The promise of early detection

With the launch of a major new research initiative, Fred Hutchinson intends to detect more cancers early and dramatically improve survival rates

When Joan McAree went for her annual gynecologic checkup in 1997, her greatest worry at the time was whether she and her identical twin Jean Christ could train hard enough to win their next 10K race.

"I thought I was a healthy person," McAree said. "I ran, I was a ski instructor, I watched what I ate. But as I found out, cancer doesn't play by the rules."

During the exam, McAree's doctor noticed that one of her ovaries felt enlarged. When she also complained of indigestion, bloating and fatigue, her physician ordered an ultrasound test, which revealed a solid mass. It was a tumor that turned out to be early-stage ovarian cancer.

"I truly feel that because my doctor listened to me, my cancer was detected relatively early — which may have saved my life," McAree said. "When ovarian cancer is caught late, which is common because the symptoms are so vague, approximately half of patients die of their disease within five years."

But her ordeal wasn't over. Five months after undergoing a complete hysterectomy to remove the cancer, her annual mammogram detected some suspicious growths. Tests revealed that McAree had breast cancer, which, thankfully, also was found at an early and highly survivable stage. She underwent a mastectomy, followed by chemotherapy and hormone therapy.

Six years later, McAree, now 55 and a community outreach specialist at Fred Hutchinson Cancer Research Center, is in good health. Yet she and her twin sister are acutely aware of another potential threat: whether Christ might also face a battle with either or both cancers.

"While my first concern was for Joan, of course I knew from the beginning that as identical twins, we share the same genes and I could be at high risk myself," said Christ, a real-estate appraiser from Seattle. "I'm also worried about that potential risk being passed along to my daughter and granddaughter."

Research participant

But if Christ does develop ovarian cancer, hers may be found far earlier than her sister's disease was — possibly long before the first telltale symptom emerges. She participates in an early cancer detection study led by Fred Hutchinson researchers and colleagues. She and others at similarly high risk for developing cancer could be among the first to benefit from a new research initiative to mine human blood serum for telltale proteins that signify the risk, presence or aggressiveness of cancer.

Because each type of cancer releases unique sets of proteins into the blood, researchers in Fred Hutchinson's Early Detection and Intervention Initiative expect that such "molecular signatures" could be used to develop blood tests for early diagnosis. They could also be used to design drugs aimed precisely at a specific subtype and stage of cancer and to monitor patients for their response to treatment.

Already, Fred Hutchinson scientists have developed highly sensitive molecular tests to monitor disease onset and progression in patients at high risk for esophageal cancer and to predict relapse in patients with leukemia. Other studies are under way to identify proteins associated with the onset of breast, colon and prostate cancer. Researchers are also working to uncover the molecular signatures unique to different subtypes of cancer, which will help doctors design and select the best treatment for patients.

Dr. Lee Hartwell, Fred Hutchinson president and director, said that although we have learned a great deal about cancer genes and cancer cells during the last 30 years, dramatic advances in treatment and outcome for many common cancers have been elusive. He said that some research dollars should be invested in efforts to develop new methods to detect cancer when it is at an early and highly treatable stage.

Better survival statistics

"The discovery of molecular signatures for earlier cancer diagnosis and improved therapies is a whole new area of science that needs to be developed — and that is what we are doing at Fred Hutchinson with the Early Detection and Intervention Initiative," he said. "Our scientists are working to develop the underpinnings of this technology, which could have a huge impact on cancer."

The rationale for developing improved diagnostic tests that can detect cancer early, he said, is based on survival statistics. "We've known for a long time that the chances of surviving cancer improve dramatically when it is caught at an early stage, while still confined to the organ of origin."

For example, five-year survival rates for breast- and prostate-cancer patients with localized, early stage disease are greater than 95 percent. Likewise, if colorectal cancer is diagnosed and treated early, the five-year survival rate approaches 90 percent.

Yet because many cancers go undetected until disease has spread to other parts of the body, overall survival rates are significantly lower. Overall rates could be much improved by detecting more cancers earlier. For example, experts project that if all colorectal-cancer cases were detected when localized, overall five-year survival rates could improve from 64 percent to 90 percent.

Surgical solution

Dr. Fred Appelbaum, director of Fred Hutchinson's Clinical Research Division and the Seattle Cancer Care Alliance, said that one reason early stage cancers can be treated more successfully is because many tumors can be completely eliminated through surgery.

"In addition, even if surgical removal is incomplete, we have a better chance of eradicating the cancer by chemotherapy when a tumor is small and there are fewer cancerous cells," he said. "This is because as a tumor grows, cells acquire mutations that can make them drug resistant."

Dramatic advances in cancer diagnostics require scientists to shift their focus from genes to proteins, Hartwell said. Proteins are the workhorse molecules of the body whose production is orchestrated by an individual's genetic blueprint, or genome. Cancer cells produce unique proteins, many of which are released into the blood serum. The prostate-specific-antigen, which forms the basis for the PSA test for prostate cancer, is an example of a secreted protein whose levels can be determined with a simple blood test.

