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Somatic variation and cancer: therapies lost in the mix


Cancer arises as a consequence of mutations in genomes of cancer cells, which over time allow them to proliferate and spread to distant sites. Large-scale sequencing of cancer genomes is revealing an increasing number of potential driver mutations that may allow specific targeting of cancer genes, proteins, and pathways. Comprehensive views of cancer genomes are also revealing enormous heterogeneity of mutation profiles, even among tumours derived from the same organs and having similar pathological characteristics. There are now many examples where mutation profiles observed in tumours have been shown to correlate with clinical features of disease, drug response, and patient outcomes. When ignored, molecular heterogeneity can lead to failures in drug development, as drugs that may have efficacy in subgroups of patients with specific molecular phenotypes may show marginal response when tested in large groups of unselected patients. This article explores issues relevant to the clinical translation of sequence-based mutation profiles in the clinical development of targeted therapies and in the future management of cancer patients.

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  1. (2011a) Cancer drugs: remedy required. Nat Med 17:231

  2. (2011b) Regulatory watch: FDA guidance on co-developing investigational drugs. Nat Rev Drug Discov 10:86.

  3. Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL (2009) American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091–2096

  4. Andre F, McShane LM, Michiels S, Ransohoff DF, Altman DG, Reis-Filho JS, Hayes DF, Pusztai L (2011) Biomarker studies: a call for a comprehensive biomarker study registry. Nat Rev Clin Oncol 8:171–176

  5. Arrowsmith J (2011) Trial watch: phase III and submission failures: 2007–2010. Nat Rev Drug Discov 10:87

  6. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697

  7. Bates SE (2010) Striving to improve outcomes in oncology: unmet expectations in a complex disease. Clin Cancer Res 16:5950

  8. Beerenwinkel N, Antal T, Dingli D, Traulsen A, Kinzler KW, Velculescu VE, Vogelstein B, Nowak MA (2007) Genetic progression and the waiting time to cancer. PLoS Comput Biol 3:e225

  9. Buchler P, Reber HA, Eibl G, Roth MA, Buchler MW, Friess H, Isacoff WH, Hines OJ (2005) Combination therapy for advanced pancreatic cancer using Herceptin plus chemotherapy. Int J Oncol 27:1125–1130

  10. Burch PA, Ghosh C, Schroeder G, Allmer C, Woodhouse CL, Goldberg RM, Addo F, Bernath AM, Tschetter LK, Windschitl HE, Cobau CD (2000) Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial. Am J Clin Oncol 23:534–537

  11. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

  12. Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, Kladny J, Gorski B, Lubinski J, Narod S (2009) Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115:359–363

  13. Cagle PT, Allen TC, Dacic S, Beasley MB, Borczuk AC, Chirieac LR, Laucirica R, Ro JY, Kerr KM (2011) Revolution in lung cancer: new challenges for the surgical pathologist. Arch Pathol Lab Med 135:110–116

  14. Caponigro G, Sellers WR (2011) Advances in the preclinical testing of cancer therapeutic hypotheses. Nat Rev Drug Discov 10:179–187

  15. Chin L, Gray JW (2008) Translating insights from the cancer genome into clinical practice. Nature 452:553–563

  16. Chin L, Andersen JN, Futreal PA (2011) Cancer genomics: from discovery science to personalized medicine. Nat Med 17:297–303

  17. Clark-Knowles KV, O’Brien AM, Weberpals JI (2010) BRCA1 as a therapeutic target in sporadic epithelial ovarian cancer. J Oncol 2010:891059

  18. Cordon-Cardo C (2004) p53 and RB: simple interesting correlates or tumor markers of critical predictive nature? J Clin Oncol 22:975–977

  19. Croce CM (2008) Oncogenes and cancer. N Engl J Med 358:502–511

  20. da Cunha Santos G, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, Squire J, Parulekar W, Moore MJ, Tsao MS (2010) Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer 116:5599–5607

