Taming the dragon: genomic biomarkers to individualize the treatment of cancer

The gradual shift from cytotoxic drugs to highly selective, targeted therapeutic agents for cancer requires a parallel effort to characterize cancers at the molecular level to guide the choice of therapy for the individual patient. Here we review the genomic technologies that can be used to develop these drug response indicators, or biomarkers. We also discuss hurdles in their development and the implementation of biomarkers in clinical practice.

[1]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

[2]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  C. Grady,et al.  How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. , 2009, Journal of the National Cancer Institute.

[4]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[5]  S. Nishizuka,et al.  Reverse-phase protein lysate microarrays for cell signaling analysis , 2008, Nature Protocols.

[6]  Jan Koster,et al.  NF1 Is a Tumor Suppressor in Neuroblastoma that Determines Retinoic Acid Response and Disease Outcome , 2010, Cell.

[7]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[8]  M. Caligiuri,et al.  IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Sabine Tejpar,et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. , 2010, The Lancet. Oncology.

[10]  Ryan D. Morin,et al.  Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution , 2009, Nature.

[11]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[12]  Young Lim Choi,et al.  EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. , 2010, The New England journal of medicine.

[13]  K. Flaherty,et al.  Inhibition of mutated, activated BRAF in metastatic melanoma. , 2010, The New England journal of medicine.

[14]  Steven P Gygi,et al.  Akt–RSK–S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases , 2010, Science Signaling.

[15]  Kam Y. J. Zhang,et al.  Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma , 2010, Nature.

[16]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[17]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[18]  Francesca Molinari,et al.  PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. , 2009, Cancer research.

[19]  Van,et al.  A gene-expression signature as a predictor of survival in breast cancer. , 2002, The New England journal of medicine.

[20]  M. Ringnér,et al.  Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity , 2007, Proceedings of the National Academy of Sciences.

[21]  J. Peterse,et al.  Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH , 2008, Breast Cancer Research and Treatment.

[22]  Alan Ashworth,et al.  A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Gudrun Schleiermacher,et al.  Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma , 2008, Nature.

[24]  Francisco M. De La Vega,et al.  Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing , 2010, Science Translational Medicine.

[25]  S J Chen,et al.  Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. , 1999, Blood.

[26]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[27]  F. Ducray,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.

[28]  Amy E. Hawkins,et al.  DNA sequencing of a cytogenetically normal acute myeloid leukemia genome , 2008, Nature.

[29]  P. Devilee,et al.  Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH , 2012, Breast Cancer Research and Treatment.

[30]  R M Stone,et al.  Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib , 2008, Leukemia.

[31]  Raoul Tibes,et al.  Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. , 2009, The New England journal of medicine.

[32]  L. Liau,et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate , 2009, Nature.

[33]  M. Stratton,et al.  Use of cancer‐specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors , 2010, Genes, chromosomes & cancer.

[34]  Silvia Benvenuti,et al.  Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. , 2005, The Lancet. Oncology.

[35]  Theresa Zhang,et al.  Pathway-Based Identification of Biomarkers for Targeted Therapeutics: Personalized Oncology with PI3K Pathway Inhibitors , 2010, Science Translational Medicine.

[36]  R. Pazdur,et al.  Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  W. McGuire,et al.  The importance of estrogen and progesterone receptor in primary breast cancer. , 1983, Progress in clinical and biological research.

[38]  L. Carey,et al.  CYP2D6 and tamoxifen: DNA matters in breast cancer , 2009, Nature Reviews Cancer.

[39]  A. Ashworth,et al.  Targeting the DNA repair defect of BRCA tumours. , 2005, Current opinion in pharmacology.

[40]  Tom Royce,et al.  A comprehensive catalogue of somatic mutations from a human cancer genome , 2010, Nature.

[41]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[42]  S. Ogawa,et al.  Oncogenic mutations of ALK kinase in neuroblastoma , 2008, Nature.

[43]  R. Diasio,et al.  Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy. , 2004, Clinical advances in hematology & oncology : H&O.

[44]  D. Haber,et al.  Circulating tumor cells: a window into cancer biology and metastasis. , 2010, Current opinion in genetics & development.

[45]  A. Sparks,et al.  The mutation spectrum revealed by paired genome sequences from a lung cancer patient , 2010, Nature.

[46]  A. V. van Kuilenburg,et al.  Increased risk of grade IV neutropenia after administration of 5‐fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: High prevalence of the IVS14+1g>a mutation , 2002, International journal of cancer.

[47]  W. Kaelin The Concept of Synthetic Lethality in the Context of Anticancer Therapy , 2005, Nature Reviews Cancer.

[48]  Zhen-yi Wang,et al.  Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. , 1988, Haematology and blood transfusion.

[49]  Joshy George,et al.  Integrated Genome-Wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemoresistance in Ovarian Carcinomas , 2009, Clinical Cancer Research.

[50]  L. V. van't Veer,et al.  Clinical application of the 70-gene profile: the MINDACT trial. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[52]  S. Goodman,et al.  Circulating mutant DNA to assess tumor dynamics , 2008, Nature Medicine.

[53]  V. Jordan,et al.  Tamoxifen: a most unlikely pioneering medicine , 2003, Nature Reviews Drug Discovery.

[54]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[55]  Adrian V. Lee,et al.  Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer , 2010, Breast Cancer Research.

[56]  E. Birney,et al.  A small cell lung cancer genome reports complex tobacco exposure signatures , 2009, Nature.

[57]  Derek Y. Chiang,et al.  EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer , 2008, Clinical Cancer Research.

[58]  H. Gómez,et al.  Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[60]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[61]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[62]  Frank Diehl,et al.  BEAMing up for detection and quantification of rare sequence variants , 2006, Nature Methods.

