health benefits before she ever joined the WHI, and she paid close attention to the study’s findings.

“The next time I saw my primary care physician, I talked with her about it and we literally started taking me off of it. I did stop, right there and then,” Ross said. “The hormone replacement therapy results caused such a sea change.”

Within a year of the study’s finding, 5 million women had dropped the therapy, reversing a long-held trend of taking hormones to relieve menopausal

Dr. Ross Prentice

symptoms. Also, there was a widespread belief that hormones would reduce women’s risk of heart disease and keep them youthful and healthy.

The WHI study singularly changed the face of women’s health around the world: Because of the decrease in hormone therapy use following the finding’s release, an estimated 20,000 U.S. women per year since 2002 have been spared from developing breast cancer, with likely tens of thousands more around the world. Researchers also determined that decreases in heart attack and stroke in postmenopausal women were likely due to the drop in hormone use.

“There’s no doubt that this is the signature finding of the WHI. It gave rise to a major change in clinical practice in this country,” said Fred Hutch’s Dr. Ross Prentice, a chronic disease prevention scientist and one of WHI’s founders.

As part of the WHI’s initial set of clinical trials, the hormone therapy studies began in 1993 to test, as previous small studies had suggested, whether long-term use of these drugs could prevent heart disease, hip fractures and other diseases. They didn’t.

“The release of these findings was really a watershed moment after which many things changed with respect to hormone therapy and disease,” said Fred Hutch’s Dr. Andrea LaCroix, a WHI investigator and public health expert. LaCroix is currently conducting another WHI study that has enlisted 8,000 participants over 62 to determine activity levels needed to maintain heart health and prevent injury from falls.

Fran Trowbridge, Hormone Study participant

Fran Trowbridge

At 80, Fran Trowbridge’s curiosity and thirst for knowledge show no signs of waning: She takes annual trips to far-flung points on the globe, serves as a library docent, and attends concerts, lectures and field trips with such frequency she often wonders how she ever had time to work.

Trowbridge didn’t hesitate to join when the study began in the early 90s. “If this body can help with anything, well, why not? I was curious about hormones, and I wanted to help other women—part of the sisterhood thing,” she said.

She remains in the WHI Extension Study, 
diligently recording any falls on a calendar.

“I feel a sense of pride when I hear or read about WHI in the news. I say, ‘Hey, I was part of that,” Trowbridge said. “I enjoy the updates about what WHI is learning. I pass them on to other retirees and they’re fascinated, too.”

Olga Lamarche, Dietary Modification and Calcium/Vitamin D participant

When Olga Lamarche joined the WHI Dietary Study, she hoped to lose some weight and learn more about nutrition: “If it hadn’t been for the study, I probably just would have given up on weight loss and said, ‘What the heck—my weight doesn’t really 
matter. Everybody’s body changes as they grow older.’”

Instead, she attended WHI dietary meetings, gleaning important insights from the knowledgeable nutritionists. Lamarche learned to read nutrition labels on foods, count fat grams, and eat a leaner diet. “WHI encouraged me to live healthy.

Now I know how important it is to be aware of what I’m doing and pay attention to nutrition,” said the 74-year-old, who credits the habits with keeping her in great health as 
she ages.

Olga Lamarche

After years of running her own travel agency and a second 
career as a paralegal, Lamarche now works part-time for a weight-loss program, helping spread the message of 
healthy eating.

“Good nutrition, as well as physical activity, the number of hours you sleep, and your attitude—you have to have an open mind for new things, and I think all of that was enhanced by the Women’s Health Initiative,” she said.

Even being in the WHI Extension Study and tracking any falls impacts LaMarche.

“It’s made me a lot more careful, and I’m making a conscious effort to be more aware of the ground in front of me by looking ahead instead of down. I’ve learned to walk better. I don’t want to mar the calendar with a fall,” she said.

With his wife, Karen, and his two lovely daughters by his side, Mark chose to think about those closest to him, all the people who stood by him as he fought leukemia nearly a quarter century ago, when he was only 21.

