The First Cell

by Azra Raza

  The cancer winter continues.

  TREATING CANCER AS one disease is like treating Africa as one country. Even in the same patient, it is not the same disease at two sites or at two different points in time. Vicious and self-obsessed, it learns to grow faster and become stronger, smarter, and more dangerous with each successive division. It is a perfect example of intelligence at a molecular level, able to perceive its environment and take actions that maximize its chances of survival. A feedback loop, using past performance to improve its efficiency, forms the basis of its seemingly purposeful behavior. It learns to divide more vigorously with time, invading new spaces, mutating to turn the expression of pertinent genes off and on, enhancing its fitness to the landscape, optimizing seed-soil cooperation. We see this metamorphosis in front of our eyes when treatment causes regression of the tumor in one area just as fresh lesions crop up in another, bearing a novel genotype, selected precisely because of their refractoriness to the administered therapy; as mini-Frankensteins, they emerge like ghosts from the machine, bent upon destroying their maker.

  The disease is fantastically complex. More fantastic is the reductionist conceit that targeting a single genetic abnormality with a single drug will be curative. This “magic bullet” concept became especially entrenched because of a couple of early successes—in the case of chronic myeloid leukemia, a chromosomal translocation in the malignant cell codes for an abnormal hybrid protein targetable with a drug, imatinib mesylate, with dramatic results. Acute promyelocytic leukemia, a particularly deadly disease, is also driven by a single abnormality. It is now curable with vitamin A. These two success stories seemed to confirm a paradigm: cancer results from a genetic mutation that can be cured with a drug.

  Unfortunately, most common cancers have proved to be more complex, with many more biologic aberrations driving the malignant phenotype. The trafficking of cancer cells is more labyrinthine, tangled, knotty, and impenetrably convoluted than the London Underground. The cell continually transforms itself, covering generations of its natural life span in mere hours, ditching genes and entire chromosomes, acquiring new mutations, revving organelles, deforming proteins, neutralizing death signals, forging ahead deliriously, driven by the unrelenting engine of malice, bursting its hot contents on unsuspecting organs, impregnating them with its potent malignant seed, callously moving on. Cancer rules over the host with despotic autocracy.

  To develop treatment strategies for so dense a disease by attempting to duplicate its complexity in tissue culture cell lines or animal models has been an unmitigated disaster. The failure rate for drugs brought into clinical trials using such preclinical drug-testing platforms is 95 percent. The 5 percent of drugs that reach approval might as well have failed, since they prolong survival of patients by no more than a few months at best. Since 2005, 70 percent of approved drugs have shown zero improvement in survival rates while up to 70 percent have been actually harmful to patients.

  These conceptual errors are due to cause more harm tomorrow than they do today. Based on available data, some 18 million new cancer cases were diagnosed worldwide in 2018, with about half as many dying of their cancers. The American Cancer Society reports that the global burden will grow to 21.7 million new cancer cases and 13 million cancer deaths by 2030 as the worldwide population grows and ages. A frequently cited statistic shows that the death rate from cancer declined in the United States by 20 percent between 1980 and 2014. There were 240 deaths per 100,000 in 1980 while only 192 deaths per 100,000 in 2014. However, this decrease is not due to improved treatments but mostly to early diagnosis and a decline in smoking. There has been a disturbing increase in cancer deaths from specific malignancies, both across the United States and in delineated pockets. Liver cancer deaths have increased by 88 percent nationwide from 1980 to 2014. Deadly breast cancers in women, prostate cancers in men, as well as mortality from cancers of the pancreas, colon, and rectum escalated among low socioeconomic groups and in impoverished regions with a high incidence of obesity. And even as lymphomas have steadily claimed a death rate of 8 per 100,000 across the United States, small pockets in Ohio, West Virginia, and Kentucky experienced an increase in deaths by up to 74 percent.

  And then there is the financial issue. Tarceva, a drug that extends the survival of pancreatic cancer patients by twelve days, costs $26,000. An eighteen-week course of cetuximab for lung cancer costs $80,000. Among the 9.5 million new cancer cases diagnosed during a fourteen-year period in America, almost half (42.4 percent) had lost all their life savings within two-plus years. Overall, cancer care cost $125 billion in 2010 and is likely to be $156 billion by 2020. And these are just billings to patients and insurers and does not include the infusion of money from other sources like philanthropies, private organizations, nonprofit funding institutions, universities, industry, and the FDA. A literature search reveals that more than 3 million papers have been published to date on cancer, the PubMed database showing 3,843,208 publications with 165,567 in 2018 alone. A good 70 percent of what is reported is not reproducible.

