In February 2007, Debbera Drake was diagnosed at Massachusetts General Hospital in Boston with stage 4 breast cancer, which was spreading to her right lung. Soon afterward, she sought a second opinion at another hospital nearby. The oncologist, not one to sugarcoat her opinions, told Drake, “You’re terminal. You have two years, max.” But six years later, the 67-year-old is cancer free and -working hard to stay that way. Every day she -exercise-walks for an hour, makes a fresh vegetable juice and eats two or three pieces of chocolate because, she says, “they have polyphenols, which fight cancer.” Most important, she takes olaparib: eight capsules in the morning, eight at night. The experimental drug is tailored to inhibit her specific condition—triple-negative breast cancer, a particularly aggressive variety that is often difficult to treat.
Drake has been using olaparib for four years, the first year in combination with other drugs, the last three by itself. Before that, she had a lumpectomy, radiation and chemotherapy, and surgery when the cancer spread to her brain. “Generally, when women are diagnosed from the start with advanced breast cancer and it spreads to the brain, they don’t have a terrific survival rate,” says Beverly Moy, MD, Drake’s oncologist. “But Deb enrolled in a clinical trial that has been remarkable for her. She is one of my superstars.”
Drake’s survival is likely due to a recent breakthrough in cancer treatment: the development of genetically targeted drugs that enable patients with previously intractable conditions such as lung cancer, melanoma and advanced breast cancer to live several years longer than expected. (These drugs are usually reserved for patients who have no other options, which is standard practice for drugs whose side effects are unknown.) “Genetic targeting is the future of cancer medicine,” says Jeffrey Abrams, MD, associate director of the Cancer Therapy Evaluation Program at the National Cancer Institute. “Now, for the very first time, doctors can profile most of a patient’s tumors, learn what’s abnormal about the tumors’ genes compared with normal genes and, with this information, treat that person’s cancer with a drug that specifically affects those abnormal genes.” So far, 33 targeted drugs are already approved by the FDA for treating specific cancers; dozens of clinical trials testing new drugs or new uses for existing medications are in progress.
A key advantage of the treatments is that they are generally less debilitating than much of the chemotherapy currently employed. Old-style chemotherapy is like a giant cannon that ravages both malignant and normal cells, causing collateral damage such as nausea, diarrhea and a weakened immune system; targeted therapy is more like an arrow shot by a marksman and, as noted in a recent study by the U.K.’s Institute of Cancer Research, leads to fewer serious side effects. The resulting improvement in people’s health is obvious. One longtime patient of oncologist Mark G. Kris at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City told the doctor, “When I’m sitting in the waiting room, everybody looks better than they used to” seven or eight years ago. The newer therapies are also much less disruptive to patients’ lives and work schedules. Says Kris: “When I started in 1983, patients treated for cancer for the first time were hospitalized for two or three days every month, just to get the treatment. With crizotinib [one of the new targeted drugs for lung cancer], you take a pill twice a day in your home.”
Mass General’s Theresa McDonnell, nursing director of the cancer center, is excited by how the new treatments affect her patients. “My image of cancer used to be the play Wit—bald, vomiting, emaciated, exhausted people just trying to cope with breathing and living,” she says. “Now we have stage 4 patients who are living full lives, working full time. And when we talk to patients, we have greater confidence and hope.”
How the new drugs work
Genetically targeted drugs aim to disrupt the growth and spread of cancer cells. Normally, your body’s cells divide in a controlled manner, but with cancer, some cells go crazy and clone themselves rapidly. Often the clones form tumors, and those tumors, if not removed in time, may send out colonies of cloned cells that multiply relentlessly in other parts of the body. Think of what happens when a virus corrupts your computer.
Each cancerous cell’s behavior is governed by instructions it receives from a protein, which in turn takes its orders from a mutated gene. One simple example of a cancer-causing mutation happens when the ends of chromosomes 22 and 9 break off and trade places. The product of this bizarre translocation, known as the Philadelphia chromosome, creates a protein that signals white blood cells to reproduce unchecked, causing a disease called chronic myelogenous leukemia (CML).