“You look at all the people around you, the ones who have influenced you, and those you have personally affected, and sometimes I ask myself this question: What if the transplant hadn’t worked?”

“I’m a very spiritual person, and I’m grateful to my Maker for giving me all these years. I’m very mindful of that,” Mark said.

He will be the first one to tell you that he was not alone on this journey. “My wife knew I had leukemia and she married me anyway. She took that risk.

“The news of my leukemia devastated my mom. She really wanted me to take care of myself, to do everything in my power to get better,” he said. He managed to keep his CML at bay for a number of years, but eventually, his doctors said only a transplant would save his life.

“One day, I’m healthy, I’m happy, I’m fit. I feel invincible. And then, I’m fighting for my life.”

With five siblings in all—and all wanting to help—it was his sister, Suzanne, who proved to be the best match as a donor.

“I was blessed with my response to the transplant and recovery, and I didn’t have severe GVHD that could have affected my healing,” he said.

Life didn’t change just for him. Karen, who was a flight attendant at the time, became his full-time caregiver on his way to recovery.

The experience was so deeply affecting that she became an oncology nurse. These days, she is the one who keeps reminding him to stay healthy.

“Karen has been very key to ensuring that I get all of my follow-up work. She doesn’t let me slip,” he said.

“It’s been a great, great blessing for me to have done so well these past few years.” Among these blessings are their two daughters, Bailey, 17, and Rebekah, 14.

“They look so much like their mom,” Mark said. “They’re amazing and wonderful.”

These days, all of the Minsons are busy living their lives in a small town in Utah. Mark runs a math tutoring business that has grown to 150 regular students.
Sure he is busy, but he is mindful about what it took to get him here—a blessing, he says, he will never forget.

If there was ever a “life well lived,” it was Don’s. Don earned a Nobel Prize for establishing bone marrow transplantation as a successful treatment for leukemia and other fatal diseases of the blood, a treatment that has saved the lives of hundreds of thousands of people around the globe.

He also left a legacy of innovative and groundbreaking research at Fred Hutch, where colleagues and friends have continued to make improvements on treating leukemias and lymphomas as well as other forms of cancer.

One of the seminal observations that Don made was the recognition that the host immune system attacked the residual cancer and was a major factor in the curative process of BMT.

This has led to a 20-year quest to develop novel immunotherapies for many forms of cancer using a person’s own immune cells. This issue of Quest is about transplantation and how far we have come since those days when Thomas was trying to convince the world that his procedure would work.

Today, thanks in large part to our own people at Fred Hutch, we’re within reach of being able to offer transplantation to nearly every patient in need. Our work has also made transplantation safer and increased survival rates dramatically. It has made it possible to transplant older patients who had absolutely no other alternatives.

No other research center matches our past and current contributions to the transplantation field—we’re leaders, and that’s why our researchers remain committed to making transplantation safer and more widely available.

Still, too many people die from blood cancers, and that’s why the work must go on—with your support.

This is exactly what friends of Fred Hutch are doing. The David and Patricia Giuliani Family Foundation wants to see us improve survival and quality of life for thousands of patients with mantle cell and follicular lymphomas. They’re offering a $1.5 million challenge at the Hutch Holiday Gala and will match the attendees’ donations dollar for dollar. Join us in the fight against cancer because together, we help save lives.

Dr. Larry Corey

President and Director

But at Fred Hutchinson Cancer Research Center, when colleagues talk about Thomas, they don’t first mention the Nobel Prize he earned for his accomplishments. Instead, they focus on his qualities—the kinds of things that have helped shape Fred Hutch culture in the past three decades. Thomas, a founding faculty member, died Oct. 20. He was 92.

“To the world, Don Thomas will forever be known as the father of bone marrow transplantation, but to his colleagues at Fred Hutch he will be emembered as a friend, colleague, mentor and pioneer,” said Dr. Larry Corey, president and director.

