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The Promise—and Heartbreak—of Cancer Genomics

We live in a liminal age of cancer and precision medicine: Despite all the advances science has made, we still know very little and often can do less.

YOU WERE A New York artist, Iowa-bred, with a narrow and idiosyncratic range of subjects. You painted bulldogs and cheerleaders, truck stops and mammoth-hunting cavemen. For two decades you inhabited a drowning world, which you nostalgized even as it vanished beneath a tidal swell of money. Its borders were 14th to Canal Street and Broadway to the East River; its capital was the Mars Bar. You were the first to help a friend and last to leave the party, and beloved by your fellow strivers. You were smart, funny, unfailingly courteous: the punk-rock pirate king of the art scene.You loved your life. “But this is wonderful!” you would bellow when a work of art or meal delighted you. You had the best gigs: artist-in-residence at the Museum of Sex; interviewer at Whitehot Magazine; art handler for Manhattan’s galleries, bicycling up and down the island’s streets with a determined expression. But in your late forties you began to feel out of sorts: burdened, headache-y, doomed. Your friends and family worried. You made dates that you had difficulty keeping; often, you slurred words after a single beer. One night in July of 2015, during a visit to your younger sister in Boston, you collapsed with a seizure.At Massachusetts General Hospital you were given a CAT scan, and spent a restless night, waking anxious and angry. The nurses wouldn’t let you step outside to smoke. “This is bullshit,” you said, and tried to leave. Your parents, also visiting Boston, begged you to stay for tests. Your technologist brother-in-law, who had been traveling, appeared and conferred outside your room with a doctor, whom he knew from his work. You heard the doctor ask, “I can see Joe is an unusual guy, but he hasn’t always been like this, has he?” The scans revealed what you most feared: an ominous cloud on the right hemisphere of your brain.

Your doctor, a kind little man in a bowtie, said you must have surgery. You shaved off your long hair, and they wheeled you to an operating room. Afterward, the left side of your body was temporarily stunned, but you had a diagnosis: anaplastic astrocytoma, a brain cancer of the star-shaped glial cells called astrocytes. Your doctor said the good news was that such cancers don’t metastasize beyond the brain. “That’s the good news?” you replied. “Tell me the bad.” The surgeon had removed a ping-pong-ball-sized mass from your prefrontal cortex and parietal lobe, carefully removing necrotic flesh and skirting healthy tissue using a map generated by fMRI. But astrocytomas are diffuse, spreading their lacy filaments throughout the supporting and insulating tissues of the brain, and they grow back. Thirty percent of the tumor was still in your skull.

Humans are shy about mortality, and families adopt clinical language to talk about what they dread. What stage is this cancer? your family asked. “We don’t like to stage gliomas anymore,” your doctor reluctantly answered. “But this would be a stage 3 or 4 tumor.” There was no stage 5. He hastened to add, “Listen, Joe, no promises, but I think you’ve had this cancer for a while. You’ve not been yourself. Some of these tumors are slow-growing. We need to sequence the cancer before we make any plans.”

YOUR DOCTOR, A distinguished Harvard Medical School professor of neurology, a PhD researcher as well as a clinician, explained that the gross morphology of cancers was misleading. Today, at teaching hospitals, doctors sequence the genes of cancerous cells and compare them to normal host cells, a technology called cancer genomics. When we know a cancer’s mutation, he said, it’s sometimes possible to customize treatment. Some of the drugs employed in precision medicine are remarkable, and if a patient has a specific mutation, they can (in combination with chemotherapy, radiation, or surgery) cure cancer, or at least make the disease a chronic illness like diabetes.He rattled off examples. Small molecule drugs can target critical proteins within cancerous cells. For instance, Iressa inhibits the expression of a protein called epidermal growth factor receptor, whose mutation is implicated in lung and breast cancers. Lung-cancer patients with EGFR mutations who took the drug lived twice as long. Or, at great expense, we can genetically engineer a patient’s immune system to target a specific protein. Kymriah coaxes a very sick child’s own T-cells to attack a protein called CD19, expressed by the B-cell lymphomas. Nearly 80 percent of children with acute lymphoblastic leukemia, who had exhausted every other hope, were still alive 12 months after being administered the therapy.
Read on: The Promise—and Heartbreak—of Cancer Genomics

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