On the Cancer Frontier

PREFACE

READING ABOUT CANCER in the media can be jarring. One of mankind’s oldest known and most deadly diseases is not only discussed far more frequently, it seems, than other serious illnesses (heart disease, for instance); it is often described as though it were part of a moral parable rather than just an enormously challenging medical science problem. The issue is often framed not in terms of the success or failure of a new treatment, or the promise of some new avenue for research, but as a contest between good and evil, competence against incompetence, good intentions versus bad.

Time, for instance, recently blared on its cover, “How to Cure Cancer,” with a subhead declaring, “Yes, it’s now possible—thanks to new cancer dream teams that are delivering better results faster.” Potential magic bullets appeared to have been found by tapping into that great American resource, teamwork, with inspiration coming from some innovative, selfless philanthropists. But only weeks later a sour article in the New York Times Sunday Magazine headlined “Our Feel-Good War on Breast Cancer” asked, with a bitter edge, “Has raising awareness become more important than saving lives?” Selflessness and courage were nowhere to be found. A blogger, responding to the article, commented afterward that “there’s an epidemic of overtreatment,” as though it were a known fact that the problem with cancer care was that some ill-intentioned doctors were doing too much for their patients, not too little.

And it is not just doctors who get judged by such moral standards. When patients overcome cancers, it is often attributed to their strong moral fiber, not good fortune that they had a form of the disease susceptible to current therapies or that they quickly obtained treatment at a good hospital. Some cancer self-help books focus on the curative powers of positive thinking, with an implication that succumbing means the patient failed, not that the disease is vicious and unimaginably difficult to stop. Cancer has fallen into a category with issues like immigration and gun control—everyone is expected to have an opinion.

The media coverage reflects the seemingly random intensity and unpredictability of the disease and a widely shared frustration that American ingenuity has failed to find the final “cure” President Nixon promised when he launched the “war on cancer” nearly a half century ago. The other war at that time, in Vietnam, was mired in an insurgency. The enemy was relentless, absorbing our bombs and then regrouping and fighting back. The war on cancer, everyone expected, would be different. I think many people felt, instinctively, that it would restore our moral edge.

From the start, the campaign against cancer was laced with a sense of heroism by being compared to the race to the moon—a race that, of course, we won. It was to be a medical Manhattan Project, another heroic success. And that has been the problem. If American scientists could build an atomic bomb in just a few years in the New Mexico desert, if they could fly a man into the heavens and land him on the moon ahead of the Soviets, if we could cure smallpox and polio, then surely nothing could prevent us from defeating cancer. How could any barrier stand in the way of American spirit, American technology, and American money?

It was a seductive narrative, which in no way prepared people for the reality that all cancers would never be curable by a single pill. The metaphorical failure of the metaphorical war on cancer felt to many people like a reaffirmation of the rottenness of the end of the Nixon era, as though it were a moral failing on the part of government that denied us a cure. It is story without foundation, one that pays no attention to the singular power and elusiveness of the disease itself.

The truth, uncomfortable and inconvenient as it may be, is that medical science has never faced a more inscrutable, more mutable, or more ruthless adversary. It is a unique disease. Cancer is, in a way, the body’s war on itself. The microscopic cellular resources we as a species rely on to multiply, survive, and defeat diseases are more or less shared in equal measure by cancers; cancers—the many maladies lumped together under that name—use all of the cell’s capabilities to defeat the treatments we throw at the disease. That has been the medical challenge, to drill deeply into those capabilities and cellular mechanisms, to understand them and then manipulate them. The real secret to cancer’s tenacity, and to the therapies that ultimately tame it, lies in our advancing ability to understand its biology. That, in part, is the subject of this book.

But the history of cancer research and treatment, particularly since Watson and Crick’s brilliant discoveries about DNA in the 1950s, has not been a straight line leading to an inevitable success. A new drug vanquishes all tumors in laboratory mice, then fails in human trials. A seemingly innocuous and long-overlooked chemical suddenly opens a promising door to a new treatment that produces measurable improvements, but often for rare cancers that affect few people. Some breakthroughs, often developed over a period of years at great expense, extend the lives of patients by just a few months. Particularly maddening are the drug trials that seem to fail—except for a near-miraculous cure of one cancer patient, which can be neither replicated nor explained.