  21. Doroshow JH (2010) Selecting systemic cancer therapy one patient at a time: is there a role for molecular profiling of individual patients with advanced solid tumors? J Clin Oncol 28:4869–4871

  22. EBCTCG (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

  23. Editorial (2010) Trial watch: adaptive BATTLE trial uses biomarkers to guide lung cancer treatment. Nat Rev Drug Discov 9:423

  24. Esteva FJ, Yu D, Hung MC, Hortobagyi GN (2010) Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol 7:98–107

  25. Farrell A (2011) A close look at cancer. Nat Med 17:262–265

  26. Freidlin B, McShane LM, Korn EL (2010) Randomized clinical trials with biomarkers: design issues. J Natl Cancer Inst 102:152–160

  27. Gerber DE, Minna JD (2010) ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell 18:548–551

  28. Green ED, Guyer MS (2011) Charting a course for genomic medicine from base pairs to bedside. Nature 470:204–213

  29. Gruver AM, Portier BP, Tubbs RR (2011) Molecular pathology of breast cancer: the journey from traditional practice toward embracing the complexity of a molecular classification. Arch Pathol Lab Med 135:544–557

  30. Hall J, Dennler P, Haller S, Pratsinis A, Sauberli K, Towbin H, Walthe K, Woytschak J (2010) Genomics drugs in clinical trials. Nat Rev Drug Discov 9:988

  31. Harries M, Smith I (2002) The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer 9:75–85

  32. Harris T (2010) Gene and drug matrix for personalized cancer therapy. Nat Rev Drug Discov 9:660

  33. Hood L, Friend SH (2011) Predictive, personalized, preventive, participatory (P4) cancer medicine. Nat Rev Clin Oncol 8:184–187

  34. Hutchinson L (2011) Personalized cancer medicine: era of promise and progress. Nat Rev Clin Oncol 8:121

  35. ICGC (2010) International network of cancer genome projects. Nature 464:993–998

  36. Isacoff WH, Bendetti JK, Barstis JJ, Jazieh AR, Macdonald JS, Philip PA (2007) Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700. J Clin Oncol 25:1665–1669

  37. Jimeno A, Tan AC, Coffa J, Rajeshkumar NV, Kulesza P, Rubio-Viqueira B, Wheelhouse J, Diosdado B, Messersmith WA, Iacobuzio-Donahue C, Maitra A, Varella-Garcia M, Hirsch FR, Meijer GA, Hidalgo M (2008) Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer. Cancer Res 68:2841–2849

  38. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972

  39. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806

  40. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765

  41. Khleif SN, Doroshow JH, Hait WN (2010) AACR-FDA-NCI Cancer Biomarkers Collaborative consensus report: advancing the use of biomarkers in cancer drug development. Clin Cancer Res 16:3299–3318

  42. Kim ES, Herbst1 RS et al. (2011) The BATTLE Trial: personalizing therapy for lung cancer. Cancer Discov 1

  43. Kimura K, Sawada T, Komatsu M, Inoue M, Muguruma K, Nishihara T, Yamashita Y, Yamada N, Ohira M, Hirakawa K (2006) Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res 12:4925–4932

  44. Kovacs A, Stenman G (2010) HER2-testing in 538 consecutive breast cancer cases using FISH and immunohistochemistry. Pathol Res Pract 206:39–42

  45. Lee CK, Lord SJ, Coates AS, Simes RJ (2009) Molecular biomarkers to individualise treatment: assessing the evidence. Med J Aust 190:631–636

  46. Liede A, Karlan BY, Narod SA (2004) Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22:735–742

  47. Link DC, Schuettpelz LG, Shen D, Wang J, Walter MJ, Kulkarni S, Payton JE, Ivanovich J, Goodfellow PJ, Le Beau M, Koboldt DC, Dooling DJ, Fulton RS, Bender RH, Fulton LL, Delehaunty KD, Fronick CC, Appelbaum EL, Schmidt H, Abbott R, O’Laughlin M, Chen K, McLellan MD, Varghese N, Nagarajan R, Heath S, Graubert TA, Ding L, Ley TJ, Zambetti GP, Wilson RK, Mardis ER (2011) Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML. JAMA 305:1568–1576

