Winning the War on Cancer: Making Progress

Making Progress

As a nurse, Ginger Empey knew how grim her prognosis was when, at 50, she was diagnosed with Breast Cancer that had already spread to other parts of her body. She had a mastectomy, but when chemotherapy failed to touch the golf-ball-sized tumors on her liver, the doctors told her to "get her affairs in order."

"I couldn't believe that three months into the disease, there was nothing available to me," Empey recalls. Fortunately for her, UCLA's Dennis J. Slamon, MD, a pioneer in the use of the next generation of cancer treatments, was about to begin recruiting patients for the final stage of a study to test a new breast cancer drug. Herceptin, which targets the gene defect that is responsible for about a quarter of all Breast Cancer cases, would supposedly fix the biological problem at the root of Empey's disease. It worked. Today, little evidence can be found of the aggressive cancer that led doctors to give Empey a death sentence 11 years ago. "My recovery was miraculous," she says.

As researchers probe the genetic roots of cancer, they are gaining an uNPRecedented understanding of how the disease develops. And this new insight into the biology of cancer promises to lead to better diagnosis and many more treatment options. In fact, significant advances in targeted anticancer therapies are being made "on an almost week-to-week, if not day-to-day, basis," according to National Cancer Institute director Andrew von Eschenbach, MD. Does this mean that an end to cancer is now within reach? We're not on the brink of eliminating the disease completely -- lung cancer, for example, continues to be a huge challenge -- but most experts agree that cancer is, as epidemiologist Philip Cole, MD, puts it, "on the run, in retreat." There are now almost 10 million cancer survivors, compared with about 3 million in 1971. And the cancer mortality rate has been dropping slowly but steadily, about 1 percent a year, for the past 12 years. (Cancer has surpassed heart disease as the No. 1 killer of people under 85, largely because the mortality rate for heart disease is declining more rapidly.)

What is within reach, according to Dr. von Eschenbach, "is an end to the suffering and deaths associated with cancer." He predicts that ten years from now, when patients hear the words "You have cancer," they will no longer hear "You will therefore suffer and die." Instead, he says, cancer will come to be seen as a manageable chronic disease like Diabetes or arthritis. Empey, for one, says the dose of Herceptin she takes every three weeks to keep her cancer under control is a small price to pay for the privilege of being alive to dance at her youngest daughter's wedding.

A Better Understanding
Decades of research into the biology of cancer have significantly improved scientists' understanding of how it develops and what drives its growth. Though only 5 to 10 percent of cancers are believed to be inherited, all cancer is genetic; that is, it develops because something in a cell's genes has gone awry. "Every time a cell in your body divides, it has to copy the entire blueprint of you," explains Dr. Slamon, chief of hematology/oncology at UCLA's Jonsson Cancer Center, "and there are mistakes frequently made when the body's machinery is copying this blueprint. We have mechanisms that repair these mistakes, but they get less efficient with age." Thus, the longer you live, the more you are at risk of developing cancer. In about 25 percent of all Breast Cancers, for example, a mutation occurs in which cells produce excess copies of a particular gene that results in the overproduction of growth factor receptors, which are like antennas on the surface of a cell that receive signals telling the cell to divide. "You get an overload of growth signals in the breast tissue," says Dr. Slamon, "and you are off to the races with the cells growing." In other cancers, the molecules that regulate cell growth, turning on and off to keep the number of cells in the body constant, get stuck in the on position, so to speak, and cancer cells multiply like rabbits. Here, too, it is a gene defect that causes the molecules to misbehave.

Smart-Bomb Designer Drugs

"Now that we're beginning to understand the process of how a cell grows and spreads, we are beginning to see places where we can intervene," says Dr. von Eschenbach. Traditional treatments like chemotherapy work by killing cancer cells, but they may also be toxic to the body's noncancerous cells. The war on cancer is evolving from the "atomic bomb" approach of wholesale destruction of both cancerous and healthy tissue to the "smart bomb" approach of isolating the target and designing treatments that will Home in and destroy only those targets, leaving the healthy cells alone.

Because targeted drugs are so specific, side effects are relatively minimal. Thus, for Doug Jenson, whose hematologist took him off the interferon he was taking to treat his chronic myeloid leukemia (CML) because he said it was "killing you faster than the leukemia," these smart drugs came in the nick of time.

In 1998, Jenson, a 64-year-old father and grandfather, had no other options. "What do you think about going on an experimental drug that no one else has ever taken?" asked Brian Druker, MD, the driving force behind Gleevec, one of the hottest new cancer medications. Gleevec would supposedly attack the enzyme that was fueling the growth of Jenson's leukemia cells. "I was so sick before I went on Gleevec that the most I could do was get up in the morning, go down the stairs, and sit in a big recliner by the window until it was time to go to bed," says Jenson, now 72. "Today I'm as good as I was before I was diagnosed. Since I've been on Gleevec, I've been to Guatemala twice, to New York City for New Year's Eve. I go to the health club; I ride my bike. My leukemia is undetectable."

Before Gleevec came along, the average survival for a patient diagnosed with CML was about four to six years. Interferon, the standard therapy for CML, could prolong survival for another one or two years, if a patient could tolerate it or was among the few who responded well. In the four years since Gleevec has been on the market, only 16 percent of newly diagnosed patients on Gleevec have relapsed. "If those numbers stay on track, the average survival could be in the 15- to 20-year range," notes Dr. Druker, director of Oregon health & science University's Center for Hematologic Malignancies. "That's a huge difference." It turns out that because the enzyme that drives the growth of a kind of stomach cancer called gastrointestinal stromal cancer (GIST) is similar to the enzyme at work in CML, Gleevec has also turned the prognosis of that disease around. "Before Gleevec, there was no effective treatment for GIST," says Dr. Druker. If the tumor wasn't operable, or the surgeon couldn't remove the entire tumor, patients lived an average of one to two years after diagnosis. More than half of the GIST patients taking Gleevec show little sign of active disease.

