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Obstacles to precision oncology: confronting current factors affecting the successful introduction of biomarkers to the clinic

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Abstract

Background

Tailoring treatment strategies to individual patients requires the availability of reliable biomarkers. Despite important investment in biomarker research, few examples of successful biomarker-drug co-development are currently seen in clinical practice. The validity of a biomarker measurement may be affected by different pre-analytical, analytical and post-analytical factors. The lack of control or oversight of any of these factors may ultimately lead to failure in translating a promising research finding into clinical practice. In the present review, we put into perspective some of the obstacles to “precision” oncology, focusing on the technical and biological hurdles that may affect the validity of a biomarker result and, ultimately, the likelihood of a new targeted agent to reach the clinic.

Conclusion

Biomarker application in precision oncology must consider the evolution of neoplastic disease, evaluate strengths and limitations of the platform used for the determination, and efficiently address specimen type and handling issues. In-depth analytical validation of a new biomarker test that includes evaluation of target stability should be performed before the test is used in clinical samples. More efficient sampling and use of high-sensitivity methodologies may overcome the influence of tumor heterogeneity on biomarker measurement. Clinical trials with biomarker endpoints may only be successful when multidisciplinary academic study teams are involved and results meet the highest quality standards.

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References

  1. J. Woodcock, Molecular medicine: how, what, and when? Clin. Pharmacol. Ther. 82(4), 376–8 (2007)

    Article  CAS  PubMed  Google Scholar 

  2. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 69(3): 89–95 (2001)

  3. R. Katz, Biomarkers and surrogate markers: an FDA perspective. NeuroRx 1(2), 189–95 (2004)

    Article  PubMed Central  PubMed  Google Scholar 

  4. E.P. Diamandis, B.R. Hoffman, C.M. Sturgeon, National academy of clinical biochemistry laboratory medicine practice guidelines for the use of tumor markers. Clin. Chem. 54(11), 1935–9 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. C.M. Sturgeon, B.R. Hoffman, D.W. Chan, S.L. Ch’ng, E. Hammond, D.F. Hayes, L.A. Liotta, E.F. Petricoin, M. Schmitt, O.J. Semmes, G. Soletormos, E. van der Merwe, E.P. Diamandis, National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in clinical practice: quality requirements. Clin. Chem. 54(8), e1–e10 (2008)

    Article  CAS  PubMed  Google Scholar 

  6. S.M. Teutsch, L.A. Bradley, G.E. Palomaki, J.E. Haddow, M. Piper, N. Calonge, W.D. Dotson, M.P. Douglas, A.O. Berg, The evaluation of genomic applications in practice and prevention (EGAPP) initiative: methods of the EGAPP working group. Genet. Med. 11(1), 3–14 (2009)

    Article  PubMed Central  PubMed  Google Scholar 

  7. G.C. Wishart, C.D. Bajdik, E. Dicks, E. Provenzano, M.K. Schmidt, M. Sherman, D.C. Greenberg, A.R. Green, K.A. Gelmon, V.M. Kosma, J.E. Olson, M.W. Beckmann, R. Winqvist, S.S. Cross, G. Severi, D. Huntsman, K. Pylkas, I. Ellis, T.O. Nielsen, G. Giles, C. Blomqvist, P.A. Fasching, F.J. Couch, E. Rakha, W.D. Foulkes, F.M. Blows, L.R. Begin, L.J. van’t Veer, M. Southey, H. Nevanlinna, A. Mannermaa, A. Cox, M. Cheang, L. Baglietto, C. Caldas, M. Garcia-Closas, P.D. Pharoah, PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2. Br. J. Cancer 107(5), 800–7 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. L.M. McShane, D.G. Altman, W. Sauerbrei, S.E. Taube, M. Gion, G.M. Clark, Reporting recommendations for tumor marker prognostic studies (remark). J. Natl. Cancer Inst. 97(16), 1180–4 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. C. Marchio, M. Dowsett, J.S. Reis-Filho, Revisiting the technical validation of tumour biomarker assays: how to open a Pandora’s box. BMC Med. 9, 41 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. C.L. Vogel, M.A. Cobleigh, D. Tripathy, J.C. Gutheil, L.N. Harris, L. Fehrenbacher, D.J. Slamon, M. Murphy, W.F. Novotny, M. Burchmore, S. Shak, S.J. Stewart, M. Press, Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20(3), 719–26 (2002)

