The Emperor of All Maladies

by Siddhartha Mukherjee

  430 This abnormality, the so-called Philadelphia chromosome: John M. Goldman and Junia V. Melo, “Targeting the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia,” New England Journal of Medicine 344, no. 14 (2001): 1084–86.

  431 The identity of the gene: Annelies de Klein et al., “A Cellular Oncogene Is Translocated to the Philadelphia Chromosome in Chronic Myelocitic Leukemia,” Nature 300, no. 5894 (1982): 765–67.

  431 The mouse developed the fatal spleen-choking: E. Fainstein et al., “A New Fused Transcript in Philadelphia Chromosome Positive Acute Lymphocytic Leukaemia,” Nature 330, no. 6146 (1987): 386–88; Nora Heisterkamp et al., “Structural Organization of the Bcr Gene and Its Role in the Ph’ Translocation,” Nature 315, no. 6022 (1985): 758–61; de Klein et al., “Cellular Oncogene Is Translocated”; Nora Heisterkamp et al., “Chromosomal Localization of Human Cellular Homologues of Two Viral Oncogenes,” Nature 299, no. 5885 (1982): 747–49.

  431 In the mid-1980s: Daniel Vasella and Robert Slater, Magic Cancer Bullet: How a Tiny Orange Pill Is Rewriting Medical History (New York: HarperCollins, 2003), 40–48; Elisabeth Buchdunger and Jürg Zimmermann, “The Story of Gleevec,” innovation.org, http://www.innovation.org/index.cfm/StoriesofInnovation/InnovatorStories/The_Story_of_Gleevec (accessed January 31, 2010).

  433 Jürg Zimmermann, a talented chemist: Howard Brody, Hooked: Ethics, the Medical Profession, and the Pharmaceutical Industry (Lanham, MD: Rowman & Littlefield, 2007), 14–15; Buchdunger and Zimmermann, “Story of Gleevec.”

  433 “[It was] what a locksmith does”: Buchdunger and Zimmermann, “Story of Gleevec.”

  433 “I was drawn to oncology as a medical student”: Brian Druker, interview with author, November 2009.

  434 In 1993, he left Boston: Ibid.

  434 “Everyone just humored me”: Ibid.

  434 In October 1992, just a few months: Ibid.

  435 “Although freedom from leukemia”: S. Tura et al., “Evaluating Survival After Allogeneic Bone Marrow Transplant for Chronic Myeloid Leukaemia in Chronic Phase: A Comparison of Transplant Versus No-Transplant in a Cohort of 258 Patients First Seen in Italy Between 1984 and 1986,” British Journal of Haematology 85 (1993): 292–99.

  435 “Cancer is complicated”: Druker, interview with author.

  435 In the summer of 1993, when Lydon’s drug: Ibid.

  435 Druker described the findings in the journal: Brian J. Druker, “Effects of a Selective Inhibitor of the Abl Tyrosine Kinase on the Growth of Bcr-Abl Positive Cells,” Nature Medicine 2, no. 5 (1996): 561–66.

  436 “The drug . . . would never work”: The story of Gleevec’s development is from Druker, interview with author.

  436 In early 1998, Novartis finally relented: Lauren Sompayrac, How Cancer Works (Sudbury, MA: Jones and Bartlett, 2004), 21.

  438 Druker edged into higher and higher: Brian J. Druker et al., “Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia,” New England Journal of Medicine 344, no. 14 (2001): 1031–37.

  438 Of the fifty-four patients: Ibid.

  438 “Before the year 2000”: Hagop Kantarjian, Georgetown Oncology Board Review Lectures, 2008.

  439 “When I was a youngster in Illinois”: Bruce A. Chabner, “The Oncologic Four-Minute Mile,” Oncologist 6, no. 3 (2001): 230–32.

  439 “It proves a principle”: Ibid.

  The Red Queen’s Race

  441 “Well, in our country,” said Alice: Lewis Carroll, Alice in Wonderland and Through the Looking Glass (Boston: Lothrop, 1898), 125.

  441 In August 2000: Details of Jerry Mayfield’s case are from the CML blog newcmldrug .com. This website is run by Mayfield to provide information to patients about CML and targeted therapy.

  442 CML cells, Sawyers discovered: See for instance M. E. Gorre et al., “Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification,” Science 293, no. 5531 (2001): 876–80; Neil P. Shah et al., “Multiple BCR-ABL Kinase Domain Mutations Confer Polyclonal Resistance to the Tyrosine Kinase Inhibitor Imatinib (STI571) in Chronic Phase and Blast Crisis Chronic Myeloid Leukemia,” Cancer Cell 2, no. 2 (2002): 117–25.