  The consensus today is that prevention is preferable to treatment. Yet actions to make this happen are obscenely lagging behind. In the meantime, precious lives are lost, resources wasted. As oncologists, we are charged with providing, from diagnosis to death, care to our cancer patients that enhances their quality of life, reduces pain and suffering. Are we accomplishing that, and if not, then why not, and what can be done to improve the outlook for future patients? Are we truly appreciating the deep tragedy of cancer at an intimate, individual level, the profound devastation of families, cancer’s social and financial impact, its searing psychologic traumas? Above all, are we doing the best we can with available options, or should we be questioning some of the draconian measures we are practicing? How good are the solutions we offer if we constantly have to ask ourselves whether the cancer or the treatment we prescribe will kill the patient? Which of the two is worse? Using chemotherapy, immune therapy, and stem cell transplant to cure cancer, as someone has aptly observed, is like beating the dog with a baseball bat to get rid of its fleas. Why is this the best we can offer?

  HOPES OF FINDING better drugs using the existing discovery platforms or using even more artificial systems of genetically engineered animals are as realistic as dissecting the brain and expecting to discover consciousness. After fifty years of developing cancer drugs this way, is it time to reassess the preclinical model?

  No.

  It is time to abandon the strategy altogether. Jeremiads alone are pointless unless a new strategy accompanies the lamentation.

  The new strategy is to stop chasing after the last cancer cell and focus on eliminating the first. Better still, prevent the appearance of the first cancer cell by finding its earliest footprints.

  To begin the ending, we must end the beginning. Prevention will be the only compassionate, universally applicable cure.

  It is not prevention through lifestyle changes. Individuals with pristine eating and exercising habits get cancer because cancer-causing mutations accumulate as natural consequences of reproduction and aging of cells. The new strategy must go beyond early detection as practiced currently through mammograms and other routine screening tests. The prevention I am talking about is through identification and eradication of transformed cancerous cells at their inception, before they have had a chance to organize into a bona fide malignant, incurable disease. This may seem an unattainable, utopian dream, but it is achievable in a reasonable time. We are already using sophisticated technology to detect the residues of disease that linger after treatment, the last cancer cell. Can we not reverse the order of things and use the tests to detect the first?

  I started focusing on a study of preleukemia, MDS, thirty-five years ago for this reason. It was clear to me even back in 1984 that AML is too complicated and difficult a disease to cure in my lifetime. I pinned my hopes on studying the preleukemic stage, findings ways to prevent it from evolving to AML. I have stuck to this strategy for all th
ese years. Among a handful of researchers with the same mind-set is Bert Vogelstein at Johns Hopkins University, who studied the transition of benign adenomas into malignant colon cancers and eventually came to the same conclusion—the best strategy is prevention and early detection. His team is leading the charge in breast, colon, pancreas, and lung cancers; they are using “liquid biopsies” to look for very early biomarkers of malignancy in bodily fluids. Vogelstein has repeatedly pointed out that 30–40 percent of all cancers can be cured today by implementing techniques to detect early markers of cancer, such as somatic DNA driver mutations; epigenetic changes; cancer-specific RNA and proteins; cancer-specific metabolites in the plasma, sputum, urine, and stools of these individuals; and by employing molecular imaging techniques. The sensitivity can be increased from roughly 40 percent to 80 percent for gynecologic cancers simply by looking for cancer-derived DNA markers in Pap smears. Fifty years from now, Vogelstein says, cancer deaths could be down by 75 percent just through prevention, early detection, and development of newer strategies to deal with early-rather than late-stage disease.

  Once my mind was made up to try to detect the first leukemia cells in an MDS patient and target their destruction at the very inception, the next challenge was a practical one. I needed leukemia cells to study. This provided the impetus for banking samples any time I performed a bone marrow biopsy on my patients. Thus began the MDS-AML Tissue Repository. This repository is the most concrete, tangible proof of my lifelong commitment to study cancer at its earliest stage, to find the first cell and to eliminate the scourge at initiation. Dating back to 1984, it is now the oldest MDS and AML repository in the world collected by a single physician. Not a single cell has been contributed by another oncologist. Today, the repository contains some sixty thousand samples from thousands of patients.

  Every vial in those freezers invokes a poignant memory; every test tube tells a story. Only I am a witness to the pain each patient—some of them more than a dozen times over the course of their illness—endured to undergo this procedure. That makes everything deeply personal for me, sacred. Some of those vials in the freezers contain parts of patients that can be thawed back to life in lab dishes decades after the patients are no more. Including Harvey. How can I afford to let any of those patients down?

  I CAN ALMOST hear some objections surfacing in the minds of my oncology and scientific colleagues.