    Article  CAS  PubMed  Google Scholar 

  11. E.H. Romond, E.A. Perez, J. Bryant, V.J. Suman, C.E. Geyer Jr., N.E. Davidson, E. Tan-Chiu, S. Martino, S. Paik, P.A. Kaufman, S.M. Swain, T.M. Pisansky, L. Fehrenbacher, L.A. Kutteh, V.G. Vogel, D.W. Visscher, G. Yothers, R.B. Jenkins, A.M. Brown, S.R. Dakhil, E.P. Mamounas, W.L. Lingle, P.M. Klein, J.N. Ingle, N. Wolmark, Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353(16), 1673–84 (2005)

    Article  CAS  PubMed  Google Scholar 

  12. A. Marchetti, C. Martella, L. Felicioni, F. Barassi, S. Salvatore, A. Chella, P.P. Camplese, T. Iarussi, F. Mucilli, A. Mezzetti, F. Cuccurullo, R. Sacco, F. Buttitta, EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J. Clin. Oncol. 23(4), 857–65 (2005)

    Article  CAS  PubMed  Google Scholar 

  13. K.T. Flaherty, I. Puzanov, K.B. Kim, A. Ribas, G.A. McArthur, J.A. Sosman, P.J. O’Dwyer, R.J. Lee, J.F. Grippo, K. Nolop, P.B. Chapman, Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363(9), 809–19 (2010)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. D.F. Ransohoff, M.L. Gourlay, Sources of bias in specimens for research about molecular markers for cancer. J. Clin. Oncol. 28(4), 698–704 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  15. D.F. Ransohoff, Bias as a threat to the validity of cancer molecular-marker research. Nat. Rev. Cancer 5(2), 142–9 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. C.A. Hudis, Trastuzumab–mechanism of action and use in clinical practice. N. Engl. J. Med. 357(1), 39–51 (2007)

    Article  CAS  PubMed  Google Scholar 

  17. P.B. Chapman, A. Hauschild, C. Robert, J.B. Haanen, P. Ascierto, J. Larkin, R. Dummer, C. Garbe, A. Testori, M. Maio, D. Hogg, P. Lorigan, C. Lebbe, T. Jouary, D. Schadendorf, A. Ribas, S.J. O’Day, J.A. Sosman, J.M. Kirkwood, A.M. Eggermont, B. Dreno, K. Nolop, J. Li, B. Nelson, J. Hou, R.J. Lee, K.T. Flaherty, G.A. McArthur, Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364(26), 2507–16 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. T.S. Mok, Y.L. Wu, S. Thongprasert, C.H. Yang, D.T. Chu, N. Saijo, P. Sunpaweravong, B. Han, B. Margono, Y. Ichinose, Y. Nishiwaki, Y. Ohe, J.J. Yang, B. Chewaskulyong, H. Jiang, E.L. Duffield, C.L. Watkins, A.A. Armour, M. Fukuoka, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361(10), 947–57 (2009)

    Article  CAS  PubMed  Google Scholar 

  19. W. De Roock, B. Claes, D. Bernasconi, J. De Schutter, B. Biesmans, G. Fountzilas, K.T. Kalogeras, V. Kotoula, D. Papamichael, P. Laurent-Puig, F. Penault-Llorca, P. Rougier, B. Vincenzi, D. Santini, G. Tonini, F. Cappuzzo, M. Frattini, F. Molinari, P. Saletti, S. De Dosso, M. Martini, A. Bardelli, S. Siena, A. Sartore-Bianchi, J. Tabernero, T. Macarulla, F. Di Fiore, A.O. Gangloff, F. Ciardiello, P. Pfeiffer, C. Qvortrup, T.P. Hansen, E. Van Cutsem, H. Piessevaux, D. Lambrechts, M. Delorenzi, S. Tejpar, 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. Lancet Oncol. 11(8), 753–62 (2010)