  48. LoRusso PM, Schnipper LE, Stewart DJ, Boerner SA, Averbuch SD, Wolf W (2010) Translating clinical trials into meaningful outcomes. Clin Cancer Res 16:5951–5955

  49. Macconaill LE, Garraway LA (2010) Clinical implications of the cancer genome. J Clin Oncol 28:5219–5228

  50. MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MA, Polyak K, Chan J, Wang Y, Fletcher JA, Santagata S, Corso G, Roviello F, Shivdasani R, Kieran MW, Ligon KL, Stiles CD, Hahn WC, Meyerson ML, Garraway LA (2009) Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 4:e7887

  51. Majewski IJ, Bernards R (2011) Taming the dragon: genomic biomarkers to individualize the treatment of cancer. Nat Med 17:304–312

  52. Mandrekar SJ, Sargent DJ (2009) Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol 27:4027–4034

  53. McClellan M, Benner J, Schilsky R, Epstein D, Woosley R, Friend S, Sidransky D, Geoghegan C, Kessler D (2011) An accelerated pathway for targeted cancer therapies. Nat Rev Drug Discov 10:79–80

  54. McDermott U, Downing JR, Stratton MR (2011) Genomics and the continuum of cancer care. N Engl J Med 364:340–350

  55. Mellinghoff IK, Sawyers CL (2002) The emergence of resistance to targeted cancer therapeutics. Pharmacogenomics 3:603–623

  56. Mendelsohn J, Tursz T, Schilsky RL, Lazar V (2011) WIN Consortium-challenges and advances. Nat Rev Clin Oncol 8:133–134

  57. Michalski CW, Weitz J, Buchler MW (2007) Surgery insight: surgical management of pancreatic cancer. Nat Clin Pract Oncol 4:526–535

  58. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966

  59. Nathanson KL (2010) Using genetics and genomics strategies to personalize therapy for cancer: focus on melanoma. Biochem Pharmacol 80:755–761

  60. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977

  61. Nelson NJ (2010) Adaptive clinical trial design: has its time come? J Natl Cancer Inst 102:1217–1218

  62. Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Buchler MW (2001) Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 358:1576–1585

  63. Ocana A, Tannock IF (2011) When are “positive” clinical trials in oncology truly positive? J Natl Cancer Inst 103:16–20

  64. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H (2007) Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297:267–277

  65. Pajic M, Scarlett CJ, Chang DK, Sutherland RL, Biankin AV (2011) Preclinical strategies to define predictive biomarkers for therapeutically relevant cancer subtypes. Hum Genet. doi:10.1007/s00439-011-0990-0

  66. Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q, Cao X, Suleman K, Kumar-Sinha C, Dhanasekaran SM, Chen YB, Esgueva R, Banerjee S, LaFargue CJ, Siddiqui J, Demichelis F, Moeller P, Bismar TA, Kuefer R, Fullen DR, Johnson TM, Greenson JK, Giordano TJ, Tan P, Tomlins SA, Varambally S, Rubin MA, Maher CA, Chinnaiyan AM (2010) Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16:793–798

  67. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

  68. Philip PA, Mooney M, Jaffe D, Eckhardt G, Moore M, Meropol N, Emens L, O’Reilly E, Korc M, Ellis L, Benedetti J, Rothenberg M, Willett C, Tempero M, Lowy A, Abbruzzese J, Simeone D, Hingorani S, Berlin J, Tepper J (2009) Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol 27:5660–5669

