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Genetic targets have led to better treatments for advanced colorectal cancer.
Jeanne Angalet’s car accident in 2005 changed her life, but not in the way she thought it would. At the time, she was 50 and working as a project coordinator for a medical device company in Alameda, Calif. One evening, while crossing the Bay Bridge, her car got smashed in the middle of a three-car pileup. The collision marked the start of multiple scans to make sure she had suffered no internal injuries. Three months later, doctors determined that the accident had left no lasting damage. But tests revealed a mass blocking most of her colon. Surgeons removed the tumor, but later found more in her peritoneum and lymph nodes, giving her a diagnosis of metastatic colorectal cancer. She started chemotherapy with a new agent at the time, the tumor blood vessel-targeting drug Avastin (bevacizumab).
Angalet says, she is one of the 10 to 12 percent of patients with advanced colorectal cancer who live longer than five years, “And I’m very grateful for that.” But she wishes her club had more members—long-term survivors of the disease—because when it becomes advanced, there are painfully few. A succession of drugs has kept Angalet’s cancer at a slow simmer. She is not cured. Nonetheless, she’s happy that she had options and that more are coming. Within her network of survivors, she says, “Many of us are optimistic.”
After years of plodding progress, colorectal cancer has welcomed new approaches to treatment, especially for patients whose disease has spread. Some drugs try to starve tumors of the blood supply they use to feed themselves. Others zero in on genetic targets that are found on cancer cells but are largely absent in healthy tissues, allowing more precise treatment. Each new genetic discovery presents opportunities for treatment.
“During the next decade, we can expect to see an explosion of new agents that will likely improve clinical outcomes further,” doctors wrote recently in the journal Gastrointestinal Cancer Research.
One of the problems complicating treatment has been that the genetic signature of cancer, even cancer that arises from the same tissue, can vary greatly from person to person. That means a different constellation of genetic flaws can contribute to a person’s cancer, and successful treatment depends on neutralizing those genes’ effects. In the handful of cancers where the main genetic drivers have been found, and blocked, patients have dramatically improved. “The tools to understand cancer, to classify patients who will benefit and to develop drugs for specific genetic alterations are all accelerating exponentially,” says Herbert Hurwitz, MD, of Duke University Medical Center in Durham, N.C.
Whenever we see new drug developments, it creates enthusiasm to move forward.
None of the medicines that have come on the market so far are home runs, doctors say, but at least in patients like Angalet, they can hit singles. In some people, the drugs are able to shrink tumors to a low point before surgery, making them easier to remove. And, as scientists continue to break the genetic code of tumors, research will reveal still more avenues to destroy tumors. “Whenever we see new drug developments, it creates enthusiasm to move forward,” says Axel Grothey, MD, of the Mayo Clinic in Rochester, Minn.
About 140,000 Americans receive a colorectal cancer diagnosis each year, making it the third most diagnosed cancer in the U.S. While efforts to encourage early detection are improving, about six in 10 patients do not learn of their disease until it has spread; for about 20 percent, the cancer has already settled into distant tissues before the malignancy is discovered. Progress in treating advanced cancer has been slower than doctors would like, but the survival trajectory is gradually moving upward.
In the 1990s, a person whose cancer had metastasized by the time of diagnosis could expect to live about 14 months. Since then, some cancer centers have achieved survival times that are longer—perhaps as high as 29 months—for patients whose metastatic liver tumors can be removed.
Doctors are not only learning the best timing and combination for existing drugs, but are regularly adding new ones to the mix. The new era of treatment began in 2004, with the approval of a fresh generation of drugs called “targeted therapies.” Unlike traditional chemotherapy, which more or less poisons rapidly growing cells, targeted therapies latch onto a particular molecule that is involved in tumor cell growth and proliferation. For example, Avastin can interfere with a tumor’s ability to grow the new blood vessels it needs to feed itself.
“[Approving Avastin] was paradigm changing,” says Richard Goldberg, MD, of The Ohio State University in Columbus. “All we’d ever had before was chemotherapy.” In clinical trials, the drug allowed patients to live about four to five months longer. “It was extending life,” Goldberg says. “It wasn’t curing people. But people are desperately wanting their lives extended.”
Consider Michael Carver, 56, of Pembroke Pines, Fla. After noticing mucus in his stool, the Air Force veteran had a colonoscopy at his local Veterans Affairs hospital in 2005. The tests showed he had stage 4 disease. After six months of Avastin and traditional chemotherapy, his tumors appeared to vanish. For the next two and a half years, he says, “life was good.” When his cancer returned, he got Avastin again.
Along with the approval of Avastin, more drugs have come on the market, drugs that work in still different ways. Another class of drugs zeroes in on a target called epidermal growth factor receptor, or EGFR—a molecule so vital for cell growth that its discoverers won a Nobel Prize. When EGFR is overexpressed or mutated, cancer cells can multiply excessively. Two drugs currently on the market—Erbitux (cetuximab) and Vectibix (panitumumab)—work by blocking EGFR.