Successes and failures in cancer research are rarely absolute because of the vexing mutability of cancer cells, one of their most fundamental characteristics. Tumors go into remission only to come roaring back later in a changed, more potent form that chemotherapeutic drugs or radiation cannot stop.

That gets at the essence of the medical difficulties: first, there is not one genetic change that causes cancer, but hundreds if not thousands, and second, though cancers can and usually do mutate within each patient, the drugs or other treatments we use against them cannot. Thus, new treatments that hit new targets must be endlessly formulated. Scientists struggle not just to understand and outwit this resourceful disease but, on a more human level, to maintain a positive outlook in the face of constant setbacks.

These are life-and-death issues, and so the cancer campaign does have moral as well as medical dimensions, but the hurdles to progress come largely from the inherently complex nature of cancer. There have been a growing number of improvements in cancer care—and outcomes. They have relied primarily on the extraordinary progress that has been made in understanding the biology of cancer. We take for granted the revolution in our understanding of how tumors develop and grow, but the leaps in our understanding of the inner nature of cells, and their malicious mutations, cancer cells, are one of the greatest achievements in the history of science. They have taken place within just the past few decades.

Scientists have now solved, for the most part, what had been the most enduring and deadly medical mystery of the preceding two thousand years: What is cancer? When you understand that achievement and the vast distance scientists have traveled, you can appreciate how close medical science has come not to “curing” all the many diseases we refer to as cancer, but to reducing and controlling cancers. We stand on the threshold of the age of cancer containment. Cancer patients will live longer, fuller lives. This book explains how.

one

CRACKING MEDICINE’S OLDEST MYSTERY

FROM MY INITIAL EXAMINATION of the bubbly, whip-smart teenager, I knew her problem was serious. I was in my third year at the College of Physicians and Surgeons, Columbia University’s medical school, confident, perhaps even a little arrogant, as I worked my way to the top of my class. It was 1948, and, like most of my classmates, I dreamed of the great things I would accomplish in my white lab coat. As I rotated through the pediatric portion of my clinical training at Columbia-Presbyterian Hospital, I had gotten in the habit of attacking each new case with energy, certain that I could offer some fresh insights to heal the children who entered the ward. But this case was different.

I read the young woman’s initial diagnosis and noticed the conspicuously swollen lymph nodes in her neck, her fever, the cough, and, most worrying, the telltale wheezing sound. There was no doubt. It was cancer, a lymphoma. For all my ambition and my freshly developed skills, I knew what this meant: this upbeat young woman was facing a death sentence. Not only did medicine have virtually nothing to offer her, we had no real understanding of where her cancer came from, why it struck, or how it killed. Worst of all, we knew almost nothing about how to slow or stop it.

That vacuum of information regarding a disease that afflicted more than a million people every year in the United States alone was startling. But at the time human cells, and cancer cells in particular, were black boxes of mystery—distant, seemingly impenetrable, and foreboding. As biologist and Nobel laureate Albert Claude later noted, “The cell was as distant from us as the stars and galaxies.” We knew more about the structure of the atom than we did about the most fundamental mechanisms of life. There had been no equivalent of an Albert Einstein, Niels Bohr, or J. Robert Oppenheimer yet in the world of cancer.

The clinical protocols dictated that we begin treating my teenage patient with a round of chemotherapy. One of the drugs was derived from a nitrogen mustard gas that, believe it or not, had been developed for warfare. At the time there were no clinical trials or pioneering new treatments we could try. As her physicians, we seemed to be going through the motions of what I was certain would be a futile exercise, and I experienced something unfamiliar: I felt defeated by her cancer. The remarkable thing was, she was not. She was a moonbeam of optimism, confidently promising me during our conversations that she would beat her cancer and furthermore that, once healthy, she was going to study to become a doctor herself.