“The work Don Thomas did to establish marrow transplantation as a successful treatment for

Dr. E. Donnall Thomas

leukemia and other otherwise fatal diseases of the blood is responsible for saving the lives of hundreds of thousands of people around the globe.”

Thomas joined the faculty of Fred Hutch in 1974 as its first director of medical oncology. He later became associate director and eventually director of the Center’s Clinical Research Division. He stepped down from that position at age 70 in 1990 and officially retired from Fred Hutch in 2002.

Thomas was a quiet but stubborn man, and yet that stubbornness was narrow and well focused. He believed that bone marrow transplantation could work against an unrelenting killer—when many others said it never would—and he surrounded himself with like-minded researchers, clinicians and nurses as he sought to make it happen.

He was generous with praise—a team player who understood that the best science comes through collaboration. When he received the 1990 Nobel Prize in physiology or medicine for his pioneering work in bone marrow transplantation, Thomas was quite explicit in praising his colleagues by name.

“It is always difficult to identify the many threads that make up the fabric of a life’s work,” he wrote in his autobiography on the Nobel website.

“I know that my philosophy and ideas have been heavily influenced by more than 20 years of daily interaction with a small group of colleagues, all of whom are now distinguished scientists in their own right.”

“We were devastated to find out that MCL had a 5 percent survival rate,” David said.

Mantle cell lymphoma is indeed a bad actor among lymphomas—difficult to control and fast growing. As the couple worked to absorb the news, Patricia’s oncologist mentioned she worked closely with Dr. Oliver Press at Fred Hutch. It was a serendipitous moment for the Giulianis.

They were already long acquainted with Press, not as an extraordinary physician-researcher, but as their friend, one of the enthusiastic parents they had cheered alongside years ago when their sons played high school football together.

“We felt grateful and relieved to know we were being supported by someone who was not only a friend, but also one of the world’s experts in MCL,” they said.

Relapses, even among patients who have had transplants, are not uncommon, and along the way patients often also become resistant to chemotherapy.

“Twice I experienced what’s been described as being brought to the verge of death, and then brought back to life,” Patricia said. The MCL is now under permanent control after three occurrences and two stem cell transplants.

Patricia’s experience has shown the Giulianis that lab-to-bedside progress is being made. “We’ve been in the cancer world since 2005, long enough to see significant advancements,” David said. “Patricia is now taking drugs that were not even available when she was first diagnosed. It gives us a sense of encouragement that we’re on a moving ship, and we can help move it faster.”

But making scientific progress is expensive. It takes investment, familiar ground for an inventor like David.

Investors helped move forward his novel ideas—the Sonicare toothbrush and its skincare sibling, Clarisonic—turning fledgling devices into ubiquitous household products.

The engineer-turned-entrepreneur and his wife of 33 years hope to accelerate promising cancer research the same way. The David and Patricia Giuliani Family Foundation, including their children, Dan and Nicole, has pledged $1.5 million to challenge the attendees of the 37th annual Hutch Holiday Gala on Dec. 1.

The goal? Funding for their friend, immunotherapy pioneer Press [see his story on page 12], and his colleagues to enable them to combine a series of highly promising innovations born of the Hutchinson Center’s immunotherapy program to create safer and more effective T-cell therapy for lymphomas.

By fueling this breakthrough work, Gala donors will help directly improve survival and quality of life for thousands of patients with lymphomas.

“The more money we raise, the more money there is for research, and the more opportunities to find cures,” Patricia said.

It’s a personal battle, to be sure, but it’s also about the community making inroads against cancer. The Giulianis hope their gift will inspire others to support research.

“We are a generous and prosperous community in the Northwest. We apply our collective willpower and resources to make things happen,” David said. “How else does anything get done?

"We’re grateful to live near a major center of research and therapy for this very rare cancer, mantle cell lymphoma,” David said. “Since Ollie is one of the world leaders, it’s an amazing connection we have. It’s confidence building for us to contribute to the Hutch and also to Dr. Press’ work since he’s already been so successful in making groundbreaking discoveries.”

