Perspectives | Published:

Molecular prescreening to select patient population in early clinical trials

Nature Reviews Clinical Oncology volume 9, pages 359366 (2012) | Download Citation


The efficacy of targeted therapies in patient populations selected for treatment on the basis of the molecular features of their tumours is shifting the current focus of treatment to biomarker-driven clinical trials. Phase I trials provide an arena for early hypothesis testing, examining not only safety and toxicity, but also target engagement, biologically effective dosages, and the appropriate patient population. In this Perspectives article, we describe this new trend in early drug development, establishing the different approaches for building a pre-screening programme in an academic institution that is involved in early drug development. Our experience establishing the phase I programme at Vall d'Hebrón serves as an example of how these approaches can be integrated in ongoing trials, and we believe these considerations will help others to implement similar programmes in their institutions.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Mapping copy number variation by population-scale genome sequencing. Nature 470, 59–65 (2011).

  2. 2.

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  3. 3.

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  4. 4.

    et al. International network of cancer genome projects. Nature 464, 993–998 (2010).

  5. 5.

    et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr. Protoc. Hum. Genet. Ch. 10, Unit 10 11 (2008).

  6. 6.

    et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–950 (2011).

  7. 7.

    et al. Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc. Natl Acad. Sci. USA 104, 19936–19941 (2007).

  8. 8.

    et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

  9. 9.

    et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12, 852–861 (2011).

  10. 10.

    et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

  11. 11.

    et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N. Engl. J. Med. 352, 895–904 (2005).

  12. 12.

    et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

  13. 13.

    Trastuzumab--mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).

  14. 14.

    et al. Cancer pharmacogenomics. Clin. Pharmacol. Ther. 90, 461–466 (2011).

  15. 15.

    , , & Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10, 514–523 (2010).

  16. 16.

    et al. Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br. J. Cancer 95, 581–586 (2006).

  17. 17.

    et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 2505–2512 (2006).

  18. 18.

    et al. ERK1/2 phosphorylation: a biomarker analysis within a phase I study with the new Raf kinase inhibitor BAY43–9006 Int. J. Clin. Pharmacol. Ther. 40, 567–568 (2002).

  19. 19.

    et al. A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors. Clin. Cancer Res. 17, 6313–6321 (2011).

  20. 20.

    , & The phase III trial in the era of targeted therapy: unraveling the “go or no go” decision. J. Clin. Oncol. 21, 3683–3695 (2003).

  21. 21.

    et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 3, 772–775 (2004).

  22. 22.

    Wellcome Trust Sanger Institute. Cosmic: Catalogue of somatic mutations in cancer .

  23. 23.

    et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14, 320–368 (2009).

  24. 24.

    et al. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry 48, 5339–5349 (2009).

  25. 25.

    , & Clinical studies of histone deacetylase inhibitors. Clin. Cancer Res. 15, 3958–3969 (2009).

  26. 26.

    & Anti-VEGF therapy: the search for clinical biomarkers. Expert Rev. Mol. Diagn. 8, 301–314 (2008).

  27. 27.

    et al. 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 (2010).

  28. 28.

    et al. Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative [abstract]. J. Clin. Oncol. 29 (suppl.), CRA2500 (2011).

  29. 29.

    , , , & Novel therapeutic targets. in non-small cell lung cancer. J. Thorac Oncol. 6, 1601–1612 (2011).

  30. 30.

    et al. Personalized treatment of lung cancer. Semin. Oncol. 38, 274–283 (2011).

  31. 31.

    et al. Project Zero Delay: a process for accelerating the activation of cancer clinical trials. J. Clin. Oncol. 27, 4433–4440 (2009).

  32. 32.

    et al. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur. J. Surg. Oncol. 36, 657–662 (2010).

  33. 33.

    et al. p53 mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 53, 2231–2234 (1993).

  34. 34.

    et al. MDM2 amplification and loss of heterozygosity at Rb and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas. J. Cancer Res. Clin. Oncol. 124, 532–540 (1998).

  35. 35.

    et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221–9230 (2008).

  36. 36.

    et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68, 8022–8030 (2008).

  37. 37.

    & Trastuzumab-DM1: building a chemotherapy-free road in the treatment of human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 29, 351–354 (2011).

  38. 38.

    Targeted therapies: chemotherapy-free option for relapsed patients with breast cancer. Nat. Rev. Clin. Oncol. 8, 317 (2011).

  39. 39.

    et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther. 8, 1725–1738 (2009).

  40. 40.

    et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–290 (2011).

  41. 41.

    et al. First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl.), a3005 (2010).

  42. 42.

    Presented at the Keystone symposia, PI 3-Kinase Signaling Pathways. (Keystone, Colorado, 2011).

  43. 43.

    Methods of molecular analysis: mutation detection in solid tumours. Mol. Pathol. 55, 73–79 (2002).

  44. 44.

    Genotyping technologies for genetic research. Annu. Rev. Genomics Hum. Genet. 10, 117–133 (2009).

  45. 45.

    , & Parallel anticancer drug development and molecular stratification to qualify predictive biomarkers: dealing with obstacles hindering progress. Cancer Discov. 1, 207–212 (2011).

  46. 46.

    et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol. Med. 2, 146–158 (2010).

  47. 47.

    et al. Cancer genomics: technology, discovery, and translation. J. Clin. Oncol. 30, 647–660 (2010).