She was fascinated, she said, by the fact that the “crab” was the Latin symbol of her illness. That was good news, she insisted. The crab crawled slowly, and she, young and fleet, would surely overcome the lymphoma. Each day when I asked her how she was feeling, seeing for myself the toll the disease and the treatments were taking on her frail body, she always found something positive to say. I knew the truth and was struck by the role reversal in our relationship: she spoke with confidence and a touch of bravado, while I was the one struggling to come to grips with the brutal progress of the disease. No medical school classroom had prepared me for these emotions.

Within weeks of the start of her treatment, the chemotherapy had left her with nausea, diarrhea, and bone marrow damage. She was deteriorating by the day. Her white blood cell count was so depleted that had she left the isolation unit of the hospital, she would have been vulnerable to devastating infections. Nevertheless, her parents sought me out one day and asked, really pleaded, if they could take her home for just a few days. It was very important to them. Their daughter’s fourteenth birthday was approaching, and they wanted her to celebrate it with family and friends, certain it would cheer her up.

It was a terrible moment. I had no choice but to pass along the judgment of her attending physician, that heading home was not an option. They burst into tears, knowing full well what that implied. I was jolted, too. The message, I felt, was that we were inadequate to the trust that this gravely ill young woman and her family had placed in us because cancer was such an efficient, relentless foe. It was killing with impunity, turning my colleagues and me into bystanders.

After I finished my three months of pediatrics, the courageous young woman was officially no longer my patient, but I made a point of visiting her most days in her hospital room. Often I spoke with her father—a Princeton professor—and we grew close. Day after day, I observed as the cancer did its terrible work. Next to the bed would be her parents and, most difficult of all, her sister, an identical twin. What a painful contrast—in the bed a desperately ill young woman, weakened and withering from a disease that medicine had no answer for, and next to her a healthy mirror image, vigorous and heartbroken. It did not last long. One day, my young cancer patient just seemed to fall asleep as she slipped into a coma and then passed away. I asked myself, was this really the best my profession had to offer?

Medicine has scaled entire ranges of mountains in the past century as it has developed the means to combat an array of injuries and illnesses. We take the progress for granted, but it is a marvel, particularly compared to the previous centuries, during which shamans, charlatans, and ersatz healers battled disease with little to show for the efforts beyond modest incremental improvements in care. We have all but eliminated terrible infectious diseases like smallpox and polio. We have made great progress in understanding and controlling the deadly AIDS epidemic. We tinker with and mend the human body and its organs today like mechanics. Surgeons can take the heart apart and reassemble it with new parts, or replace it altogether. Serious burns were once painful and certain killers, but the survival rate has risen significantly. We crack genetic codes every day. The miraculous, in short, has become routine.

Cancer, however, is in a class by itself. Back in the 1940s, its assaults were so unyielding, so unsparing, that the disease was considered too dark a subject for most people to discuss—even doctors. The idea of a cancer survivor was almost an oxymoron. I never discussed the death of my young lymphoma patient with anyone, but the experience was critical in shaping my career. It persuaded me that I did not have the stomach to deal day to day with cancer sufferers at the clinical level, one at a time, particularly children. The drama behind losing patients never ceased to overpower me, even much later in my career. I recall the pain when a cousin of mine, a doctor in Colorado, a neonatal surgeon, in fact, contacted me at Memorial Sloan-Kettering Cancer Center for treatment of a melanoma.

He had initially just found a spot on his back. When he arrived in New York, we learned that it had already metastasized all over his body, reaching his lymph nodes and his brain. I was in the room with him when he was told of the extent of the disease. He was a middle-aged man with a family, and it was terrible news to have to absorb. He was sitting up in bed, and he looked at me, imploringly, and sputtered, “I don’t want to die. I’m too young to die.” He passed away the next day. I had built up substantial emotional armor by that time, but his words pierced it. Cancers are brutal emotional opponents as well as daunting physical challenges.

Maybe it was a weakness, but I had to acknowledge my limits. I feared as far back as my student days that my emotional reactions would impair my ability to analyze situations objectively and provide the best treatment options. If I were to have any impact in defeating this illness, it would have to be in the research laboratory and the classroom. I knew that, under any circumstances, the odds would be long. During my student years, to even utter the word cancer meant you had crossed a line, going from “This is a difficult medical problem” to “There’s not much we can do.”