  442 “an arrow pierced through the center of the protein’s heart”: Attributed to John Kuriyan; quoted by George Dmitri to the author at a Columbia University seminar, November 2009.

  442 In 2005, working with chemists: Jagabandhu Das et al., “2-Aminothiazole as a Novel Kinase Inhibitor Template. Structure-Activity Relationship Studies toward the Discovery of N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-(piperazinyl)]-2-methyl-4-pyrimidinyl](amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a Potent pan-Src Kinase Inhibitor,” Journal of Medicinal Chemistry 49, no. 23 (2006): 6819–32; Neil P. Shah et al., “Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor,” Science 305, no. 5682 (2004): 399–401; Moshe Talpaz et al., “Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias,” New England Journal of Medicine 354, no. 24 (2006): 2531–41.

  443 twenty-four novel drugs: For a full list, see National Cancer Institute, targeted therapies list, http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted (accessed February 23, 2010). This website also details the role of such drugs as Avastin and bortezomib.

  443 Over a decade: “Velcade (Bortezomib) Is Approved for Initial Treatment of Patients with Multiple Myeloma,” U.S. Food and Drug Administration, http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm094633.htm (accessed January 31, 2010); “FDA Approval for Lenalidomide,” National Cancer Institute, U.S. National Institutes of Health, http://www.cancer.gov/cancertopics/druginfo/fda-lenalidomide (accessed January 31, 2010).

  444 In 1948, epidemiologists identified a cohort: Framingham Heart Study, the National Heart, Lung and Blood Institute and Boston University, http://www.framinghamheartstudy.org/ (accessed January 31, 2010).

  445 In May 2008, two Harvard epidemiologists: Nicholas A. Christakis, “The Collective Dynamics of Smoking in a Large Social Network,” New England Journal of Medicine 358, no. 21 (2008): 2249–58.

  447 “Cancer at the fin de siècle”: Harold J. Burstein, “Cancer at the Fin de Siècle,” Medscape Today, February 1, 2000, http://www.medscape.com/viewarticle/408448 (accessed January 31, 2010).

  Thirteen Mountains

  448 “Every sickness is a musical problem”: W. H. Auden, “The Art of Healing (In Memoriam David Protetch, M.D.),” New Yorker, September 27, 1969.

  448 The revolution in cancer research: Bert Vogelstein and Kenneth Kinzler, “Cancer Genes and the Pathways They Control,” Nature Medicine 10, no. 8 (2004): 789–99.

  449 “The purpose of my book”: Susan Sontag, Illness as Metaphor and AIDS and Its Metaphors (New York: Picador, 1990), 102.

  450 The Human Genome Project: “Once Again, Scientists Say Human Genome Is Complete,” New York Times, April 15, 2003.

  450 the Cancer Genome Atlas: “New Genome Project to Focus on Genetic Links in Cancer,” New York Times, December 14, 2005.

  450 “When applied to the 50 most common”: “Mapping the Cancer Genome,” Scientific American, March 2007.

  450 In 2006, the Vogelstein team revealed: Tobias Sjöblom et al., “The Consensus Coding Sequences of Human Breast and Colorectal Cancers,” Science 314, no. 5797 (2006): 268–74.

  450 In 2008, both Vogelstein’s group and the Cancer Genome Atlas: Roger McLendon et al., “Comprehensive Genomic Characterization Defines Human Glioblastoma Genes and Core Pathways,” Nature 455, no. 7216 (2008): 1061–68. Also see D. Williams Parsons et al., “An Integrated Genomic Analysis of Human Glioblastoma Multiforme,” Science 321, no. 5897 (2008): 1807–12; and Roger McLendon et al., “Comprehensive Genomic Characterization.”

  452 Only a few cancers are notable exceptions: C. G. Mullighan et al., “Genome-Wide Analysis of Genetic Alterations in Acute Lymphoblastic Leukemia,” Nature 446, no. 7137 (2007): 758–64.

  452 “In the end,” as Vogelstein put it: Bert Vogelstein, comments
on lecture at Massachusetts General Hospital, 2009; also see Vogelstein and Kinzler, “Cancer Genes and the Pathways They Control.”

  453 Other mutations are not passive players: The distinction between passenger and driver mutations has generated an enormous debate in cancer genetics. Many scientists suspect that the initial analysis of the breast cancer genome may have overestimated the number of driver mutations. Currently, this remains an open question in cancer genetics. See, for instance, Getz et al., Rubin et al., and Forrest et al., Science 317, no 5844: 1500, comments on Sjöblom article above.