  48. 48.

    et al. Quantifying EGFR alterations in the lung cancer genome with nanofluidic digital PCR arrays. Clin. Chem. 56, 623–632 (2010).

  49. 49.

    et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).

  50. 50.

    et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

  51. 51.

    Human cancers express mutator phenotypes: origin, consequences and targeting. Nat. Rev. Cancer 11, 450–457 (2011).

  52. 52.

    & Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105–117 (2010).

  53. 53.

    , & Microvesicles: messengers and mediators of tumor progression. Cell Cycle 8, 2014–2018 (2009).

  54. 54.

    et al. Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. Br. J. Cancer 101, 1724–1730 (2009).

  55. 55.

    , , & Circulating tumor cells as pharmacodynamic biomarker in early clinical oncological trials. Cancer Treat Rev. 37, 579–589 (2011).

  56. 56.

    , , & Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer. Breast Cancer Res. Treat 123, 613–625 (2010).

  57. 57.

    et al. Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer. Ann. Surg. 251, 275–280 (2010).

  58. 58.

    et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359, 366–377 (2008).

  59. 59.

    et al. mRNA and microRNA expression profiles in circulating tumor cells and primary tumors of metastatic breast cancer patients. Clin. Cancer Res. 17, 3600–3618 (2011).

  60. 60.

    et al. Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci. Transl. Med. 3, 111ra121 (2011).

  61. 61.

    US National Library of Medicine. .

  62. 62.

    US National Library of Medicine. .

  63. 63.

    US National Library of Medicine. .

  64. 64.

    et al. An adaptive randomized discontinuation trial of XL184 (BMS-907351) in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl.), aTPS188 (2010).

  65. 65.

    et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379, 633–640 (2012).

  66. 66.

    & Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann. Oncol. 22, 1717–1725 (2011).

  67. 67.

    et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44–53 (2011).

  68. 68.

    BATTLE to personalize lung cancer treatment. Novel clinical trial design and tissue gathering procedures drive biomarker discovery. Cancer 116, 3307–3308 (2010).

  69. 69.

    , , & WIN Consortium--challenges and advances. Nat. Rev. Clin. Oncol. 8, 133–134 (2011).

  70. 70.

    et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12, 735–742 (2011).

  71. 71.

    et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737–744 (1996).

  72. 72.

    et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 (2006).

  73. 73.

    , & A phase II study of the dual MET/VEGFR2 inhibitor XL880 in patients with papillary renal carcinoma [abstract]. J. Clin. Oncol. 26 (Suppl.), a5103 (2008).

  74. 74.

    et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J. Clin. Oncol. 29, 1271–1279 (2011).

  75. 75.

    et al. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751, 871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 11, 129–135 (2009).

  76. 76.

    et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin. Cancer Res. 17, 2502–2511 (2011).

  77. 77.

    et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 361, 1173–1178 (2009).

  78. 78.

    et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

  79. 79.

    et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J. Clin. Oncol. 28, 2512–2519 (2010).

Download references


We thank Claudia Aura, Javier Hernandez, Jose Jimenez, Ludmila Prudkin, Elisabeth Llonch, Laurence Le Breton, Gessami Sanchez-Oller, Debora Moreno, Nuria Murtra, Irene Braña, Begoña Graña, Gemma Sala, Susana Muñoz, and many others for their work in the design, implementation and organization of the pre-screening programme. We also thank Javier Cortés, Joan Carles, Enriqueta Felip, Josep María del Campo, Joan Seoane, Violeta Serra, Leticia de Mattos, and Mafalda Oliveira for their support to this programme and scientific input in the design of it. We thank Malte Peters, Michael Goldbrunner, and Wolfgang Wick from Novartis for their commitment in prescreening patients for PI3K inhibitors. We also thank Joann Aaron (freelance writer, Houston, US) for scientific editing of this article.

Author information


  1. Medical Oncology Department, Vall d'Hebrón University Hospital, Spain

    • Jordi Rodón
    • , Cristina Saura
    • , Rodrigo Dienstmann
    •  & Josep Tabernero
  2.  Pathology Department, Vall d'Hebrón University Hospital, Spain

    • Santiago Ramón y Cajal
  3.  Vall d'Hebrón Institute of Oncology, Passeig Vall d'Hebrón, 119–129, 08035 Barcelona, Spain

    • Ana Vivancos
    •  & José Baselga


  1. Search for Jordi Rodón in:

  2. Search for Cristina Saura in:

  3. Search for Rodrigo Dienstmann in:

  4. Search for Ana Vivancos in:

  5. Search for Santiago Ramón y Cajal in:

  6. Search for José Baselga in:

  7. Search for Josep Tabernero in:


All authors contributed to the discussion of content and reviewed and edited the manuscript before submission. J. Rodón, R. Dienstmann and J. Tabernero researched data for the article and contributed significantly to the writing of the manuscript before submission. A. Vivancos also contributed significantly to the writing. J. Baselga, S. Ramón y Cajal and C. Saura contributed to researching the data for the article.

Competing interests

Baselga declares he is a consultant and he serves as a scientific advisor of Aragon, AstraZeneca, Bayer-Onix, Chugai, Constellation, Exelixis, Intellikine, Merck, Novartis, Roche-Genentech, Sanofi. J Tabernero declares he is a consultant and receives grant support from Novartis and Roche-Genentech. The other authors declare no competing interests.

Corresponding author

Correspondence to Jordi Rodón.

About this article

Publication history



Further reading