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Two years ago, Louise Jacobs was idly playing with a necklace when she felt a couple of tiny lumps around her collarbone. She thought they were calcium deposits. She was wrong. Jacobs had advanced lung cancer that had already spread to her lymph nodes. Because the tumors had infiltrated healthy tissue, surgery was not an option. "It was devastating," says the teacher, 56, from Atlanta. "I never smoked, my husband never smoked, and nobody in my immediate family had ever had cancer."
Jacobs immediately started the only treatment doctors had to offer — attacking the tumors with intensive chemotherapy and radiation to try to kill the malignant growths. For seven weeks, her body was bombarded with radiation twice a day and poisoned with toxic chemotherapy drugs once a week.
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One year later, Jacobs got the bad news that cancer was starting to grow again in her lungs. This time, however, the doctors had something else to offer. Two new anticancer drugs that target cancer cells more precisely and with less toxicity had been approved by the FDA. (Two more have since been approved.) Jacobs' doctors at the M.D. Anderson Cancer Center in Houston enrolled her in a clinical trial for a combination of two of those agents, Tarceva and Avastin, last August. "The difference is like night and day," says Jacobs. "I take a pill every day, and every three weeks I go in for an infusion, which takes about 30 minutes." After nearly a year on the experimental cocktail, she has seen her primary lung cancer shrink more than 50%.
Jacobs is part of an exciting vanguard — the first wave of cancer patients who are benefiting from a more targeted, molecular-based assault on the disease. Old-fashioned chemotherapy and radiation treatments were blunt weapons that killed healthy cells along with malignant ones; the treatments were far too toxic for most patients to endure. By comparison, the new-generation drugs are precision-guided missiles that zero in on tumors with a minimum of collateral damage. Used in combination with advanced techniques for classifying tumors by their molecular signatures and screening patients by their DNA, the drugs are transforming cancer from a deadly disease into a chronic condition that can be managed indefinitely. The FDA, responsible for approving new drugs, acknowledged the trend earlier this year when it issued new guidelines for evaluating this type of molecular and genetic data. "The bench and bedside have merged," says Dr. Roy Herbst of M.D. Anderson Cancer Center. "We are truly in the molecular-targeted era."
After years of feeling that they were losing the war on cancer, doctors and researchers gathered at the American Society of Clinical Oncology meeting in New Orleans reported last week that they finally have a deep enough understanding of the molecular underpinnings of cancer to offer patients new hope. "The paradigm is changing," says Dr. David Sidransky, a cancer specialist at Johns Hopkins Medical Institution. "New targeted drugs are coming, and we have to figure out how to use them."
Identifying Mutations
The detective work required to combat cancer effectively starts with the malignant cell itself. A tumor is essentially an accumulation of mutations. It grows uncontrollably because its DNA, laboring under the weight of layer upon layer of genetic errors, has become unstable and unable to repair itself. By studying those mutations, scientists can learn quite a bit about how a particular cancer cell became malignant and the molecular pathways it uses to get the nutrients it needs to fuel growth. One or several of those mutations may turn out to be the tumor's Achilles' heel — a weakness that makes it vulnerable to a particular drug.
At the meeting in New Orleans, two groups of scientists, one based at Massachusetts General Hospital (MGH) and another at the Dana-Farber Cancer Institute, reported on their search for such a weakness among a small group of lung-cancer patients taking gefitinib (trade name: Iressa), a recently approved drug that blocks a key protein known as the epidermal growth factor. Cancer cells need epidermal growth factor to continue dividing; design a drug that blocks its action, and you can slow or even prevent further growth.
In the MGH trial, doctors studied 16 cancer patients who were treated with Iressa. Nine saw their tumors shrink, but the drug had little effect on the rest. It turns out that eight of the nine patients who benefited from gefitinib had mutations in the receptor that binds to the cancer's epidermal growth factor; none of the patients who didn't respond had the mutations. Growth factors tend to fit into receptors on a cell's surface like keys into locks. Somehow, the changes in the eight patients made their receptor locks a better fit for the gefitinib key.
In the Dana-Farber study, researchers looked at a larger number of patients in the U.S. and Japan and found a similar pattern with a different set of mutations in the same receptor. "Knowing that those drugs will work brings us closer to being able to screen patients and target the right drugs to them," says Dr. Thomas Lynch, who led the MGH study. His group is analyzing still more lung-cancer patients, and if the results hold up, doctors may soon be able to identify these super-responding patients as soon as their cancers are diagnosed. That will allow physicians to bypass chemotherapy and start these patients on gefitinib as their first line of treatment.
Tracking Changes
Cancer cells are not static creatures. As a tumor develops, it begins to change genetically and physically, and scientists are trying to identify those changes through the various compounds a cancer cell secretes as it ages. As they are released in the blood or urine, those compounds offer doctors a window onto the disease, allowing them to see what the cancer cells are doing without having to biopsy the tumor. "A tumor that was removed three years ago and has spread is probably not the same tumor anymore," notes Howard McLeod, a professor of oncology at Washington University in St. Louis, Mo. "For a tumor to have survived a first-line therapy, something changed to give it an advantage. For it to survive second-line therapy, something else changed. And for it to survive long enough to spread to other sites, then something more is different."
The better that researchers know a cancer, the better their chances of defeating it. Those odds also improve if doctors have more than one way to fight it. As they fill in the details — at the molecular level — of the world in which tumors thrive, doctors are becoming convinced that a one-drug-one-cancer approach is not sufficient. Just as AIDS physicians currently use a multi-drug approach to attack HIV at different stages of its life cycle, so too are cancer doctors beginning to surround tumor cells with combinations of agents that can weaken a growing cancer by chipping away at its life-support systems.
Already it is clear that the nature of those support systems is more important than where in the body the cancer originated. "The source of the cancer becomes less of an issue over time than trying to understand the signaling pathways the cell is using," says Dr. James Abbruzzese of M.D. Anderson Cancer Center. In coming years, doctors will think not of breast cancers and colon cancers but rather of growth-factor cancers and signaling cancers.
Matching Patients
After a doctor identifies a cancer and chooses a combination of drugs to combat it, there is still no guarantee that the drugs will work. That's because no two patients are alike. Subtle differences in their genetic code often determine how well a cancer drug will be tolerated and how quickly it will be broken down in the body. Some people produce enzymes that can neutralize the more toxic side effects of anticancer drugs, while others either lack such agents or have genes that produce the opposite effect, making them more sensitive to the drug's adverse effects. Researchers at MGH, for example, found that changes in the gene coding for an enzyme involved in DNA repair can mean the difference between breast-cancer patients who can tolerate chemotherapy and those with a twofold greater chance of experiencing a toxic reaction.
When it works, the new paradigm can achieve dramatic results. Most of the newly approved drugs work in only 10% to 30% of patients, but in those patients, tumors routinely shrink to less than half their size. The number of new drugs that have been approved is small, their cost is high (at least $20,000 per cycle), and progress is slow. The five-year survival rate for all cancers is 63%, up from 51% in 1975, according to the American Cancer Society. But most of that improvement is attributed to the effectiveness of antismoking campaigns, not to better drugs. Thanks to patients like Louise Jacobs, who is helping to make new, smarter treatments part of standard cancer care, that may soon change.
- Alice Park/New Orleans