  453 In a recent series of studies, Vogelstein’s team: See, for example, Rebecca J. Leary, “Integrated Analysis of Homozygous Deletions, Focal Amplifications, and Sequence Alterations in Breast and Colorectal Cancers,” Proceedings of the National Academy of Sciences of the United States of America 105, no. 42 (2008): 16224–29; Siân Jones et al., “Core Signaling Pathways in Human Pancreatic Cancer Revealed by Global Genomic Analyses,” Science 321, no. 5897 (2008): 1801–6.

  454 “Cancer,” as one scientist recently put it: Emmanuel Petricoin, quoted in Dan Jones, “Pathways to Cancer Therapy,” Nature Reviews Drug Discovery 7 (2008): 875–76.

  455 In a piece published in the New York Times: “To Fight Cancer, Know the Enemy,” New York Times, August 5, 2009.

  456 In 2000, the so-called Million Women Study: Valerie Beral et al., “Breast Cancer and Hormone-Replacement Therapy in the Million Women Study,” Lancet 362, no. 9382 (2003): 419–27.

  456 The second controversy also has its antecedents: See, for instance, F. J. Roe and M. C. Lancaster et al., “Natural, Metallic and Other Substances, as Carcinogens,” British Medical Bulletin 20 (1964): 127–33; and Jan Dich et al., “Pesticides and Cancer,” Cancer Causes & Control 8, no. 3 (1997): 420–43.

  457 In 2005, the Harvard epidemiologist David Hunter: Yen-Ching Chen and David J. Hunter, “Molecular Epidemiology of Cancer,” CA: A Cancer Journal for Clinicians 55 (2005): 45–54.

  457 In the mid-1990s, building on the prior decade’s advances: Yoshio Miki et al., “A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1,” Science 266, no. 5182 (1994): 66–71; R. Wooster et al., “Localization of a Breast Cancer Susceptibility Gene, BRCA2, to Chromosome 13q12–13,” Science 265, no. 5181 (1994): 2088–90; J. M. Hall et al., “Linkage of Early-Onset Familial Breast Cancer to Chromosome 17q21,” Science 250, no. 4988 (1990): 1684–89; Michael R. Stratton et al., “Familial Male Breast Cancer Is Not Linked to the BRCA1 Locus on Chromosome 17q,” Nature Genetics 7, no. 1 (1994): 103–7.

  457 An Israeli woman: Breast cancer patient O. B-L. (name withheld), interview with author, December 2008.

  458 In the mid-1990s, John Dick: Tsvee Lapidot et al., “A Cell Initiating Human Acute Myeloid Leukaemia After Transplantation into SCID Mice,” Nature 367, no. 6464 (1994): 645–58.

  459 Indeed, as the fraction of those affected by cancer creeps: “One in three” is from the recent evaluation by the National Cancer Institute. See http://www.cancer.gov/newscenter/tip-sheet-cancer-health-disparities. The number “one in two” comes from the NCI seer statistics, http://seer.cancer.gov/statfacts/html/all.html, but includes all cancer sites, summarized in Matthew Hayat et al., “Cancer Statistics, Trends and Multiple Primary Cancer Analyses,” Oncologist 12 (2007): 20–37.

  ATOSSA’S WAR

  461 We aged a hundred years: Anna Akhmatova, “In Memoriam, July 19, 1914,” in The Complete Poems of Anna Akhmatova, vol. 1 (Chicago: Zephyr Press, 1990), 449.

  461 It is time, it is time for me too to depart: Aleksandr Solzhenitsyn, Cancer Ward (New York: Farrar, Straus and Giroux, 1974), 476.

  461 On May 17, 1973: “A Memorial Tribute in Honor of Dr. Sidney Farber, 1903–1973,” Thursday, May 17, 1973. Gift of Thomas Farber to the author.

  464 It is impossible to enumerate: Atossa’s case and her survival numbers are speculative, but based on several sources. See, for instance, “Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials,” Lancet, 365, no. 9472: 1687–1717.

  465 In 1997, the NCI director, Richard Klausner: See Barnett S. Kramer and Richard D. Klausner, “Grappling with Cancer—Defeatism Versus the Reality of Progress,” New England Journal of Medicine 337, no. 13 (1997): 931–35.

  467 The new drug was none other than Gleevec: See, for example, H. Joensuu, “Treatment of Inoperable Gastrointestinal Stromal Tumors (GIST) with Imatinib (Glivec, Gleevec),” Medizinische Klinik (Munich) 97, suppl. 1 (2002): 28–30; M. V. Chandu de Silva and Robin Reid, “Gastrointestinal Stromal Tumors (GIST): C-kit Mutations, CD117 Expression, Differential Diagnosis and Targeted Cancer Therapy with Imatinib,” Pathology Oncology Research 9, no. 1 (2003): 13–19.