Spend even a short amount of time with the Giulianis and you’ll hear one word mentioned repeatedly: grateful. They’re grateful for their family, for Sabine (the German stem cell donor who saved Patricia’s life), and for the opportunity to propel research.

“I’m grateful every day for every day,” Patricia said. “And I’m incredibly grateful to the Hutch.”

Little did he know that he would find cancer—especially blood cancers—a fascinating biomedical problem, and that he would develop pioneering treatments bringing hope and cures to thousands.

“That just shows how naïve I was,” said Press, now one of the world’s leading researchers of lymphoma, a cancer of immune cells called lymphocytes. "People still say that treating cancer must be depressing, but it’s not for me. I have patients that I treated 25 years ago and they’re still here and they’re cured. It’s exhilarating.”

The once-reluctant oncologist has been at the forefront of developing new therapies—particularly approaches that harness the immune system, known as immunotherapy—for blood cancers like leukemia, multiple myeloma, and especially lymphoma.

For more than 25 years, Press and his colleagues have worked to overcome a vexing problem in cancer treatment: Traditional external radiation doesn’t distinguish between cancerous and healthy cells, so the radiation wipes out everything in its path. Press’ groundbreaking use of radiolabeled antibodies—radioactive molecules that stick to malignant cells—has offered a highly effective way to spare normal cells while blasting the cancer with high doses of radiation. Combined with stem cell transplantation, this approach has produced some of the best lymphoma cure rates in the world and reduced harmful side effects for patients.

Press has also had unprecedented success in treating follicular lymphoma with radiolabeled antibodies, either alone or sequentially with chemotherapy, boosting the five-year survival rate for these patients from 64 percent to 87 percent.

In addition to radioimmunotherapy, Press has been investigating ways to modify a patient’s own T-cells to fight lymphoma. With support from private donors (he currently holds the Dr. Penny E. Petersen Memorial Chair for Lymphoma Research, endowed by James and Sherry Raisbeck) and the Lymphoma Research Foundation, Press and colleagues have genetically modified the T-cells to recognize a signature protein on the surface of tumor cells.

The tumor-targeting T-cells are infused back into patients to seek out and destroy the cancer.

He’s refining the approach to create more powerful and longer lasting T-cells to fully eradicate the cancer, representing a new treatment possibility for current and future follicular and mantle cell lymphoma patients. One day, this less toxic approach may replace transplantation as a front-line therapy.

Press, who is also a professor of medicine and an adjunct professor of bioengineering at the University of Washington, has trained a cadre of researchers who have become full-fledged contributors at the Hutchinson Center, refining the use of various immunotherapies to treat various blood cancers.

And as testament to his leadership in the field, he was elected by his peers across the nation to serve as co-chairman of the National Cancer Institute’s Lymphoma Steering Committee, a group that establishes lymphoma research priorities for the United States.

In his lab, another of Press’ therapeutic approaches for leukemia and lymphoma shows great promise, with 100 percent cure rates so far in model organisms. Known as pretargeting, this multistep delivery method allows five times more radiation therapy to reach the cancer than with standard radiation, all while avoiding healthy tissue.

Press said the dual roles of lab research and patient care have complementary rewards.

“One absolutely propels the other. There are times when things are going really well in the lab and it’s very rewarding, but other times I hit brick walls in research,” he said. “Then I go to the clinic and know I’m making a tangible difference there. I see patients who were given our research treatments when standard treatment failed and they were out of options, and they’ve been in remission for 20-plus years. It’s so gratifying.”

Storb, who is one of the most respected bone marrow transplantation experts in the world and one of the founding members of Fred Hutchinson Cancer Research Center, immediately called a Fred Hutch statistician and put him to work on his hunch.

And sure enough, the data strongly suggested that within the group of patients he was studying, there was a higher rate of graft-vs.-host-disease among those whose white blood cell counts exceeded a certain threshold.