Gleevec is a drug designed to inhibit this mutation, which is found in all CML patients. In the drug’s first clinical trial, 53 out of 54 patients experienced complete remission, making Gleevec arguably the most successful targeted medication in existence. It is also one of the earliest: Gleevec came on the market in 2001. Nearly two thirds of the clinical trial’s original patients stayed on it. About 17 percent developed resistance within five years, and many were shifted to a -second-generation drug, on which they are still being maintained.
One reason Gleevec is so successful is that it targets “the best and most well-defined molecular abnormality known in oncology,” according to its developer, Brian Druker, MD, of Oregon Health and Science University. Most other cancers result from several constantly changing mutations, which makes them much more difficult to treat. So the future of cancer therapy lies in cocktails of different drugs, which may combine a targeted drug with either a traditional chemotherapy or another type of cutting-edge approach, or both. The goal is to turn cancer into a chronic disease like AIDS, giving patients a more or less normal life span, provided they continue to take the appropriate drugs.
The new normal versus the old normal
Kari Worth of Napa, California, now 46, had staved off stage 4 melanoma for six years, but in 2009 the cancer recurred. By that time, two miracle drugs had been introduced. The first was ipilimumab, a form of immunotherapy that harnesses the patient’s immune system to attack the disease. The second was vemurafenib, a targeted drug aimed at the BRAFmutation in skin cells that’s evident in half the patients with melanoma.
“The great majority of patients who have the BRAF mutation respond to the targeted drug vemurafenib within a few weeks,” says University of California, Los Angeles, oncologist Antoni Ribas. Early tests of vemurafenib produced astonishing results: Melanoma tumors shrank and even vanished; patients got out of their wheelchairs and walked again. But after six or seven months, on average, the tumors began to reappear, for different reasons. Sometimes tumors developed new mutations or other alterations; other times the cancer cells found ways to evade the drug. In short, says Ribas, vemurafenib works for a lot of patients, but its benefits are often “not durable.”
In contrast, he notes, “the immunity drug ipilimumab gives a benefit to just a small proportion of melanoma patients, but that improvement tends to be lasting.” So oncologists have been testing a combination of these two drugs, both of which are approved by the FDA and are on the market. “We’re developing a whole bunch of clinical trials that try to improve both agents,” says Ribas. New trials either combine vemurafenib with the immunotherapy drug or pair it with a newer drug that targets another mutation, potentially thwarting the development of resistance and also decreasing side effects.
In 2003, when Kari Worth was diagnosed with stage 4 melanoma, treatments were limited, so she underwent what’s called biochemotherapy, a taxing regimen that repeatedly delivers an infusion of three chemo drugs and two immunotherapy drugs, producing devastating side effects such as extreme nausea and systemic inflammation. “It was horrendous,” she recalls. “I was hospitalized 25 times in two and a half years.” But the treatment worked. Once Worth had surgery to remove a tumor from her lung, where the cancer had spread, she was pronounced NED, “no evidence of disease.”
By the time Worth was back fighting cancer in 2009, her treatment was nothing like what she had previously endured. At UCLA she was given the targeted drug vemurafenib, which she took twice a day at home. “Initially my tumor went away and everything was good, but 10 months later the cancer came back,” she says. After surgery that removed a pectoral muscle, Worth was briefly stable and then began the immunity drug ipilimumab, which bought her three months until the melanoma reached her brain and was treated with Gamma Knife radio-surgery, a precisely targeted, non-invasive radiation procedure. This was followed by more ipilimumab, which appeared to halt the cancer. As of fall 2012, Worth had been through 12 infusions of ipilimumab and more radiation and was in a two-year trial of a promising new immunotherapy drug called Merck MK 3475, which involves 30-minute infusions every three weeks and produces minimal side effects.
At the same time Worth’s life has been saved, it has also been changed. “I used to have a career, but being treated for cancer is pretty much a full-time job,” she says. “I have an 11-year-old and a 12-year-old. My kids don’t treat me any differently. I’m just their mom, and I do the laundry and everything else. I’m busy, and life is full.”