A decade ago, the enthusiasm for EGFR inhibitors was hard to exaggerate: While Erbitux was still in development, a 2001 Los Angeles Times story declared the drug was “set to make one of the biggest splashes of 2002,” and Businessweek featured it on a cover. By the time the drug came on the market, it had shown an ability to delay tumor growth by about four months overall when combined with chemotherapy. Vectibix was approved two years later. Although it did not improve survival time, the Food and Drug Administration (FDA) gave it the green light because it did shrink tumors in some patients.
Today, few, if anyone, would hail these drugs as miracles. But progress is being made. In August, the FDA approved Zaltrap (ziv-aflibercept), a drug that, similar to Avastin, impedes a tumor’s blood supply. In a phase 3 clinical trial, patients who used the drug plus chemotherapy had a modest survival benefit. In September, the FDA approved Stivarga (regorafenib), a drug that interferes with both blood vessel growth and cancer cell proliferation. In the CORRECT trial presented this past summer at the American Society of Clinical Oncology (ASCO) annual meeting, Stivarga was shown to extend the lives of patients who had exhausted all other treatments by a median of 1.4 months—a 29 percent increase in overall survival.
Despite these positive developments, most drugs available for advanced cancer simply delay the time before a patient runs out of options, says Nancy Roach, founder of the patient advocacy group Fight Colorectal Cancer. “They get treated with something until it doesn’t work, and they move on to the next thing.” But she says the idea of just moving along a chain of somewhat effective—and always expensive—drugs isn’t good enough. “People aren’t getting cured, so we’re not where we want to be.”
More success depends on more knowledge. Doctors believe that the track record of these drugs can be improved as scientists learn which patients most benefit and which chemotherapy combinations are most effective. For that, scientists must uncover a tumor’s genetic secrets.
For example, one reason Stivarga did not perform better was because more than half the patients saw no effect at all, says Grothey, one of the CORRECT study researchers. Those whose tumor growth did stall appeared to live longer. The problem now is that still too little is known about the genetic tricks of colon cancer to understand how so many tumors were resistant. “I’m confident in the next year or so we will be able to identify patients who will benefit from this drug,” he says.
A similar scenario has played out with the EGFR inhibitors. After the drugs were developed, scientists figured out that about 40 percent of patients were not responding—it turns out they had a mutation in a gene called KRAS. When this mutation appears, Erbitux and Vectibix do not work because the mutant gene is still able to activate cancer growth. Today, before an EGFR inhibitor is prescribed, doctors perform a test to see whether a patient has that mutation.
Too little is known about the genetic tricks of colon cancer to understand how so many tumors were resistant. “I’m confident in the next year or so we will be able to identify patients who will benefit from [Stivarga].”
Scientists hope to one day develop a drug that will help patients who have KRAS mutations, although research presented at the ASCO meeting suggests this will be a formidable challenge because the tumors are so genetically diverse. Stopping tumors with KRAS mutations will require treatment that can hit many different targets simultaneously, Channing Der, PhD, of the University of North Carolina at Chapel Hill said during the 2012 gastrointestinal cancer meeting sponsored by ASCO. “This is much more complicated than we had previously envisioned,” said Der, who has studied KRAS for almost three decades.
The KRAS mutation test identifies who shouldn’t get a certain drug, says Brian Wolpin, MD, of the Dana-Farber Cancer Institute in Boston. For those with a KRAS mutation, an EGFR inhibitor simply won’t work. But for most treatments, “we still don’t know who should be getting it.” That’s the ultimate goal—to be able to know that a tumor has a certain set of mutations and prescribe a strategy to match. Otherwise, it’s like trying to win a chess game using the same moves every time against every player; a quick checkmate is easy if you know your opponent’s moves in advance.
Finding targets takes time, and sometimes findings that seem promising turn out to be false leads. Earlier this year, for example, a clinical trial of the experimental drug brivanib alaninate produced disappointing results, showing no overall survival benefit although there were some positive trends in progression-free survival. But other potential targets await testing.
There’s another problem, too, that has thwarted the ability of doctors to cure metastatic tumors regardless of where they come from. Even when drugs successfully wipe out a tumor, some microscopic remnants might escape treatment—either because they are resistant or just more genetically nimble than the original cancer. Rarely does chemotherapy obliterate every single metastatic cell, Wolpin says. “Those bits of cancer that survive are able to ignite new tumors.” Studies are just now beginning to define what those cells are, why they resist treatment and how they can be conquered.
Wolpin believes the knowledge will come. “I think the future is very bright,” he says. “Even though we have not been as successful up to this point as we would like in identifying appropriate targets, that’s changing.”
While waiting for the science to catch up, patients with advanced colorectal cancer see each day as a new beginning, Carver says. Like Angalet, he spends a large part of each week supporting fellow patients he’s found through the Colon Cancer Alliance and relishing time with the people he loves.
“I can’t not think about what the future holds because too many of my friends have run out of options,” Carver says. “That is one of the scariest positions to be in.” But as long as he has choices, he says, he has hope, which is the one therapy no patient can do without.