GVHD—and relapse of cancer—are two of the most feared complications stemming from bone marrow and stem cell transplants to treat leukemia and other cancers. From mild rashes to serious damage in the digestive tract, GVHD occurs when transplanted immune cells from a donor react against the tissue of a transplant recipient. In some of the worst cases, GVHD significantly reduces a person’s quality of life or even results in death.

Storb asked himself a question as he looked at the data: Was the transplantation process disturbing natural and healthy bacterial populations in patients’ guts and skin, the epicenters for GVHD?

Within the body of a healthy adult, microbial cells—collectively known as the human microbiome—outnumber human cells 10 to one. But these microscopic communities remain largely unstudied, leaving huge questions unanswered about their influence upon human nutrition, development, physiology, immunity and disease.

For Storb, the potential link between GVHD and a compromised microbiome is filled with possibilities. Could drugs used to fight pathogenic bacteria and viruses in immune-suppressed patients also hurt healthy bacteria, many of which play an important role in immunity, and lead to GVHD?

“We could do a transplant to fight leukemia and other cancers, and we could follow it with a microbiome transplant to bring a patient’s unique microbial population to normal levels, and that may offer a solution for some people with GVHD,” he said. “This is a really exciting lead.”

Storb doesn’t have the funding yet to follow his lead, but his willingness to look at a problem in a completely new way points to how things are done at Fred Hutch, the pioneer of bone marrow and stem cell transplantation and indisputably the world’s major contributor to advances in the field.

Innovative thinking leads to breakthroughs, and at Fred Hutch, researchers are free to take their ideas into new directions.

In nearly four decades of research, Fred Hutch investigators have never stopped asking the tough questions, even when it meant questioning their own work in transplantation.

These questions—and the answers—have led to immense improvements in the transplantation field. It’s this obsessive attention to detail that has contributed to making Fred Hutch into a premier research center with some of the best survival rates in the world for transplant patients at its treatment arm, Seattle Cancer Care Alliance.

With continued advances in technology and medicine, it’s also becoming easier to envision the promise of “precision medicine,” where therapeutic strategies—from what drugs to use to what mutating genes to target—are tailored precisely for each patient fighting cancer, a remarkable shift from one-size-fits-all treatments used in the past.

“For years we have known that when we transplant bone marrow, we are also transplanting the donor’s immune system, and that the transplanted immune system can recognize the patient’s leukemia and help destroy it,” said Dr. Fred Appelbaum, director of Fred Hutch’s Clinical Research Division.

“We have long dreamed of being able to harness this effect and amplify it,” Appelbaum said. “Incredibly, we now have that capability; we are conducting studies in which we are isolating the cells that recognize a patient’s leukemia, manipulating them to increase their numbers and their potency, and using these to treat patients. It’s a very exciting time."

Here’s a guy who forged lungs of steel through thousands of miles of training—a fierce rider who competed on the open roads and cyclocross trails—and he couldn’t get enough air. He didn’t know it then, but he also didn’t have enough platelets, which help the blood clot. Alone on a training ride, he was one spill away from disaster.

When his gums started bleeding as he brushed his teeth, Beattie knew something was very wrong. The culprit that had started tearing his body apart was acute myelogenous leukemia, and it came with a grim prognosis: a 20 percent chance of being alive in two years.

The way of besting these odds rested on a bone marrow transplant, a Nobel Prize-winning treatment developed at Fred Hutchinson Cancer Research Center.

But Beattie could not find a donor with enough shared biological characteristics to make a transplant viable—not a single match among the 20 million people registered as donors worldwide.

Dr. Colleen Delaney

“The doctors were saying I had better odds of getting hit by two meteorites in a day than finding a donor,” Beattie said.

As he searched for answers, a friend sent him an article about Fred Hutch’s Dr. Colleen Delaney, whose pioneering work harnessing lifesaving cells from
umbilical cord blood was making national and international headlines.