  The first objection will likely be that I am ignoring the 68 percent of all cancers we are managing to cure today. My answer is that most of it was achieved several decades ago with the surgery-chemoradiation therapies. Recent advances relate primarily to improvement in cancer mortality due to early detection, not meaningful advances in the treatment of metastatic cancers. An exciting exception, and one worth applauding wholeheartedly, is the introduction of novel immune therapies. Two fine scientists, James P. Allison and Tasuku Honjo, won the Nobel Prize in 2018 for their pioneering work in this field. As a result of their groundbreaking work, many hopeless lung cancer, melanoma, lymphoma, and acute lymphoblastic leukemia patients are living years beyond their predicted survival, and a few are even cured. It is great, but the immune approaches are not universally curative and, at present, help very few patients. At a minimum, the cellular therapies are financially draining; at worst, they may cause very severe side effects because of their superefficient killing. The sudden simultaneous deaths of billions of cancer cells in a person with a very high tumor burden cause life-threatening toxicities, as cytokine storms damage the liver and lungs while the kidneys choke on cellular debris. Finally, a small but definite fraction of treated patients, ranging between 7 and 30 percent, experience inexplicable resurgence and paradoxical hyperprogression of their tumors. All these side effects could possibly be avoided if the same therapy is instituted when the tumor burden is low. Indeed, harnessing the body’s own natural killers to eliminate the first cancer cells will be the ideal treatment in the future.

  Another constant refrain I hear from practicing oncologists goes something like this: “In the last twenty-five years, a shift toward better survival is seen in many cancers. Breast and prostate cancer and chronic myeloid and chronic lymphocytic leukemia have truly become diseases that patients live with and not die from. Even in lung cancer, which was the most depressing malignancy for decades, there is a trend toward survival improvement, albeit at great expense. There are at least ten to twelve targetable mutations. An additional 20–25 percent of patients respond to immunotherapy.” I have no disagreement with this assessment. Of course there has been progress in many areas. It reminds me of something that a beloved Raza family friend, the late Syed V. S. Kashmiri, a fantastic immunologist and scientist in his own right, once said to my youngest brother: “Abbas, if one day, the sun rose in the west, practically the whole world would stop and stare. But there is a handful of people who watched it rise in the east every day and wondered why. These are the people who change the world.” I quote Kashmiri Sahib because we, too, have been taking much for granted. We often talk about our patients only registering the positive parts of conversations. As oncologists, we are doing the same by focusing on the minority of our patients who benefit for limited durations. The time has come for us to think about the majority who don’t, but who suffer the ghastly toxicities of therapies and end up losing their life savings in the process.

  I can likewise anticipate criticism from the scientists cataloging paradigm-shifting progress in the molecular and genetic understanding of cancer pathology resulting from animal studies or in vitro tissue cultures. I agree that these modalities are the basis for deep insights into the biology of cancer and must continue. Nevertheless, as you will soon discover, these tools come in for ringing condemnation in this book. In no way am I advocating that we abandon such invaluable research tools. My problem is using these systems for oncologic drug development where they have proved of little benefit to the patients. Of course, individual researchers and oncologists who are trapped in a system cannot be held responsible because they would lose research grants or be sued for malpractice and negligence if they don’t follow the prescribed guidelines. I know because I am one of them. Every bit of criticism applies as much to me as to any researcher or oncologist reading the book. My criticism is directed not at us but at the system we have unwittingly evolved and the culture we have unintentionally created collectively both in clinical practice and basic cancer research.

  Finally, and most importantly, both oncologists and basic scientists might feel that I am too pessimistic, not just in my view of the past but also of the future. This, too, is a patently false conclusion. In fact, while being realistic about the past and present, I am exceedingly optimistic about the future of cancer treatment. The pessimism you might sense in the coming pages is not because I have a fatalistic or nihilistic attitude. Rather, it is an expression of deep frustration at the status quo. Too many lives are being lost because of our own unshakable hubris, convinced as we are that we possess the power to untangle the intricacies of as complex a disease as cancer. It is like saying we will cure aging. It may happen, but not any time soon. As you reach the end of this book, you will be sharing my hope for a much brighter outcome for future cancer patients. It will happen because we will have learned to avoid cancer’s tragic, end-stage pain and suffering altogether by nipping it in the bud. I predict a radical shift in all of health care in the coming decades. Early detection of neurologic, metabolic, cardiac, and oncologic diseases will naturally follow once we implement sensors designed to gauge disease-caused perturbations years ahead of their actual clinical appearances. This is how over the next few years, effective, evidence-based preventive modalities will be developed, refined, and perfected.

  ALTHOUGH ISSUES OF science are critical to this book, its true raison d’être is to improve the outcome for individuals negotiating cancer’s capricious, pernicious challenges. I hope this book will be a source of empowerment—rather than discouragement—for cancer patients at several levels. For o
ne, as we will see, not every gloomy prognosis comes to pass. For another, the fact that thousands of oncologists and researchers are working day and night to find better solutions for cancer is a powerful truth, as well. On a daily basis, I witness the astonishing, selfless devotion to patients displayed by my fellow oncologists in a hundred ways, great and small, just like the basic science researchers who work tirelessly to devise new experiments to test their hypotheses, reach out selflessly to collaborate and help us understand the inner happenings of cancer at a molecular level. Their dedication to cancer patients is humbling and inspiring. Most importantly, the book should assure any cancer patient reading it that they are not alone. We are in this conversation together. Every one of us has a fifty-fifty chance of being in their shoes tomorrow. The stories of men and women, young and old, facing grim choices reflect our collective challenges, give a voice to our anxieties as a species as well as to our vulnerabilities, our frailties.