[63]  A. Iafrate,et al.  Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. , 2008, Cancer research.

[64]  M. Casey,et al.  A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses , 2008, Breast Cancer Research and Treatment.

[65]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[66]  Mehmet Toner,et al.  Detection of mutations in EGFR in circulating lung-cancer cells. , 2008, The New England journal of medicine.

[67]  S. Hanash,et al.  The grand challenge to decipher the cancer proteome , 2010, Nature Reviews Cancer.

[68]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[69]  R. Chiu,et al.  Next-generation sequencing of plasma/serum DNA: an emerging research and molecular diagnostic tool. , 2009, Clinical chemistry.

[70]  Gary D Bader,et al.  International network of cancer genome projects , 2010, Nature.

[71]  H. Varmus,et al.  KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib , 2005, PLoS medicine.

[72]  K. Coombes,et al.  Deriving chemosensitivity from cell lines: Forensic bioinformatics and reproducible research in high-throughput biology , 2009, 1010.1092.

[73]  Klaus Pantel,et al.  Circulating tumour cells in cancer patients: challenges and perspectives. , 2010, Trends in molecular medicine.

[74]  C. Streuli Faculty Opinions recommendation of EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. , 2004 .

[75]  L. Mazzucchelli,et al.  Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[77]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[78]  Tak W. Mak,et al.  Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations , 2010, The Journal of experimental medicine.

[79]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[80]  C. Sawyers,et al.  Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. , 2007, The Journal of clinical investigation.

[81]  Richard Pazdur,et al.  Tasigna for Chronic and Accelerated Phase Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia Resistant to or Intolerant of Imatinib , 2008, Clinical Cancer Research.

[82]  K. Coombes,et al.  Microarrays: retracing steps , 2007, Nature Medicine.

[83]  Derek Y. Chiang,et al.  Subtype-specific genomic alterations define new targets for soft tissue sarcoma therapy , 2010, Nature Genetics.

[84]  Ken Chen,et al.  Recurring mutations found by sequencing an acute myeloid leukemia genome. , 2009, The New England journal of medicine.

[85]  H. Dressman,et al.  Genomic signatures to guide the use of chemotherapeutics , 2006, Nature Medicine.

[86]  J. Schapiro,et al.  Drug-resistance genotyping in HIV-1 therapy: the VIRAD APT randomi sed controlled trial , 1999, The Lancet.

[87]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[88]  Tian-Li Wang,et al.  Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma , 2010, Science.

[89]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[90]  F. Monzon,et al.  Diagnosis of metastatic neoplasms: molecular approaches for identification of tissue of origin. , 2010, Archives of pathology & laboratory medicine.

[91]  D. Gary Gilliland,et al.  Activating mutations in ALK provide a therapeutic target in neuroblastoma , 2008, Nature.

[92]  A. Ashworth,et al.  Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. , 2008, Cancer cell.

[93]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[94]  J. Cohen,et al.  Re: How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. , 2010, Journal of the National Cancer Institute.

[95]  Richard A. Moore,et al.  ARID1A mutations in endometriosis-associated ovarian carcinomas. , 2010, The New England journal of medicine.

[96]  M. Hammond,et al.  Variable specimen handling affects hormone receptor test results in women with breast cancer: a large multihospital retrospective study. , 2010, Archives of pathology & laboratory medicine.

[97]  J. Sparano,et al.  TAILORx: trial assigning individualized options for treatment (Rx). , 2006, Clinical breast cancer.

[98]  W. McGuire,et al.  Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[99]  Emmanuel Barillot,et al.  Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells , 2008, Breast Cancer Research.

[100]  D. Berry,et al.  I‐SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy , 2009, Clinical pharmacology and therapeutics.

[101]  A. Gemma,et al.  F1000 highlights , 2010 .

[102]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[103]  Michael S. Krzemnicki,et al.  Challenges and perspectives , 2009 .

[104]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[105]  M. Moroni,et al.  Somatic mutation of EGFR catalytic domain and treatment with gefitinib in colorectal cancer. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[106]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[107]  A. Iafrate,et al.  Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling , 2007, Proceedings of the National Academy of Sciences.

[108]  Omar Abdel-Wahab,et al.  The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. , 2010, Cancer cell.

[109]  U. Germing,et al.  Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies , 2006, Clinical Cancer Research.

[110]  A. Bardelli,et al.  Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. , 2010, JAMA.

[111]  Manuel Hidalgo,et al.  Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[113]  Violeta Serra,et al.  Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. , 2008, Cancer research.

[114]  J. Asara Faculty Opinions recommendation of Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors. , 2010 .

[115]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[116]  J. Singer,et al.  UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia , 2007, Leukemia.

[117]  Joshua F. McMichael,et al.  Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft , 2010, Nature.

[118]  I. Weinstein Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[119]  G. Mills,et al.  Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. , 2009, Cancer research.

[120]  Karthik Devarajan,et al.  Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies , 2010, Science Signaling.

[121]  L. Wessels,et al.  Do predictive signatures really predict response to cancer chemotherapy? , 2010, Cell cycle.

[122]  M. Ychou,et al.  Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[123]  A. D. Van den Abbeele,et al.  Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. , 2002, The New England journal of medicine.

[124]  J. Maguire,et al.  Solution Hybrid Selection with Ultra-long Oligonucleotides for Massively Parallel Targeted Sequencing , 2009, Nature Biotechnology.

[125]  K. Hede Breast cancer testing scandal shines spotlight on black box of clinical laboratory testing. , 2008, Journal of the National Cancer Institute.

[126]  Z. Estrov,et al.  Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. , 2010, Blood.