Her efforts were a ray of hope to Beattie, one of the nearly 40 percent of blood cancer patients who need a transplant—16,000 annually—but can’t find a match. For most ethnic minorities, the chance of finding a donor is even lower.

“The Hutch invented transplantation,” he learned after reading his friend’s article. “Why wouldn’t I go there for a transplant?” And so, he did.

Not too long ago, seeking a suitable donor for a transplant patient was like looking for the proverbial needle in a haystack. But today, thanks to the relentless inventiveness of investigators and physicians—with the bulk of groundbreaking research contributions coming from Fred Hutch and its treatment arm, Seattle Cancer Care Alliance—there are plenty more needles in that haystack, so many that we’re coming closer than ever to reaching the long-sought goal of being able to offer a transplant for every patient in need.

“We can do transplants for just about everybody, and we have several ways of getting there,” said Dr. Paul Martin, director of Fred Hutch’s Long-Term Follow-Up Program, which monitors the health of several thousand transplant patients who have undergone the procedure here in the past four decades.

“But blood or marrow transplantation is a very complicated procedure, and every situation is unique,” he said. “That’s why everyone at the Hutch and SCCA is dedicated to making transplantation safer and more widely available to those who need it.”

A nutrition researcher at Fred Hutchinson Cancer Research Center, Kratz studies how obesity increases the risk of cancer and other chronic health problems—and he is conducting some of the world’s most innovative studies on how improving a person’s eating habits might break that link. His work could ultimately redefine the guidelines that tell us what we should eat, and could help people know exactly which foods elevate their cancer risk.

“Obese people have a much higher risk of getting cancer and of dying from it,” Kratz said. “If we can understand why this is and how diet contributes to it, we can prevent many of these deaths.”

Dr. Mario Kratz

Kratz’s research exemplifies how the Hutchinson Center is at the forefront of understanding—and potentially defusing—what is becoming a major new cancer epidemic. Being overweight or inactive is known to increase a person’s risk of some of the most common cancers—including colorectal cancer, breast cancer and certain prostate cancers—and is also linked to cancers of the esophagus, pancreas, kidney, thyroid and gallbladder.

With more than two-thirds of Americans now obese or overweight, the National Cancer Institute projects obesity will lead to about 500,000 new cases of cancer in the United States by the year 2030.

The threat is so severe that the Hutchinson Center’s Dr. Anne McTiernan, whose groundbreaking research pinpoints how weight loss and exercise reduce cancer risk, likens obesity to another insidious problem that took decades to diminish.

“Obesity is almost like the new smoking,” McTiernan recently told the Los Angeles Times. “The effect isn’t as big for most cancers, but it’s so prevalent that it will have a huge impact.”

It’s a problem with global implications. Earlier this year, the respected medical journal The Lancet reported that sedentary lifestyles, often associated with obesity, kill 5.3 million people worldwide per year—slightly more than smoking.

“I saw the tragedy and harsh reality of that,” she said of her parents’ weight-related health challenges. “The future I saw for myself loomed very large. I was motivated by my potential for those diseases.”

Sally von Bargen

Overweight since childhood, von Bargen realized she was on a slippery slope toward weight-related illnesses, including cancer, heart disease and diabetes.

Last year, the 63-year-old Seattle resident signed up for Fred Hutchinson Cancer Research Center’s Vitamin D, Diet and Activity study, a yearlong project to test whether vitamin D supplementation affects weight loss efforts in overweight and obese postmenopausal women.

Von Bargen had no idea she was about to put her body to the test at one of the most comprehensive preventive study sites in the world—a place where researchers are pioneering ways to reduce the risk of cancer and other diseases. She wanted to do her part for science as a volunteer, and perhaps learn something about staying healthy along the way.

“I thought maybe I could change my life. Maybe I could be something I had never been before: physically fit and healthy. For me to even have a vision of having my weight within a healthy range was unknown territory,” she said.

