by Sid Holt
DuBuc has worked hard to protect her kids from the experiences that defined her childhood: the chaotic home life, most of all, and the lack of supervision that she believes got her into trouble. “That’s my number-one life mission,” she told me. “Raising my kids to be empathetic, good citizens.” As DuBuc recounted her memories of Indian Oaks Academy—the assaults she witnessed as a girl, the grueling therapies—her son raced over, wearing a pirate’s eye patch and a sword at his hip.
As the kids settled down to watch Shrek, Leah rummaged in the basement for her old green binder. Inside was the apologetic letter from the Brighton Police lieutenant and the countless appeals she’d written to politicians, judges, and journalists, hoping for a break. She peeled open the sticky pages of her photo album, which chronicled her travels to Japan and India and her lobbying in Lansing.
Together, we flipped from back to front, pausing often to talk. By the time we reached the opening pages, it was nearly midnight. We’d landed on a photograph of a ten-year-old DuBuc at a dance recital, her emerald-green tank top contrasting with her flaming-red hair. She was holding a carnation. In a moment, DuBuc would get up to look in on her sleeping son and daughter, wishing for them what Jeremiah 29:11 had spoken of—“hope, and a future”—before double-checking the deadbolts. But for now she sat in silence. “That’s me,” she finally said. “A kid.”
New York Times Magazine
FINALIST—REPORTING
Born in New Delhi in 1970, Siddhartha Mukherjee studied at Stanford and Oxford universities before attending medical school at Harvard. He now works at the Columbia University Medical Center. His first book, The Emperor of All Maladies: A Biography of Cancer, won the Pulitzer Prize for General Nonfiction in 2011. This piece, from “The Improvisational Oncologist,” was published as part of a six-part package called “The New Anatomy of Cancer” in the annual Health Issue of the New York Times Magazine. The Ellies judges described “The Improvisational Oncologist” as “a lucid, beautifully written introduction to the latest treatments”—what Mukherjee calls an “artisanal approach in oncology.”
Siddhartha Mukherjee
The Improvisational Oncologist
The bone-marrow biopsy took about twenty minutes. It was ten o’clock on an unusually chilly morning in New York in April, and Donna M., a self-possessed seventy-eight-year-old woman, had flown in from Chicago to see me in my office at Columbia University Medical Center. She had treated herself to orchestra seats for The Humans the night before and was now waiting in the room as no one should be asked to wait: pants down, spine curled, knees lifted to her chest—a grown woman curled like a fetus. I snapped on sterile gloves while the nurse pulled out a bar cart containing a steel needle the length of an index finger. The rim of Donna’s pelvic bone was numbed with a pulse of anesthetic, and I drove the needle, as gently as I could, into the outer furl of bone. A corkscrew of pain spiraled through her body as the marrow was pulled, and then a few milliliters of red, bone-flecked sludge filled the syringe. It was slightly viscous, halfway between liquid and gel, like the crushed pulp of an overripe strawberry.
I had been treating Donna in collaboration with my colleague Azra Raza for six years. Donna has a preleukemic syndrome called myelodysplastic syndrome, or MDS, which affects the bone marrow and blood. It is a mysterious disease with few known treatments. Human bone marrow is normally a site for the genesis of most of our blood cells—a white-walled nursery for young blood. In MDS, the bone-marrow cells acquire genetic mutations, which force them to grow uncontrollably—but the cells also fail to mature into blood, instead dying in droves. It is a dual curse. In most cancers, the main problem is cells that refuse to stop growing. In Donna’s marrow, this problem is compounded by cells that refuse to grow up.
Though there are commonalities among cancers, of course, every tumor behaves and moves—“thinks,” even—differently. Trying to find a drug that fits Donna’s cancer, Raza and I have administered a gamut of medicines. Throughout all this, Donna has been a formidable patient: perennially resourceful, optimistic, and willing to try anything. (Every time I encounter her in the clinic, awaiting her biopsy with her characteristic fortitude, it is the doctor, not the patient, who feels curled and small.) She has moved nomadically from one trial to another, shuttling from city to city and from one drug to the next, through a landscape more desolate and exhilarating than most of us can imagine; Donna calls it her “serial monogamy” with different medicines. Some of these drugs have worked for weeks, some for months—but the transient responses have given way to inevitable relapses. Donna is getting exhausted.