Choosing to pursue cancer research or treatment in the late 1940s was regarded as an eccentric if not unfortunate career detour, particularly for a student with a lot of promise. For decades, the only effective treatment for most cancers was surgical removal of solid tumors, and the track record was limited at best. “Cures” could be achieved only in patients where tumors were discovered so early that they could be removed before any cancer cells had metastasized—which was the case less than 20 percent of the time.

The whole specialty of oncology was regarded with a bit of disdain because the causes of cancer were so mercurial and treatments so limited. If you were smart and gifted, you went into top-drawer specialties like cardiology, surgery, or internal medicine, as almost all of my medical school classmates had done. Focusing solely on curing cancer at that time was akin to a biologist deciding to build a career around the study of “Bigfoot.”

Dr. C. P. Rhoads, the first director of the Sloan-Kettering Institute, frankly acknowledged the condescending view some had of his field. “It is seen as the activity of the enthusiast,” Rhoads commented in the institution’s 1949 annual report. “To engage in it at all is seen as audacious; to enter upon it seriously is seen as Quixotic; to adopt it as a career is deemed fool hardy. The statement is often made that to seek a better knowledge of the control and cure of cancer is as absurd as to search for the spring of eternal youth, or the mystical basis of life itself.”

Rhoads was, in a sense, prescient. The search for the origins of cancer—and, thus, the search for vulnerabilities that doctors could then exploit to defeat it—has required that we dive as deeply into the molecular basis of life as science can take us. It calls for research into some of the most profound and fundamental processes of life—the study of how cells replicate, how genes express their functions, what regulates genetic behavior, how cells protect themselves, and how seemingly random “mistakes” in gene replication can cause the transformation of normal cells into lethal cancerous cells.

Seeking the causes of cancer was not unlike physicists deconstructing the atom to understand the fundamental nature of matter, except that the laws of physics are immutable; cancer is a moving target. Cancer cells grow and change constantly, and their mutability is often the key to the deadliness of their attacks. Cancer is, in short, the existential illness. As long as cell division is the means by which we propagate and survive as a species, cancers will develop.

By 1949 we had discovered a great deal about the architecture of the atom and how to unleash its power, but we understood little about the inner activities of the cell, or of DNA. By my last year of medical school, cancer had barely been covered in our curriculum. That year I chaired a group of students presenting the annual honors research seminar. Wanting to focus on the most challenging subject we could think of, we chose cancer.

We organized a series of papers with titles like “Heredity and Neoplasia,” “Hormonal Aspects of Neoplasia,” and “Viruses as Etiological Agents of Cancer.” We pored over medical journals, consulted our professors to refine our understanding, and laid out what were the state-of-the-art theories of the disease.

We were proud of our comprehensiveness, but, in hindsight, the explanations we provided were relatively primitive. Most, in fact, were just plain wrong. We—like many others in the medical profession—even failed to recognize some contemporary discoveries on the makeup of genes that, over time, would open a window into the ways cancers develop and spread.

For instance, in 1943 Oswald Avery and two associates at the Rockefeller Institute (now Rockefeller University) demonstrated that the chemical known as DNA contained the hereditary elements in cells. And it was known as far back as the 1920s that these chemicals resided in the nucleus of the cell. Nevertheless, the scientific field had not embraced those findings. The ideas were new, and there was no scientific consensus. Medical researchers understood that genetic mutations were in some way associated with cancer, but many believed that the components of heredity were located in the cell’s cytoplasm, the larger gellike region surrounding the nucleus. One respected journal that we cited in our honors seminar reported that “the gene is invisible and is recognized by its effects.”

We also failed to note, like the authors of the articles we were citing, the new discovery, in 1949, that parts of genes can be reshuffled, or “transposed,” essentially creating new genes from the bits and pieces of older ones, with new characteristics. Dr. Barbara McClintock, who would later win a Nobel Prize for her work, discovered these “jumping genes,” as some called them, while studying the mutability in the colors of corn kernels. This important insight led to the critical understanding that DNA, the complex of acids and sugars that make up our genes, is not a static structure, as many had supposed. No mention was made of this in our seminar.