On the first day of the study, von Bargen realized that the Hutchinson Center’s Prevention Center was not a typical fitness club or restaurant. Located in the Hutchinson Center’s Robert M. Arnold research building on South Lake Union, it is an exacting place, where what she ate was scrutinized, and how she moved—and how often she moved—was scrupulously recorded.

There were body fat and bone density scans during her time at the Center; blood draws and many other tests as well—a comprehensive approach to studying nutrition and fitness and their relation to decreasing the risk of diseases such as cancer that attracts visiting researchers from throughout the world.

“The Hutchinson Center is a strong leader in studies of diet, physical activity, obesity and cancer risk because of our scientific expertise and excellent facilities,” said Dr. Ross Prentice, director of the Public Health Sciences Division, the arm of the Hutchinson Center that studies large populations to find ways to reduce the risk of cancer and other diseases.

Dr. Ross Prentice

“Our research programs, such as the Women’s Health Initiative, have developed data resources on nutrition and physical activity biomarkers well beyond those found elsewhere in the U.S. or worldwide,” he said.

This is where von Bargen transformed her health en route to helping science. She committed to taking a daily study pill, cutting calories, working out, and more. Her study goal was to lose 23 pounds. She lost 75 pounds, nearly a third of her starting weight.

“I just worked the plan. I can say—unequivocally—that I will never gain that weight back again because now I know how to exercise and eat to be healthy,” she said.

She admits there were times on the treadmill when she wanted to throw in the towel. “I would literally say to myself, ‘It’s OK. This has a higher purpose.’ I would just close my eyes and think, ‘Twenty minutes for science,’ and the time would go by.”

The one-of-a-kind Prevention Center where von Bargen burned calories is a scientific laboratory, but not the kind with petri dishes or microscopes.

Instead, people of all ages and sizes jog on treadmills or pedal stationary bikes. Down the hall, there are walk-in freezers filled with scientifically customized, ready-to-heat meals for nutrition research. Here, scientists and study participants rub shoulders with yoga instructors, athletic trainers and chefs in the pursuit of applicable, evidence-based approaches to prevent cancer and other diseases.

It’s people like von Bargen who inspire Matt Van Doren, manager of the Exercise Research Center. “I love working with study participants and seeing the fruits of their labor. It’s great seeing the positive changes in people as they go from being sedentary to adopting a new, more active and healthy lifestyle,” he said.

Since the facility opened in 2001, more than 1,800 volunteers have taken part in exercise studies at the site—some of whom had never before set foot in a gym or ridden a bike.

The exercise center’s staff members coach volunteers through their exercises, and use technologies to measure everything from exercise tolerance to muscular function—even how many calories someone burns while at rest. The results: landmark studies linking exercise to cancer risk-factor reduction, and how exercise positively affects prognosis and quality of life in cancer survivors.

Not that he is going anywhere, mind you. At one point, he didn’t have much of a chance to live more than three months. But an innovative approach pioneered at the Hutchinson Center to treat blood cancers saved his life from a devastating type of multiple sclerosis and gave him 12 more years and counting.

It has been a long journey to get here, to this quiet place of contemplation where little seems to faze him. “The first time I looked in the mirror after my transplant, I did not see myself. I know that sounds strange, but that wasn’t me,” James said.

James Ellison

“I now see myself,” he said.

James was 38 when he was diagnosed with primary progressive multiple sclerosis in late 1999. To hear that there was no cure and that he had but just a few months to live was devastating news for James, his loving wife and his four young children.

James’ type of MS quickly ravages the body in a short amount of time. “I was completely bedridden, I had zero balance, and I couldn’t control my movements. I couldn’t even sign my own name,” he said.

At the time, the use of blood stem cell transplantation to treat primary progressive MS was quite rare—only about 50 people before him had received stem cells worldwide to treat MS. At the Hutchinson Center, he became the third recipient of stem cells to fight the disease.