    Article  PubMed  Google Scholar 

  20. S. Querings, J. Altmuller, S. Ansen, T. Zander, D. Seidel, F. Gabler, M. Peifer, E. Markert, K. Stemshorn, B. Timmermann, B. Saal, S. Klose, K. Ernestus, M. Scheffler, W. Engel-Riedel, E. Stoelben, E. Brambilla, J. Wolf, P. Nurnberg, R.K. Thomas, Benchmarking of mutation diagnostics in clinical lung cancer specimens. PLoS One 6(5), e19601 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. C.R. Taylor, R.M. Levenson, Quantification of immunohistochemistry–issues concerning methods, utility and semiquantitative assessment II. Histopathology 49(4), 411–24 (2006)

    Article  CAS  PubMed  Google Scholar 

  22. M.R. Schweiger, M. Kerick, B. Timmermann, M.W. Albrecht, T. Borodina, D. Parkhomchuk, K. Zatloukal, H. Lehrach, Genome-wide massively parallel sequencing of formaldehyde fixed-paraffin embedded (FFPE) tumor tissues for copy-number- and mutation-analysis. PLoS One 4(5), e5548 (2009)

    Article  PubMed Central  PubMed  Google Scholar 

  23. E.J. Duncavage, V. Magrini, N. Becker, J.R. Armstrong, R.T. Demeter, T. Wylie, H.J. Abel, J.D. Pfeifer, Hybrid capture and next-generation sequencing identify viral integration sites from formalin-fixed, paraffin-embedded tissue. J. Mol. Diagn. 13(3), 325–33 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. M. Srinivasan, D. Sedmak, S. Jewell, Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Am. J. Pathol. 161(6), 1961–71 (2002)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Y. Bai, J. Tolles, H. Cheng, S. Siddiqui, A. Gopinath, E. Pectasides, R.L. Camp, D.L. Rimm, A.M. Molinaro, Quantitative assessment shows loss of antigenic epitopes as a function of pre-analytic variables. Lab. Invest. 91(8), 1253–61 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. A.F. Baker, T. Dragovich, N.T. Ihle, R. Williams, C. Fenoglio-Preiser, G. Powis, Stability of phosphoprotein as a biological marker of tumor signaling. Clin. Cancer Res. 11(12), 4338–40 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. L. De Cecco, V. Musella, S. Veneroni, V. Cappelletti, I. Bongarzone, M. Callari, B. Valeri, M.A. Pierotti, M.G. Daidone, Impact of biospecimens handling on biomarker research in breast cancer. BMC Cancer 9, 409 (2009)

    Article  PubMed Central  PubMed  Google Scholar 

  28. K.B. Engel, H.M. Moore, Effects of preanalytical variables on the detection of proteins by immunohistochemistry in formalin-fixed, paraffin-embedded tissue. Arch. Pathol. Lab. Med. 135(5), 537–43 (2011)

    PubMed  Google Scholar 

  29. V. Espina, K.H. Edmiston, M. Heiby, M. Pierobon, M. Sciro, B. Merritt, S. Banks, J. Deng, A.J. VanMeter, D.H. Geho, L. Pastore, J. Sennesh, E.F. Petricoin 3rd, L.A. Liotta, A portrait of tissue phosphoprotein stability in the clinical tissue procurement process. Mol. Cell. Proteomics 7(10), 1998–2018 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. V. Espina, C. Mueller, K. Edmiston, M. Sciro, E.F. Petricoin, L.A. Liotta, Tissue is alive: new technologies are needed to address the problems of protein biomarker pre-analytical variability. Proteomics Clin. Appl. 3(8), 874–882 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. S.M. Hewitt, F.A. Lewis, Y. Cao, R.C. Conrad, M. Cronin, K.D. Danenberg, T.J. Goralski, J.P. Langmore, R.G. Raja, P.M. Williams, J.F. Palma, J.A. Warrington, Tissue handling and specimen preparation in surgical pathology: issues concerning the recovery of nucleic acids from formalin-fixed, paraffin-embedded tissue. Arch. Pathol. Lab. Med. 132(12), 1929–35 (2008)