Another exciting advance is the study of angiogenesis, the process by which tumors create new blood vessels, says William W. Li, MD, president and medical director of the Angiogenesis Foundation. Without it, tumors can't grow past the size of a grain of rice. A new therapy called antiangiogenesis cuts off the blood supply necessary for tumor growth. Avastin, the first antiangiogenesis designer drug, improved survival when added to standard chemotherapy in patients with advanced nonsquamous, non-small cell lung cancer (the No. 1 cause of cancer death in the United States) by 30 percent, compared with patients on chemo alone. Approved last year for the treatment of advanced colorectal cancer, Avastin was also found to shrink tumors, and extend life, in metastatic Breast Cancer patients. "Avastin is the flagship in a fleet of antiangiogenesis drugs that are part of a medical revolution," says Dr. Li, noting that there are 97 such drugs currently undergoing human clinical trials worldwide. Stop the growth of blood vessels, and you should theoretically prevent the spread of cancer.

Pharmaceutical companies are focused on getting new targeted therapies approved and marketed as quickly as possible. And the pace of research surrounding these drugs is staggering. "There are so many exciting discoveries that we had to spend extra time at this year's annual meeting teaching doctors about all the new findings that benefit their patients," says David Johnson, MD, immediate past president of the American Society of Clinical Oncology. "The sense of urgency is there, because the advances we're seeing are really substantive." For example, though the drug Herceptin is now commercially available, it is approved only for women with advanced Breast Cancer who take it in combination with chemotherapy, or alone if they've already had one or more regimens of chemotherapy. Two recent studies showed that when Herceptin was combined with chemotherapy in women with earlier-stage disease, the recurrence rate decreased by more than 50 percent, compared with those who only had chemo. None of these new therapies is a magic bullet, however: Over time, cancers could become resistant to certain antiangiogenesis drugs, and some genetic-based therapies benefit only patients who have the specific gene mutation being targeted (350 have been identified so far). In fact, the National Cancer Institute will begin work on identifying them all so that diagnosis and treatment eventually may be tailored according to tumor type.

Breakthroughs in Diagnosis

Doctors are already able to test for genetic mutations that make a person more susceptible to certain cancers (a gene defect known as BRCA2, for example, is linked to increased risk of breast, ovarian and prostate cancers). Eventually, by testing for the presence of certain gene mutations, doctors may be able to detect cancers long before they produce any symptoms, which is when they're most curable.

Though widespread screening has led to earlier diagnosis in several cancers, current diagnostic methods are not perfect. Tools like mammography can miss cancers. And a commonly used blood test for prostate cancer, the PSA test, cannot distinguish between aggressive tumors and those that would remain slow-growing for years, leading, in the opinion of some experts, to overtreatment.

A new tool called a DNA micro-array allows scientists to analyze the patterns of gene activity in a cell. Using this information, scientists at the University of California, San Diego, for example, may distinguish between the aggressive prostate cancers and those that are unlikely to cause any trouble.

And there are other exciting diagnostic developments on the horizon: "Imagine a future when you prick your finger or pee into a cup or lick a stick that has special sensors to find out if you have cancer," suggests Dr. Li. This scenario may not be as far-fetched as it sounds. Several groups of scientists are working on blood, saliva and urine tests to detect traces of proteins produced by aberrant genes. "Just as a hunter looks for signs, like footprints, that a deer is nearby, investigators are looking for clues, or biomarkers, that can tell them that cancer is around, even if they can't see it," says Dr. Johnson.

Advances in imaging techniques allow scientists to look at the molecular activity going on inside of cancer cells, not just at their structure. "Today, imaging not only sees a lump, but a PET scan, for example, sees the biochemistry occurring within the tumor," says Dr. von Eschenbach. "It lets us watch the cell's metabolism at work." Because cancer cells use more glucose than healthy cells, the PET scan, which creates an image based on cells' uptake of glucose, may be able to zero in on cancerous growth or detect angiogenesis within a tumor. What's more, doctors can use PET scans to gauge whether a targeted therapy has succeeded in shutting off the metabolism of tumor cells. "We don't have to wait three months to see if a patient is getting better; we can tell in 24 to 48 hours," notes Dr. von Eschenbach.

MRI, meanwhile, is proving to be a promising adjunct to the imperfect art of mammography. "Whereas ordinary mammography looks at calcium deposits and masses, MRI looks at blood vessels," explains Larry Norton, MD, deputy physician-in-chief for Breast Cancer programs at Memorial Sloan-Kettering Cancer Center in New York City. "All cancers have abnormal blood vessels."

Another potential alternative to mammography, which would not require radiation, is also under investigation. Called optical imaging, this technique would allow doctors to create images of the abnormal blood vessels in a tumor by passing light rays through breast tissue.

A Hopeful Future
Dr. Druker likens the current state of cancer research to the way we thought about infection before the advent of antibiotics. "In the early 1900s, infections were the leading cause of death in this country," he explains. "Now, when a new infection comes along-HIV, Ebola, West Nile-it makes headlines. In the future, I believe cancer will be seen the same way: Some forms will be eradicated; others will be highly treatable. And we will see someone dying of cancer as no more commonplace than someone dying of infection."

The future can't come soon enough for those with cancer now, but Doug Jenson believes patients and their families should be encouraged. "They'd sent me Home, saying there was nothing they could do for me," he says. "I'm still here and doing great. I have ten grandkids, including two granddaughters I never would have met if not for Gleevec. Who knows what they'll come up with next?"