The Cancer Chronicles Page 19

  For Curran, medulloblastoma had been mostly an abstraction until he met children who were being treated for the disease. He knew that for most patients the prognosis was relatively good—the five-year survival rate was as high as 80 percent. For some patients, however, the cancer is recurrent and fatal. Even when the treatments are successful, the side effects can be ruinous. Surgery is usually followed by radiation beamed into the vulnerable brains of children.

  “I met one kid, a teenager, who was more than five years free of his disease,” Curran told the audience. “He was about sixteen. He was blond haired, blue eyed. He was joking around with the physician. But he was beginning to realize that the rest of his class was continuing to advance and he was leveling off. He began to see that the rest of life was going to be a terrible struggle for him and his family. Working in the lab doesn’t give you that kind of perspective. I couldn’t get the images out of my head.”

  He began searching for a better treatment, a drug that would strike at the heart of the cancer without such debilitating effects. First he went to the head of the pathology laboratory at St. Jude and asked for access to the tissue bank, the repository of tumors that had been removed from children over the years. There were only five brain tumors of any kind. He would have to collect his own. Five years passed before he had enough to begin his experiments. By that time research from other labs had emerged suggesting that some medulloblastomas—about 20 percent of all cases—were driven by a genetic defect involving the sonic hedgehog gene. Curran knew the story of the cyclopean lambs, whose birth defects arose from eating lilies with a natural substance—cyclopamine—that repressed the hedgehog pathway. Some cancers, conversely, like basal cell carcinoma and medulloblastoma, appeared to be caused by too much sonic hedgehog activity. Cyclopamine might, in theory, correct the problem and cause the tumors to shrink.

  Since cyclopamine was toxic, expensive, and difficult to work with, Curran wanted an alternative. Sitting in a bar after a meeting on brain genetics and development in Taos, New Mexico, he discussed the problem with an authority on hedgehog signaling. He told Curran about some new compounds that were being developed by a biotech company in Massachusetts for the specific purpose of blocking the hedgehog pathway by interfering with a protein called smoothened. Curran went on to show that the substance shrank medulloblastoma tumors in mice. But in younger rodents it also inhibited bone development. Whether the same would occur in children was an open question, but for those with the recurrent form of the disease, facing an early death, the risk might be worth it. Twelve of them enrolled in a clinical trial, and by the time of the Boston workshop there were signs that the drug, vismodegib, was safe and that it was repressing the tumors. Phase II trials were just beginning, but it would still be years before the treatment might be ready for consideration by the FDA. (It has recently been approved for basal cell carcinoma and is also being tested against a few other cancers.)

  Vismodegib for medulloblastoma, vemurafenib for melanoma. The names, so weirdly similar, sound like they were spit out by a machine shuffling Scrabble tiles. But they are not without meaning. The suffix “-degib” indicates a hedgehog signaling inhibitor, “vi” comes from “vision” (the drug is “forward looking,” a spokesman for Genentech told me), and “smo” from the smoothened protein. As for vemurafenib, “vemu” is for the BRAF V600E mutation and “rafenib” means a raf gene inhibitor. But the prefixes and often the infixes (the syllables in the middle of the word) are often arbitrary concoctions. Pharmaceutical companies propose the names to a body called the United States Adopted Names Council, which makes the final decision. A researcher told me that the companies pick unwieldy generic names like vemurafenib so that doctors will more readily adopt the catchier brand names, in this case Zelboraf. Vismodegib is sold as Erivedge.