Her biopsy that morning was thus part routine and part experiment. Minutes after the marrow was drawn into the syringe, a technician rushed the specimen to the lab. There he extracted the cells from the mixture and pipetted them into tiny grain-size wells, 500 cells to a well. To each well—about 1,000 in total—he will add a tiny dab of an individual drug: prednisone, say, to one well, procarbazine to the next and so forth. The experiment will test about 300 medicines (many not even meant for cancer) at three different doses to assess the effects of the drugs on Donna’s cells.
Bathed in a nutrient-rich broth suffused with growth factors, the cells will double and redouble in an incubator over the course of the following two weeks, forming a lush outgrowth of malignant cells—cancer abstracted in a dish. A computer, taught to count and evaluate cells, will then determine whether any of the drugs killed the cancerous cells or forced them to mature into nearly normal blood. Far from relying on data from other trials, or patients, the experiment will test Donna’s own cancer for its reactivity against a panel of medicines. Cells, not bodies, entered this preclinical trial, and the results will guide her future treatment.
I explained all this to Donna. Still, she had a question: What would happen if the drug that appeared to be the most promising proved unsuccessful?
“Then we’ll try the next one,” I told her. “The experiment, hopefully, will yield more than one candidate, and we’ll go down the list.”
“Will the medicine be like chemotherapy?”
“It might, or it might not. The drug that we end up using might be borrowed from some other disease. It might be an anti-inflammatory pill, or an asthma drug. It might be aspirin, for all we know.”
My conversation with Donna reflected how much cancer treatment has changed in the last decade. I grew up as an oncologist in an era of standardized protocols. Cancers were lumped into categories based on their anatomical site of origin (breast cancer, lung cancer, lymphoma, leukemia), and chemotherapy treatment, often a combination of toxic drugs, was dictated by those anatomical classifications. The combinations—Adriamycin, bleomycin, vinblastine, and dacarbazine, for instance, to treat Hodgkin’s disease—were rarely changed for individual patients. The prospect of personalizing therapy was frowned upon: The more you departed from the standard, the theory ran, the more likely the patient would end up being undertreated or improperly managed, risking recurrence. In hospitals and clinics, computerized systems were set up to monitor an oncologist’s compliance with standard therapy. If you chose to make an exception for a particular patient, you had to justify the choice with an adequate excuse. Big Chemo was watching you.
I memorized the abbreviated names of combination chemo—the first letter of each drug—for my board exams, and I spouted them back to my patients during my clinic hours. There was something magical and shamanic about the multiletter contractions. They were mantras imbued with promise and peril: ABVD for Hodgkin’s, CMF for breast cancer, BEP for testicular cancer. The lingo of chemotherapists was like a secret code or handshake; even the capacity to call such baleful poisons by name made me feel powerful. When my patients asked me for statistical data, I had numbers at my fingertips. I could summon the precise chance of survival, the probability of relapse, the chance that the chemo would make them infertile or cause them to lose their hair. I felt omniscient.
Yet as I spoke to Donna that morning, I realized how
much that omniscience has begun to wane—unleashing a more experimental or even artisanal approach in oncology. Most cancer patients are still treated with those hoary standardized protocols, still governed by the anatomical lumping of cancer. But for patients like Donna, for whom the usual treatments fail to work, oncologists must use their knowledge, wit, and imagination to devise individualized therapies. Increasingly, we are approaching each patient as a unique problem to solve. Toxic, indiscriminate, cell-killing drugs have given way to nimbler, finer-fingered molecules that can activate or deactivate complex pathways in cells, cut off growth factors, accelerate or decelerate the immune response or choke the supply of nutrients and oxygen. More and more, we must come up with ways to use drugs as precision tools to jam cogs and turn off selective switches in particular cancer cells. Trained to follow rules, oncologists are now being asked to reinvent them.