Another example is a protein often produced in abundance by ovarian-cancer cells. Jean Christ participates in an ovarian cancer early detection study led by Fred Hutchinson and the Marsha Rivkin Center for Ovarian Cancer Research that measures the levels of this protein, called CA125. By looking for subtle shifts in the low levels of the protein produced by her healthy ovaries, researchers hope to detect the earliest signs of cancer in Christ's blood, should it ever develop. The center has begun research to discover additional diagnostic proteins for ovarian and other cancers, which will ultimately be used to monitor high-risk individuals through research studies.

"Even though this is a relatively unexplored area of cancer research, the fact that a few markers already have been identified for cancer detection gives us confidence that this approach can be successful for many types of cancer," Hartwell said. "We've barely scratched the surface in terms of examining the million or so proteins in the blood, many of which may be useful markers for early detection."

Appelbaum said with Fred Hutchinson's strength in laboratory research, population sciences and patient care, the center is well positioned to discover new biomarkers, put them into clinical practice and analyze their effects on improving cancer survival. Yet both he and Christ acknowledge that advances in medicine also depend heavily on the public-both for participation in research studies and financial support.

"When Joan was diagnosed, my strongest feeling was, what could I do to help?" Christ said. "Participating in this study helps me feel that I'm contributing to research that may not only help me, but could help others. It's the only way questions will be answered."

Barbara Berg, Ph.D., is staff science writer for Fred Hutchinson.

Listwin Family Foundation gift launches $100 million effort for early cancer detection

The Listwin Family Foundation has made a $13 million commitment to Fred Hutchinson's Early Detection and Intervention Initiative, which is aimed at developing tests that could alert doctors to the earliest signs of cancer. The gift provides the foundation for a $100 million, seven-year fund-raising effort to support the initiative.

Fred Hutchinson launched the initiative earlier this year with $3 million from the Listwin foundation, $2 million from the Paul G. Allen Foundation for Medical Research, and $1.4 million from the W.M. Keck Foundation. Contributors at the 2002 Hutch Holiday Gala provided $1.3 million in additional funding.

Donald J. Listwin, head of the Listwin foundation, announced an additional $10 million gift at the 2003 Hutch Holiday Gala on Dec. 6.

The goal of the Early Detection and Intervention Initiative is to develop ways to catch cancer at its earliest stages when it is most treatable. Researchers will also work on intervention strategies to prevent cancer in people at high risk and to treat more effectively cancer patients who relapse.

"Early detection provides one of the most promising opportunities to reduce the incidence of advanced cancer and cancer deaths," said Dr. Lee Hartwell, the center's president and director. "This kind of work holds the greatest hope for major strides in understanding cancer, and gifts from private foundations and individuals are critical to support early research efforts."

Hartwell said Fred Hutchinson also plans to encourage early cancer detection efforts worldwide through research partnerships with other institutions.

"Engineers think there's no problem so big that it can't be solved with the right amount of leadership, intellect and time," said Listwin, an electrical engineer by training and president and chief executive officer of Openwave Systems Inc. "I'm very excited about Dr. Hartwell's focus on the role technology can play in helping identify and analyze biological clues to cancer."

Improving diagnosis of ovarian cancer

A team of Seattle researchers, including Fred Hutchinson scientists, has identified a protein that could improve diagnosis of ovarian cancer, a disease that often goes undetected until it is advanced and difficult to cure.

Researchers found that a protein known as HE4 was more effective at distinguishing true cancers from benign ovarian disease than the only other commercially available test, which detects the presence of a protein called CA125.

HE4 is a protein that is secreted by ovarian-cancer cells into the bloodstream. Center researchers Drs. Nicole Urban and Martin McIntosh and colleagues at the Pacific Northwest Research Institute found that the HE4 test successfully identified cancer in 30 of 37 blood-serum samples from women known to have the disease. The CA125 test identified 29 cases. When used together, both biomarkers detected 33 of the 37 cancer cases. However, the number of women with benign ovarian disease who have elevated levels of HE4 is far smaller than with CA125. This indicates that the HE4 test yields fewer false-positive diagnoses.

“If the HE4 biomarker performs well in larger studies, HE4 could become a cancer-screening test that reduces the number of needless surgeries performed as a result of false-positive diagnoses,” said Urban, who directs the Pacific Ovarian Cancer Research Consortium, a multi-institutional grant from the National Cancer Institute, which funded the study.

Molecular markers: Research gold in our blood

To find proteins that signal the presence or risk of disease, researchers obtain blood samples from cancer patients, from people at high risk for developing cancer and from healthy individuals.

Proteins from the serum portion of the blood are first broken into smaller pieces. Based on a fragment’s size and chemical composition, a technique known as mass spectrometry assigns each what is essentially a unique “bar code” identification tag that allows it to be tracked and quantified. Using this method, scientists look for protein differences in samples of serum from healthy individuals compared to those with a specific disease or those at risk.

Because multiple proteins are likely to vary, such differences are called protein profiles. Once reliable protein profiles are identified, diagnostic tests can be developed that measure the levels of these proteins in an individual’s blood. These tests might be used to monitor those at high risk for cancer as well as to monitor cancer patients for their response to therapy.