  José Baselga, a scientist at Massachusetts General Hospital, de- scribed the latest findings on trastuzumab, better known as Herceptin, the drug that seeks out and blocks the HER2 receptor, shutting down signals that encourage cancerous growth. (The suffix “-mab” indicates that it is a monoclonal antibody—a molecule designed to home in on a specific target.) What was now being called “super Herceptin” or trastuzumab emtansine (T-DM1 for short), went a step further, carrying along a cytotoxin and injecting it directly into the malignant cell—chemo delivered right where you want it a molecule at a time. The poison itself is dangerously toxic to the body. But when aimed so precisely, it promised to work as a heat-seeking missile against HER2-positive cancer cells. Now this sounded close to a miracle drug—potent chemo without so many side effects. Baselga said that Herceptin alone had dramatically increased the survival rate for early stage HER2-positive breast cancer from 30 percent ten years earlier to 87.5 percent today. He predicted that super Herceptin, in combination with another HER2-targeting drug called pertuzumab, could bring this to over 92 percent.

  For metastatic cancer the numbers would be much lower, but here too people were hoping for a miracle. Two and a half years after the Boston meeting pertuzumab became Perjeta—another product from Genentech. Combined with Herceptin and old-fashioned chemo it increased progression-free survival—the time before the tumors came back or the patient died—by about six months. As for super Herceptin the wait continued. Some positive results from a clinical trial were used to push for accelerated approval from the FDA, and some patients were outraged when the agency insisted on waiting for Phase III. At a rally outside Boston City Hall, a woman who had been diagnosed with stage 4 HER2 breast cancer five years earlier addressed a small group of people—several of them wore pink T-shirts—and demanded an investigation. “People with the illness need to be in on the discussion. Not just people sitting up in an ivory tower making decisions.” They were probably expecting too much. When Phase III results were in, the best that could be said for metastatic breast cancer was that super Herceptin “reduced the risk of cancer worsening or death by 35 percent.” The drug did finally receive approval. But for the most aggressive cancers, the state of the art is still measured in months added to what is left of a truncated life.

  While waiting for the banquet that followed Baselga’s talk, I spoke to a researcher from a southern university about the fact that it was National Breast Cancer Awareness Month and all the attention that was being captured and the money that was being raised. She said she could easily understand why of all malignancies, breast cancer strikes such a deep emotional chord. It is not just because it is one of the most common. Breast cancer is an assault on femininity, female sexuality, and deepest of all, motherhood. But she also seemed a little envious. An unintended consequence of the pink ribbon enthusiasm is to distract from rarer cancers. Her area of research was pancreatic cancer, which has a discouragingly low survival rate. There are often no symptoms. “You go to the doctor with indigestion and find out you have three months to live.” Another example of neglected cancers would be UPSC, the one Nancy had.

  A whole culture has sprung up around breast cancer. The writer Barbara Ehrenreich, a victim herself, has called it a cult and believes that it trivializes the condition—as though breast cancer were just another life passage, something to get through like menopause or divorce. Not only can you dress in pink, she writes, you can accessorize—with pink rhinestone jewelry. You are told that chemotherapy “smoothes and tightens the skin, helps you lose weight,” that baldness is something to celebrate, that your new crop of hair “will be fuller, softer, easier to control, and perhaps a surprising new color.”

  As for that lost breast: After reconstruction, why not bring the other one up to speed? Of the more than 50,000 mastectomy patients who opt for reconstruction each year, 17 percent go on, often at the urging of their plastic surgeons, to get additional surgery so that the remaining breast will “match” the more erect and perhaps larger new structure on the other side.

  At first Ehrenreich’s criticisms sounded harsh to me. Beyond providing comfort and raising money for research, the hope is to get more women into the cli
nic for yearly mammograms. But it is no longer clear how many lives that saves. More in situ cancers are diagnosed—the tiny, slow growing, “stage zero” tumors a woman is likely to outlive without treatment. But the deadliest cancers can appear so suddenly—within days perhaps after a woman’s annual mammogram—and can expand so relentlessly that they often elude detection before spiraling beyond control. A recent epidemiological study of 600,000 women concluded that it is “not clear whether screening does more good than harm.” For every life that is prolonged ten women will be treated unnecessarily. But there is no way to know in advance which women those will be.