  69. Polyak K, Garber J (2011) Targeting the missing links for cancer therapy. Nat Med 17:283–284

  70. Rodríguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17:330–339

  71. Rosenberger WF, Lachin JM (1993) The use of response-adaptive designs in clinical trials. Control Clin Trials 14:471–484

  72. Safran H, Iannitti D, Ramanathan R, Schwartz JD, Steinhoff M, Nauman C, Hesketh P, Rathore R, Wolff R, Tantravahi U, Hughes TM, Maia C, Pasquariello T, Goldstein L, King T, Tsai JY, Kennedy T (2004) Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 22:706–712

  73. Sargent DJ, Conley BA, Allegra C, Collette L (2005) Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 23:2020–2027

  74. Schilsky RL (2010) Personalized medicine in oncology: the future is now. Nat Rev Drug Discov 9:363–366

  75. Seruga B, Hertz PC, Wang L, Booth CM, Cescon DW, Krzyzanowska M, Tannock IF (2010) Absolute benefits of medical therapies in phase III clinical trials for breast and colorectal cancer. Ann Oncol 21:1411–1418

  76. Shekhar MP (2011) Drug resistance: challenges to effective therapy. Curr Cancer Drug Targets 11:613–623

  77. Showalter SL, Charles S, Belin J, Cozzitorto J, Einstein P, Richards NG, Sauter PK, Kennedy EP, Witkiewicz A, Brody JR, Yeo CJ (2010) Identifying pancreatic cancer patients for targeted treatment: the challenges and limitations of the current selection process and vision for the future. Expert Opin Drug Deliv 7:273–284

  78. Solit DB, Rosen N (2011) Resistance to BRAF inhibition in melanomas. N Engl J Med 364:772–774

  79. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724

  80. Tabernero J, Macarulla T (2009) Changing the paradigm in conducting randomized clinical studies in advanced pancreatic cancer: an opportunity for better clinical development. J Clin Oncol 27:5487–5491

  81. TCGA CGARN (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

  82. TCGA (2008b) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

  83. Tursz T, Andre F, Lazar V, Lacroix L, Soria JC (2011) Implications of personalized medicine-perspective from a cancer center. Nat Rev Clin Oncol 8:177–183

  84. van der Heijden MS, Brody JR, Gallmeier E, Cunningham SC, Dezentje DA, Shen D, Hruban RH, Kern SE (2004) Functional defects in the Fanconi anemia pathway in pancreatic cancer cells. Am J Pathol 165:651–657

  85. van der Heijden MS, Brody JR, Dezentje DA, Gallmeier E, Cunningham SC, Swartz MJ, DeMarzo AM, Offerhaus GJ, Isacoff WH, Hruban RH, Kern SE (2005) In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 11:7508–7515

  86. Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, De Jesus-Acosta A, Jones S, Maitra A, Hruban RH, Eshleman JR, Klein A, Laheru D, Donehower R, Hidalgo M (2011) Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther 10:3–8

  87. Von Hoff DD, Stephenson JJ Jr, Rosen P, Loesch DM, Borad MJ, Anthony S, Jameson G, Brown S, Cantafio N, Richards DA, Fitch TR, Wasserman E, Fernandez C, Green S, Sutherland W, Bittner M, Alarcon A, Mallery D, Penny R (2010) Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol 28:4877–4883

  88. Wheeler DL, Dunn EF, Harari PM (2010) Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 7:493–507

  89. Wistuba II, Gelovani JG, Jacoby JJ, Davis SE, Herbst RS (2011) Methodological and practical challenges for personalized cancer therapies. Nat Rev Clin Oncol 8:135–141

  90. Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, Wang W, Livingston DM, Joenje H, de Winter JP (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39:159–161

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Biankin, A.V., Hudson, T.J. Somatic variation and cancer: therapies lost in the mix. Hum Genet 130, 79–91 (2011).

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  • Pancreatic Cancer
  • Gemcitabine
  • Trastuzumab
  • Sorafenib
  • Erlotinib