410 In 1982, a postdoctoral scientist: Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998), 17.
411 "It would have been an overnight test": Ibid.
411 although Padhy's discovery was published: Lakshmi Charon Padhy et al., "Identification of a Phosphoprotein Specifically Induced by the Transforming DNA of Rat Neuroblastomas," Cell 28, no. 4 (1982): 865-71.
A City of Strings
412 In Ersilia, to establish the relationships: Italo Calvino, Invisible Cities (Boston: Houghton Mifflin Harcourt, 1978), 76.
412 In his book Invisible Cities: Ibid.
413 In the summer of 1984: Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998).
414 In 1982, Genentech unveiled the first: "A New Insulin Given Approval for Use in U.S.," New York Times, October 30, 1982.
414 in 1984, it produced a clotting factor: "Genentech Corporate Chronology," http://www .gene.com/gene/about/corporate/history/timeline.html (accessed January 30, 2010).
414 in 1985, it created a recombinant version: Ibid.
414 It was under the aegis: L. Coussens et al., "3 Groups Discovered the Neu Homolog (Her-2, Also Called Erb-b2)," Science 230 (1985): 1132-39. Also see T. Yamamoto et al., Nature 319 (1986): 230-34, and C. King et al., Science 229 (1985): 974-76.
415 In the summer of 1986: Bazell, Her-2, and Dennis Slamon, interview with author, April 2010.
415 Dennis Slamon, a UCLA oncologist: Ibid.
415 a "velvet jackhammer": Eli Dansky, "Dennis Slamon: From New Castle to New Science," SU2C Mag, http://www.standup2cancer.org/node/194 (accessed January 24, 2010).
415 "a murderous resolve": Ibid.
415 In Chicago, Slamon had performed a series: See, for example, I. S. Chen et al., "The x Gene Is Essential for HTLV Replication," Science 229, no. 4708 (1985): 54-58; W. Wachsman et al., "HTLV x Gene Mutants Exhibit Novel Transcription Regulatory Phenotypes," Science 235, no. 4789 (1987): 647-77; C. T. Fang et al., "Detection of Antibodies to Human T-Lymphotropic Virus Type 1 (HTLV-1)," Transfusion 28, no. 2 (1988): 179-83.
415 If Ullrich sent him the DNA probes: Details of the Ullrich and Slamon collaboration are outlined in Bazell, Her-2, and from Slamon, interview with author.
416 In a few months: D. Slamon et al., "Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the Her-2/Neu Oncogene," Science 235 (1987): 177-82.
417 In the mid-1970s, two immunologists at Cambridge University: See Nobel Lectures, Physiology or Medicine, 1981-1990, ed. Jan Lindsten (Singapore: World Scientific Publishing, 1993).
418 "allergic to cancer": Merrill Goozner, The $800 Million Pill: The Truth Behind the Cost of New Drugs (Berkeley: University of California Press, 2004), 195.
418 Drained and dejected: Ibid.
418 "Nobody gave a shit": Bazell, Her-2, 49.
419 "When I was finished with all that": Ibid. Also Barbara Bradfield, interview with author, July 2008.
419 But there was more river to ford: Ibid.
420 "His tone changed," she recalled: Ibid.
420 "I was at the end of my road": Ibid
420 "Survivors look back and see omens": Joan Didion, The Year of Magical Thinking (New York: Vintage, 2006), 152.
420 On a warm August morning in 1992: Bradfield, interview with author. Details of the trial and the treatment are from Bradfield's interview, from Bazell's Her-2, and from Slamon, interview with author, April 2010.
Drugs, Bodies, and Proof
423 Dying people don't have time or energy: "Dying for Compassion," Breast Cancer Action Newsletter 31 (August 1995).
423 It seemed as if we had: Musa Mayer, Breast Cancer Action Newsletter 80 (February/March 2004).
423 "True success happens": Breast Cancer Action Newsletter 32 (October 1995).
424 The number of women enrolled in these trials: Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998), 160-80.
424 "We do not provide . . . compassionate use": Ibid., 117.
424 "If you start making exceptions": Ibid., 127.
424 "Why do women dying of breast cancer": "Dying for Compassion," Breast Cancer Action Newsletter.
424 "Scientific uncertainty is no excuse": Charlotte Brody et al., "Rachel's Daughters, Searching for the Causes of Breast Cancer: A Light-Saraf-Evans Production Community Action & Resource Guide," http://www.wmm.com/filmCatalog/study/rachelsdaughters.pdf (accessed January 31, 2010).
424 Marti Nelson, for one, certainly could not: Marti Nelson's case and its aftermath are described in Bazell, Her-2.
427 On Sunday, May 17: Bruce A. Chabner, "ASCO 1998: A Commentary," Oncologist 3, no. 4 (1998): 263-66; D. J. Slamon et al., "Addition of Herceptin to First-Line Chemotherapy for HER-2 Overexpressing Metastatic Breast Cancer Markedly Increases Anti-Cancer Activity: A Randomized, Multinational Controlled Phase III Trial (abstract 377)," Proceedings of the American Society of Clinical Oncology 16 (1998): 377.
427 In the pivotal 648 study: Slamon et al., "Addition of Herceptin to First-Line Chemotherapy," 377.
428 In 2003, two enormous multinational studies: Romond et al. and Piccart-Gebhart et al., New England Journal of Medicine 353 (2005): 1659-84.
428 "The results," one oncologist wrote: Gabriel Hortobagyi, "Trastuzumab in the treatment of breast cancer," editorial, New England Journal of Medicine, 353, no. 16 (2005): 1734.
428 "The company," Robert Bazell, the journalist: Bazell, Her-2, 180-82.
A Four-Minute Mile
430 The nontoxic curative compound: James F. Holland, "Hopes for Tomorrow versus Realities of Today: Therapy and Prognosis in Acute Lymphocytic Leukemia of Childhood," Pediatrics 45:191-93.
430 Why, it is asked, does the supply of new miracle drugs: Lewis Thomas, The Lives of a Cell (New York: Penguin, 1978), 115.
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 Jurg Zimmermann, "The Story of Gleevec," innovation.org, http://www.innovation.org/index.cfm/StoriesofInnovation/InnovatorStories/The_Story_of_Gleevec (accessed January 31, 2010).
433 Jurg 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 siecle": Harold J. Burstein, "Cancer at the Fin de Siecle," 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 Sjoblom 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 Sjoblom 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; Sian 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 Fa
milial 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.
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 66