The thought that every individual cancer might require a specific individualized treatment can be profoundly unsettling. Michael Lerner, a writer who worked with cancer patients, once likened the experience of being diagnosed with cancer to being parachuted out of a plane without a map or compass; now it is the oncologist who feels parachuted onto a strange landscape, with no idea which way to go. There are often no previous probabilities and even fewer certainties. The stakes feel higher, the successes more surprising and the failures more personal. Earlier, I could draw curtain upon curtain of blame around a patient. When she did not respond to chemotherapy, it was her fault: She failed. Now if I cannot find a tool in the growing kit of drugs to target a cancer’s vulnerabilities, the vector feels reversed: It is the doctor who has failed.
Yet the mapless moment that we are now in may also hold more promise for patients than any that has come before—even if we find the known world shifting under our feet. We no longer have to treat cancer only with the blunt response of standard protocols, in which the disease is imagined as a uniform, if faceless, opponent. Instead we are trying to assess the particular personality and temperament of an individual illness so that we can tailor a response with extreme precision. It’s the idiosyncratic mind of each cancer that we are so desperately trying to capture.
• • •
Cancer—and its treatment—once seemed simpler. In December 1969, a group of cancer advocates led by the philanthropist Mary Lasker splashed their demand for a national war on cancer in a full-page ad in the New York Times: “Mr. Nixon: You Can Cure Cancer.” This epitomized the fantasy of a single solution to a single monumental illness. For a while, the centerpiece of that solution was thought to be surgery, radiation, and chemotherapy, a strategy colloquially known as “slash and burn.” Using combination chemotherapy, men and women were dragged to the very brink of physiological tolerability but then pulled back just in time to send the cancer, but not its host, careering off the edge.
Throughout the 1980s and 1990s, tens of thousands of people took part in clinical trials, which compared subjects on standard chemo combinations with others administered slightly different combinations of those drugs. Some responded well, but for many others, relapses and recurrences were routine—and gains were small and incremental for most cancers. Few efforts were made to distinguish the patients; instead, when the promised cures for most advanced malignancies failed to appear, the doses were intensified and doubled. In the Margaret Edson play Wit, an English professor who had ovarian cancer recalled the bewildering language of those trials by making up nonsensical names for chemotherapy drugs that had been pumped into her body: “I have survived eight treatments of hexamethophosphacil and vinplatin at the full dose, ladies and gentlemen. I have broken the record.”
To be fair, important lessons were garnered from the trials. Using combinations of chemotherapy, we learned to treat particular cancers: aggressive lymphomas and some variants of breast, testicular, and colon cancers. But for most men and women with cancer, the clinical achievements were abysmal disappointments. Records were not broken—but patients were.
A breakthrough came in the 2000s, soon after the Human Genome Project, when scientists learned to sequence the genomes of cancer cells. Cancer is, of course, a genetic disease at its core. In cancer cells, mutated genes corrupt the normal physiology of growth and ultimately set loose malignant proliferation. This characteristic sits at the heart of all forms of cancer: Unlike normal cells, cancer cells have forgotten how to stop dividing (or occasionally, have forgotten how to die). But once we could sequence tens of thousands of genes in individual cancer specimens, it became clear that uniqueness dominates. Say two identical-looking breast cancers arise at the same moment in identical twins; are the mutations themselves in the two cancers identical? It’s unlikely: By sequencing the mutations in one twin’s breast cancer, we might find, say, 74 mutated genes (of the roughly 22,000 total genes in humans). In her sister’s, we might find 42 mutations, and if we looked at a third, unrelated woman with breast cancer, we might find 18. Among the three cases, there might be a mere five genes that overlap. The rest are mutations particular to each woman’s cancer.
No other human disease is known to possess this degree of genetic heterogeneity. Adult-onset diabetes, for example, is a complex genetic disease, but it appears to be dominated by variations in only about a dozen genes. Cancer, by contrast, has potentially unlimited variations. Like faces, like fingerprints—like selves—every cancer is characterized by its distinctive marks: a set of individual scars stamped on an individual genome. The iconic illness of the twentieth century seems to reflect our culture’s obsession with individuality.