  The same dilemma is faced by men over their own most common cancer, that of the prostate. PSA blood tests can provide early warning, but again they lead to a disturbing number of unnecessary biopsies and surgeries. As with the in situ breast carcinomas, prostate cancers can also smolder harmlessly for decades. About 70 percent of men in their seventies who die of other causes have been found on autopsy to have prostate cancers that they probably knew nothing about. A man rendered impotent and incontinent by surgery may be left to wonder if he should have resisted the pressure to get tested. As with breast cancer, the hype—often well meaning but also driven by the profit motive—has been criticized for overselling the value of early diagnosis. Sports stadiums have become a popular recruiting ground. Urologists offer free tickets in return for an office visit and advertise on arena billboards. A Florida doctor places advertisements on the deoderizer pucks that sit inside the urinals of public restrooms: “Strike Out at the Urinal?” Prostate surgery will increase the flow, though possibly more than you want.

  After the meeting at the Parker House I returned to my hotel—a Howard Johnson that was practically adjacent to Fenway Park. The walls and carpets exuded the nicotine smell absorbed from generations of Red Sox fans. I wondered how many of them were going from the stadium with its third-hand smoke to the urologist for a prostate test. I had picked the location because it was near Dana-Farber, where I had an appointment to interview Franziska Michor, who had recently been chosen as one of “the best and brightest” by Esquire magazine. She was described as “the Isaac Newton of biology.” Michor had a PhD from Harvard in evolutionary biology and her thesis was titled “Evolutionary Dynamics of Cancer.” After all the talks about translational science, what I expected to learn about now was the most theoretical of research, vital to understanding the phenomenon of cancer but many stories removed from the clinic.

  Random variation and natural selection are the driving forces of cancer as they are of life, and Michor was studying the process with mathematical models. We think of Mendel’s peas and Darwin’s finches, but it was the quantitative science of population genetics that put our current ideas about evolution—the modern evolutionary synthesis—on sure footing. It was one thing to believe that evolution occurred—that much was soon evident—but could an accumulation of tiny, discrete mutations truly give rise to new species and to the seemingly smooth, gradual changes of evolution? The population geneticists showed with their equations that this was possible, and by the 1930s the modern synthesis was in place. By applying a statistical approach to cancer, researchers in the 1950s uncovered some of the early clues that tumors, like the creatures of the earth, also develop through an accumulation of mutations.

  As she sat in her office, Michor described how evolutionary biology and mathematics are making sense of some of the idiosyncrasies of cancer. The revolution in genetic sequencing is making it possible to read out the long list of changes that occur in a cancer cell and even upload them to the Internet. Scientists have been staggered by the numbers, which can reach into the thousands. Most of these, however, are likely to be “hitchhiker” or “passenger” mutations. A cancer cell is one that is mutating wildly beyond control. Many mutations will contribute nothing to the development of the tumor but are simply carried along for the ride. The challenge is to sift through them all and identify the driver mutations, and Michor’s lab was working on a model of cancer evolution that she hopes will help make this possible. She was also studying tumors at various stages of their development and trying to figure out the order in which the mutations occur. Is an oncogene mutated first and then a tumor suppressor, or is it the other way around? Perhaps both steps are preceded by damage to a gene essential to DNA repair. Or perhaps there is not one trajectory a cancer cell can follow but many different ones. Knowing a tumor’s history might lead to more effective treatments. If a certain mutation tends to arise early on, it would be the one to target. For all its abstract appeal, Michor’s work was very much in the spirit of translational research, with the fate of patients not far from her mind.

  In another recent paper she and some colleagues considered how oncologists might draw on evolutionary biology to understand how cancer cells can so quickly overcome the obstacles thrown in their path. According to a notion called punctuated equilibrium, championed by paleontologists Niles Eldredge and Stephen Jay Gould, life doesn’t always evolve at a steady pace. After long periods of quiet, there can be bursts of genetic innovation. Is that what drives a cancer when, after laying low for a while, it abruptly metastasizes into fresh territory or develops the power to resist the latest chemotherapy?