  Glossary

  Acute lymphoblastic leukemia: a variant of white blood cell cancer that affects the lymphoid lineage of blood cells.

  Acute myeloid leukemia: a variant of white blood cell cancer that affects the myeloid lineage of blood cells.

  Apoptosis: the regulated process of cell death that occurs in most cells, involving specific cascades of genes and proteins.

  Carcinogen: a cancer-causing or cancer-inciting agent.

  Chimeric gene: A gene created by the mixing together of two genes. A chimeric gene might be the product of a natural translocation, or might be engineered in the lab.

  Chromosome: a structure within a cell comprised of DNA and proteins that stores genetic information.

  Cytotoxic: Cell-killing. Usually refers to chemotherapy that works by killing cells, particularly rapidly dividing cells.

  DNA: Deoxyribonucleic acid, a chemical that carries genetic information in all cellular organisms. It is usually present in the cell as two paired, complementary strands. Each strand is a chemical chain made up of four chemical units—abbreviated A, C, T, and G. Genes are carried in the form of a genetic “code” in the strand and the sequence is converted (transcribed) into RNA (see p. 534) and then translated into proteins (see p.534).

  Enzyme: a protein that accelerates a biochemical reaction.

  Gene: a unit of inheritance, normally comprised of a stretch of DNA that codes for a protein or for an RNA chain (in special cases, genes might be carried in the RNA form).

  Genetic engineering: the capacity to manipulate genes in organisms to create new genes, or introduce genes into heterologous organisms (e.g., a human gene in a bacterial cell).

  Genome: the full complement of all genes within the organism.

  Incidence: In epidemiology, the number (or fraction) of patients who are diagnosed with a disease in a given period of time. It differs from prevalence because incidence reflects the rate of new diagnosis.

  Kinase: a protein enzyme that attaches phosphate groups to other proteins.

  Metastatic: cancer that has spread beyond its local site of origin.

  Mitosis: the division of one cell to form two cells that occurs in most adult tissues of the body (as opposed to meiosis, which generates germ cells in the ovary and the testes).

  Mutation: An alteration in the chemical structure of DNA. Mutations can be silent—i.e., the change might not affect any function of the organism—or can result in a change in the function or structure of an organism.

  Neoplasm, neoplasia: an alternative name for cancer.

  Oncogene: A cancer-causing or cancer-promoting gene. Activation or overexpression of a proto-oncogene (see below) promotes the transformation of a cell from normal to a cancer cell.

  Prevalence: in epidemiology, the number (or fraction) of affected patients in any given period of time.

  Primary prevention: prevention aimed at avoiding the development of a disease, typically by attacking the cause of the disease.

  Prospective trial: a trial in which a cohort of patients is followed forward in time (as opposed to retrospective, in which a cohort of patients is followed backward).

  Protein: A chemical comprised, at its core, of a chain of amin
o acids that is created when a gene is translated. Proteins carry out the bulk of cellular functions, including relaying signals, providing structural support, and accelerating biochemical reactions. Genes usually “work” by providing the blueprint for proteins (see DNA, p. 533). Proteins can be modified chemically by the addition of small chemicals such as phosphates or sugars or lipids.

  Proto-oncogene: A precursor to an oncogene. Typically, proto-oncogenes are normal cellular genes that, when activated by mutation or overexpression, promote cancer. Proto-oncogenes typically code for proteins that are associated with cell growth and differentiation. Examples of proto-oncogenes include ras and myc.

  Randomized trial: a trial in which treatment and control groups are randomly assigned.

  Retrovirus: an RNA virus that keeps its genes in the form of RNA and is capable, by virtue of an enzyme, reverse transcriptase, to convert its genes from the RNA form into a DNA form.

  Reverse transcriptase: An enzyme that converts a chain of RNA into a chain of DNA. Reverse transcription is a property of retroviruses.

  RNA: Ribonucleic acid, a chemical that performs several functions in the cells, including acting as an “intermediate” message for a gene to become a protein. Certain viruses also use RNA, not DNA, to maintain their genes (see Retrovirus, above).

  Secondary prevention: Prevention strategies that are aimed at early detection of a disease, typically by screening asymptomatic men and women. Typically, secondary prevention strategies attack early, pre-symptomatic stages of the disease.

  Transfection: the introduction of DNA into a cell.

  Transgenic mice: mice in which a genetic change has been artificially introduced.

  Translocation (of a gene): the physical reattachment of a gene from one chromosome to another.

  Tumor suppressor gene (also called anti-oncogene): A gene that, when inactivated fully, promotes the progression of a cell into a cancer cell. Tumor suppressors usually protect a cell from one step on the progression toward cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer. Typically, this occurs in combination with other genetic changes.