If each individual cancer has an individual combination of gene mutations, perhaps this variability explains the extraordinary divergences in responses to treatment. Gene sequencing allows us to identify the genetic changes that are particular to a given cancer. We can use that information to guide cancer treatment—in effect, matching the treatment to an individual patient’s cancer.
Many of the remarkable successes of cancer treatments of the last decades are instances of drugs that were matched to the singular vulnerabilities of individual cancers. The drug Gleevec, for instance, can kill leukemia cells—but only if the patient’s cancer cells happen to carry a gene mutation called BCR-ABL. Tarceva, a targeted therapy for lung cancer, works powerfully if the patient’s cancer cells happen to possess a particular mutant form of a gene; for lung-cancer patients lacking that mutation, it may be no different from taking a placebo. Because the medicines target mutations or behaviors that are specific to cancer cells (but not normal cells), many of these drugs have surprisingly minimal toxicities—a far cry from combination chemotherapies of the past.
A few days after Donna’s visit to the clinic, I went to my weekly meeting with Raza on the ninth floor of the hospital. The patient that morning was K.C., a seventy-nine-year-old woman with blood cancer. Raza has been following her disease—and keeping her alive—for a decade.
“Her tumor is evolving into acute leukemia,” Raza said. This, too, is a distinctive behavior of some cancers that we can now witness using biopsies, CT scans, and powerful new techniques like gene sequencing: We can see the cancers morphing from smoldering variants into more aggressive types before our eyes.
“Was the tumor sequenced?” I asked.
“Yes, there’s a sequence,” Raza said, as we leaned toward a screen to examine it. “P53, DNMT3a and Tet2,” she read from the list of mutant genes. “And a deletion in Chromosome 5.” In K.C.’s cancer, an entire segment of the genome had been lopped off and gone missing—one of the crudest mutations that a tumor can acquire.
“How about ATRA?” I asked. We had treated a few patients carrying some of K.C.’s mutations with this drug and noted a few striking responses.
“No. I’d rather try Revlimid, but at a higher dose. She’s responded to it in the past, and the mutations remain the same. I have a hunch that it might work.”
As Raza and I returned to K.C.’s room to inform her of the plan, I couldn’t help thinking that this is what it h
ad come down to: inklings, observations, instincts. Medicine based on premonitions. Chemo by hunch. The discussion might have sounded ad hoc to an outsider, but there was nothing cavalier about it. We parsed these possibilities with utmost seriousness. We studied sequences, considered past responses, a patient’s recent history—and then charged forward with our best guess. Our decisions were spurred by science, yes, but also a sense for the art of medicine.
Oncologists are also practicing this art in areas that rely less on genes and mutations. A week after Donna’s biopsy, I went to see Owen O’Connor, an oncologist who directs Columbia’s lymphoma center. O’Connor, in his fifties, reminds me of an amphibious all-terrain vehicle—capable of navigating across any ground. We sat in his office, with large, sunlit windows overlooking Rockefeller Plaza. For decades, he explained, oncologists had treated relapsed Hodgkin’s lymphoma in a standard manner. “There were limited options,” O’Connor said. “We gave some patients more chemotherapy, with higher doses and more toxic drugs, hoping for a response. For some, we tried to cure the disease using bone-marrow transplantation.” But the failure rate was high: About thirty percent of patients didn’t respond, and half of them died.
Then a year or two ago, he tried something new. He began to use immunological therapy to treat relapsed, refractory Hodgkin’s lymphoma. Immunological therapies come in various forms. There are antibodies: missile-like proteins, made by our own immune systems, that are designed to attack and destroy foreign microbes (antibodies can also be made artificially through genetic engineering, armed with toxins and used as “drugs” to kill cancer cells). And there are drugs that incite a patient’s own immune system to recognize and kill tumor cells, a mode of treatment that lay fallow for decades before being revived. O’Connor used both therapies and found that they worked in patients with Hodgkin’s disease. “We began to see spectacular responses,” he said.