As I reread our senior symposium papers today, I am struck by how little we questioned the accepted explanations for cancer. The simple truth was that scientists did not fully understand the differences between healthy cells, which multiply at a methodical pace and are programmed to die after they have served their purposes, and cancer cells, whose signature is a frantic rate of division and a zombielike resistance to the normal death cycle. Nor had the profession yet learned that cancer cells begin as healthy cells before being subverted by genetic mutations.

Our papers were advanced compared to the state of medical thinking in the first decades of the twentieth century. I recently found a small pamphlet published in 1911, The Facts About Cancer, which explains that most cancers begin with some sort of irritation of the skin and warns that cancers of the mouth are often initiated by “ragged, dirty teeth,” which cause abrasions that can blossom into malignancies. Prevention, it adds, should involve a visit to the dentist and a thorough cleaning.

But my graduating class stood on the cusp of not one but a series of revolutions in our understanding of the cell’s biology. The study of cancer was about to enter a new era. A number of major breakthroughs, especially the discovery of the structure of DNA by James Watson and Francis Crick in 1953—the famous double helix—altered the course of cancer research, my career, and, in time, medicine’s ability to control cancers. This book will describe those breakthroughs, which are still unfolding, and explain how a string of brilliant scientific insights has been slowly but progressively translated into treatments that are transforming patients’ lives.

The double helix structure of DNA, the storehouse of human genetic instructions. In healthy cells, DNA replicates millions of times without fault, but in rare instances there are “mistakes,” creating mutations that can lead to cancers.

From those early days in my career more than sixty years ago, I have witnessed and participated in one of the greatest sustained scientific assaults in history, perhaps misleadingly called the “war on cancer.” As dean of Columbia’s medical school, vice president of health sciences at the university, director of Columbia’s Cancer Center, and then, for twenty years, president of the exceptional Memorial Sloan-Kettering Cancer Center, I helped guide many of these scientific and medical leaps, while contributing a pioneering anticancer drug, known as a “targeted therapy.”

“War” is a metaphor that suggests a campaign with a beginning and an end, and it is not uncommon to hear questions about whether the “war on cancer” has really accomplished much; after all, despite an investment of billions of dollars and decades of work, there is still no “cure” for most cancers, no therapy that can prevent them with certainty. It took less than a decade to get to the moon, yet we are more than forty years into this war without a conclusion, or even a clear sign of when it will end, if at all.

That may be true, but it is also, I believe, a misguided way of looking at the issue. Given the malleability of the disease, and its roots in the way cells divide and grow, that is the wrong question. The prospect of finding a single “cure” for all cancers is unlikely. The enemy will always have more faces than we have weapons at any one time. Wars are won and lost; this is a contest with our inner nature, our inner mechanisms. We can, in time, control them, but not “defeat” them.

This is partly a reflection of the fact that, as we have learned, there is no such single thing as “cancer.” We commonly talk about “breast cancer” or “colon cancer,” but we are finding that no two cancers, even the same clinical types, are exactly the same. At the basic level of their genetic signatures and the proteins they use to conduct their cells’ business, we have found that each tumor usually contains many abnormalities, and no two cancers probably match exactly. Studies of many colon and breast cancer tumors have found hundreds of different gene mutations. Just in the ones we have classified so far, it is estimated that there are more than 150 types of cancer.

Adding to this maddening complexity, researchers have found that 99.9 percent of the DNA in cancerous tissue may be identical to the DNA in the normal surrounding cells. That 0.1 percent difference may contain the information that kills, but which altered genes should the researcher or physician target in the patient? Recent research has found that the typical cancer cell has, on average, forty-five abnormalities in the genes and cell pathways that can drive the unrestrained growth of the tumor.

There is, however, cause for optimism, more, in fact, than is commonly understood and a lot more than we had even a decade ago. In terms of important scientific advances, the war has surpassed the expectations that doctors and scientists, my mentors, friends, and colleagues, had in the 1940s or even the 1970s. And that science is, over time, being translated into successful therapies.