“Hutchinson Center doctors harvested my stem cells and picked the healthiest ones. ‘What are they worth?’ people asked me. Well, they’re priceless—the difference between life and death,” he said.

James’ mom had died of MS, so he understood the implications of the disease all too well. “I didn’t think I was going to see my kids grow up,” he said.

But he pulled through, and he went on to do something extraordinary: Publicly fighting for the rights of patients in Washington state—even as he fought for his own life—after his health insurer declined to pay for his stem cell transplant.

James took his struggles to the media and his situation was widely covered by newspapers and television, here in Seattle and nationally. He was even interviewed by the BBC.

He was widely credited for playing a pivotal role in the passage of the Patients’ Bill of Rights in Washington. Former Gov. Gary Locke signed a proclamation touting his bravery, leadership and perseverance for justice.

“If I die tomorrow, I know I have made a difference for the people of this state,” he said.

These days, his focus is entirely on family.

“My wife died two years ago. I never in my life expected for things to happen this way. It was a horrible experience to lose her,” he said. “I owe the past 12 years of my life to the Hutchinson Center, and thanks to the Hutch, I’m now creating memories with my children.

“I want to be able to say we have done everything with the extra time we have been given."

Being overweight or inactive is also linked to cancers of the esophagus, pancreas, kidney, thyroid and gallbladder. Like all such risk factors, the link is not absolute for persons with a high body mass index. However, one study found that the heaviest patients—those with a BMI of at least 40—had cancer death rates 52 percent higher for men and 62 percent higher for women. About 17 percent of all breast cancers, nearly 33,000 cases per year, are attributed to excess body fat; for colorectal cancer, it’s 9 percent, or 13,200 cases per year.

While these numbers may seem relatively small, the epidemic of obesity is increasing in our country. The National Cancer Institute projects obesity will lead to about 500,000 new cases of cancer in the U.S. by the year 2030. Unfortunately, the American lifestyle is extending globally, with sedentary lifestyles becoming prevalent throughout the world. Some studies suggest that obesity is associated with a higher mortality around the world than smoking.

This is why the work of our cancer prevention researchers is so important. We study obesity because our mission is to prevent, detect and treat cancer and other life-threatening diseases. We have assembled a top team of researchers who want to understand—and defuse—obesity’s role
in cancer.

Our world-leading researchers have conducted exacting studies for many years on nutrition and exercise and their relation to cancer risk. And they have produced many landmark studies linking exercise to cancer risk-factor reduction. They have also shown that exercise positively affects prognosis and quality of life in cancer survivors.

While we ultimately want to understand the mechanism by which weight gain causes a genetic disease like cancer, our research teams are much more pragmatic as they attempt to define strategies to reduce this risk. At the Center, Dr. Mario Kratz and his colleagues study hormones, insulin and the role of inflammation as cancer-risk triggers.

Kratz is particularly interested in inflammation. In some obese people, the tissue gets inflamed and stays that way as long as they remain obese. Kratz believes that understanding what contributes to inflammation will help us understand the link between obesity and cancer and other diseases, such as diabetes and cardiovascular disease.

Recently, Dr. Anne McTiernan, from our Public Health Sciences Division, found that postmenopausal overweight or obese women who lost weight through a reduced calorie diet significantly lowered their levels of certain types of estrogen, testosterone, inflammation indicators and insulin—limiting their cancer risk.

Better nutrition and more exercise certainly have proven to be important components in reducing cancer risk. But our researchers also are studying what physiological factors are triggered by obesity that leads to increases in cancer risk.

The research conducted by McTiernan, Kratz and colleagues is often made possible by study volunteers. We feature one of them in this issue of Quest. Sally von Bargen signed up for one of our studies and lost 75 pounds in one year.

We hope that you will partner with us to continue funding this important research so we can better understand obesity’s links to cancer and develop effective strategies to alter the risk. If you are interested in donating to this endeavor, please contact the Hutchinson Center at (206) 667-4399 or (800) 279-1618.