  Ideas from mathematics and evolutionary biology are also being used to show how cancer might be understood through game theory—which was originally devised to find optimal strategies for war. Among the lessons to emerge is that on the battlefield and in the biosphere it sometimes pays for adversaries to cooperate. Robert Axelrod, a political scientist, has suggested how that might apply to competing cancer cells. The evolution of a tumor appears to be a winner-take-all situation. As the cells divide and mutate, one lineage gains the upper hand, developing the hallmarks of cancer, while the others drop out along the way. That seems like a very inefficient battle plan, and Axelrod has proposed an alternative: Some of the cancer cells may evolve the ability to collaborate. Picture two cells sitting side by side. Through a serendipitous mutation the first cell can produce a powerful substance that stimulates its own growth. The other cell lacks this ability, but because of its proximity it is also exposed. It too continues to thrive. As it does, it may learn to synthesize a different product that the first cell lacks. Both will now continue to flourish—at least for a while. Ultimately one lineage may come out on top, but meanwhile the tumor can expand at a rate that wouldn’t otherwise be possible.

  Not long after my trip to Boston, I sat in on a presentation in which Stand Up to Cancer described its vision of translational research and introduced some of its dream teams. The lecture room was packed and latecomers were turned away at the door. I found a place to stand in back and watched a slickly produced video in which a young woman doing cancer research at the University of North Carolina offered this slogan: “Cancer isn’t getting smarter but we are.” At first that sounded wrong to me. Inside the body the cancer cells—competing, perhaps cooperating—are continually developing new talents. They evolve the ability to induce angiogenesis and to resist apoptosis and the immune system—and everything else the body throws at them. And once treatment begins, they learn to circumvent the smartest drugs people can devise. No wonder the improvement in survival rates has been so slow. But there is a limit to a cancer’s education. Ultimately either the cancer or the patient will die. Either way the evolutionary trajectory is halted. The next cancer must start from scratch.

  But what if a cancer could break free? I thought of a recent issue of Harper’s Magazine. Prominent on the cover were the words “Contagious Cancer” and a painting of a chimerical beast—part bird, part horse, part reptile, part human—dancing in a frenzy with a look of murder on its snaggle-toothed face. It was a painting by the surrealist Max Ernst. It illustrated an article by David Quammen, one of today’s best nature writers, and he focused on an affliction discovered in the mid-1990s on the island of Tasmania called devil facial tumor disease. It soon became clear that the lumps—each “an ugly mass, rounded an
d bulging, like a huge boil”—were being transmitted from one Tasmanian devil to another. This was not through viral infection. When the vicious creatures bit one another’s faces, tumor cells were passed along. This was a cancer that had evolved to where it could metastasize to another host. Through genomic sequencing scientists have since traced the origin of the cancer to a single female—“the immortal devil”—whose mutated DNA can be found in all of the tumors.

  Another contagious cancer in the animal kingdom is canine transmissible venereal tumor. Again this is not spread by infection but by the direct exchange of cancer cells. In hamsters a different sarcoma can be transferred by injection from one animal to another until the evolving tumor learns to make the jump on its own. It can also be spread between hamsters by mosquitoes.

  Quammen described three cases in humans—all medical professionals—in which cancer cells from a laboratory or hospital had become implanted in a wound. In one case, a young woman who poked herself with a syringe acquired colon cancer in her hand. A medical student died of metastatic cancer that began when he pricked himself after withdrawing liquid from a breast cancer patient. Those metastases ended with the recipient. But it is not impossible that a cancer might arise in the wild that has stumbled down an evolutionary pathway that ultimately allows it to leap from person to person. For a cancer like that, its education wouldn’t end. It would continue to evolve as it spread across the land. Increment by increment, it would get smarter.