Even with the new drugs, a true cure—defined as permanent remission—may not always be possible. “I tell people that dealing with cancer is a marathon, not a sprint,” says Lecia Sequist, MD, an oncologist specializing in lung cancer at Mass General. “What we’re trying to do is get six months out of this treatment and three months out of the next treatment, then four months out of the next. We’re trying to piece together a series of treatments, and every year theories advance. If we can just get you to next year, then our goal will be to get you to the year after.”
An explosion of information
Achieving that goal has become more and more likely: The pace of finding new genetic targets is really speeding up, in part because of the work of The Cancer Genome Atlas (TCGA), funded by the National Institutes of Health. For instance, last September a team of TCGA researchers led by the pathologist and cancer researcher Matthew Meyerson, MD, PhD, of the Dana-Farber Cancer Institute in Boston published the first comprehensive genome analysis of squamous cell lung cancer, a major and hard-to-treat type that causes 40,000 deaths a year and for which no targeted therapies exist. Analyzing 178 tumors, the researchers discovered multiple genes with significant mutations that might be targeted by drugs currently in clinical trials (some for other diseases) and that could be tried on patients with this particular form of lung cancer.
The study is just one of 20 genetic analyses of different types of cancer that TCGA is scheduled to complete by 2014. Focusing on cancers with a poor prognosis and a large public health impact, TCGA gathers and evaluates cancerous tissue samples from research institutions across the country and releases the results in a public database. Meyerson credits the fast discovery of additional molecular targets to a spectacular fivefold-to-tenfold improvement in genome-sequencing technology over the past few years, to which TCGA is contributing. “It’s amazing to think what we’re doing today compared to five years ago. The quantity is better, the quality is better,” he says.
TCGA’s research has revealed some overlap in mutations causing different cancers. For example, the BRAF mutation, prominent in melanoma, also -figures—albeit less strongly—in colon and other cancers. And Gleevec, which targets a gene common to everyone who suffers from CML, is now used to treat several other rare cancers. Because of the success of genetic targeting, some authorities have come to believe that the primary cancer site may not ultimately be the primary focus of treatment. That is, rather than treating colon cancer, oncologists may treat, say, the BRAF mutation, regardless of its location.
The newest frontier: slowing cancer’s spread
Oncologists point out that patients usually don’t die from the original cancer. Nearly 90 percent of cancer deaths are due to metastasis, which is the migration of tumor cells from the primary site to other parts of the body. So the story of cancer is often a tale of traveling cells that, if they grow, destroy the function of distant organs. In other words, if doctors can figure out how to slow or halt the spread, they will probably save lives.
Metastasis is driven by genes, which direct where a cancer will spread, explains Joan Massagué, PhD, chair of the Cancer Biology and Genetics Program at MSKCC. Tissues in different parts of the body have barriers against foreign invaders, so the cancerous cells that succeed must have the propensity to bypass one or another of these obstacles, such as the normally impenetrable network of capillaries in the lungs and the brain. Researchers at MSKCC have found particular genes that enable cancer cells to multiply, as well as other genes that do the opposite and are missing in cancer tumors that have spread.
Says Larry Norton, MD, deputy physician-in-chief for Breast Cancer Programs at MSKCC: “With breast cancer, we have evidence that the primary cancer sends out little packets of information called exosomes that go to organs, particularly the lung, and start the process of tumor formation even before the cancer cells get there. Whenever you have a chemical signal and a receiver for the signal, you have the potential for intervention. And
this is part of what targeted therapy is all about.”
The last question I asked all the cancer researchers I spoke to was, “Suppose I were to go on vacation. How long would I have to go away to come back and find the whole landscape changed?” Those who were willing to answer gave a variety of responses. “At the pace we are going in melanoma, a five-year vacation would make a big difference,” said UCLA’s Antoni Ribas. MSKCC’s Larry Norton replied, “It’s changing all the time. Your vacation should be a weekend. In 10 years, I hope, I am going to have to find another job.”
Most cancer researchers, I think, would agree with Brian Druker of Oregon Health and Science University, who observed, “If you looked at World War II prior to D-Day, you’d have said, ‘We’re never going to crack this.’ My view is that at least we’ve arrived on the beaches.”
Katharine Davis Fishman’s last article for Morewas the award-winning “Boning Up on Bone Drugs,” June 2010.
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