    PubMed  Google Scholar 

  32. F. Medeiros, C.T. Rigl, G.G. Anderson, S.H. Becker, K.C. Halling, Tissue handling for genome-wide expression analysis: a review of the issues, evidence, and opportunities. Arch. Pathol. Lab. Med. 131(12), 1805–16 (2007)

    CAS  PubMed  Google Scholar 

  33. P. Micke, M. Ohshima, S. Tahmasebpoor, Z.P. Ren, A. Ostman, F. Ponten, J. Botling, Biobanking of fresh frozen tissue: RNA is stable in nonfixed surgical specimens. Lab. Invest. 86(2), 202–11 (2006)

    Article  CAS  PubMed  Google Scholar 

  34. S. Siddiqui, D.L. Rimm, Pre-analytic variables and phospho-specific antibodies: the Achilles heel of immunohistochemistry. Breast Cancer Res. 12(6), 113 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  35. M.E. Hammond, D.F. Hayes, M. Dowsett, D.C. Allred, K.L. Hagerty, S. Badve, P.L. Fitzgibbons, G. Francis, N.S. Goldstein, M. Hayes, D.G. Hicks, S. Lester, R. Love, P.B. Mangu, L. McShane, K. Miller, C.K. Osborne, S. Paik, J. Perlmutter, A. Rhodes, H. Sasano, J.N. Schwartz, F.C. Sweep, S. Taube, E.E. Torlakovic, P. Valenstein, G. Viale, D. Visscher, T. Wheeler, R.B. Williams, J.L. Wittliff, A.C. Wolff, American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J. Clin. Oncol. 28(16), 2784–95 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  36. T. Khoury, Delay to formalin fixation alters morphology and immunohistochemistry for breast carcinoma. Appl. Immunohistochem. Mol. Morphol. 20(6), 531–42 (2012)

    Article  CAS  PubMed  Google Scholar 

  37. V.M. Neumeister, V. Anagnostou, S. Siddiqui, A.M. England, E.R. Zarrella, M. Vassilakopoulou, F. Parisi, Y. Kluger, D.G. Hicks, D.L. Rimm, Quantitative assessment of effect of preanalytic cold ischemic time on protein expression in breast cancer tissues. J. Natl. Cancer Inst. 104(23), 1815–24 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. B.P. Portier, Z. Wang, E. Downs-Kelly, J.J. Rowe, D. Patil, C. Lanigan, G.T. Budd, D.G. Hicks, D.L. Rimm, R.R. Tubbs, Delay to formalin fixation ’cold ischemia time’: effect on ERBB2 detection by in-situ hybridization and immunohistochemistry. Mod. Pathol. 26(1), 1–9 (2013)

    Article  CAS  PubMed  Google Scholar 

  39. M. Dowsett, T.O. Nielsen, R. A’Hern, J. Bartlett, R.C. Coombes, J. Cuzick, M. Ellis, N.L. Henry, J.C. Hugh, T. Lively, L. McShane, S. Paik, F. Penault-Llorca, L. Prudkin, M. Regan, J. Salter, C. Sotiriou, I.E. Smith, G. Viale, J.A. Zujewski, D.F. Hayes, Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in breast cancer working group. J. Natl. Cancer Inst. 103(22), 1656–64 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. I.F. Pinhel, F.A. Macneill, M.J. Hills, J. Salter, S. Detre, R. A’Hern, A. Nerurkar, P. Osin, I.E. Smith, M. Dowsett, Extreme loss of immunoreactive p-Akt and p-Erk1/2 during routine fixation of primary breast cancer. Breast Cancer Res. 12(5), R76 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  41. J. Huang, R. Qi, J. Quackenbush, E. Dauway, E. Lazaridis, T. Yeatman, Effects of ischemia on gene expression. J. Surg. Res. 99(2), 222–7 (2001)

    Article  CAS  PubMed  Google Scholar 

  42. A. Spruessel, G. Steimann, M. Jung, S.A. Lee, T. Carr, A.K. Fentz, J. Spangenberg, C. Zornig, H.H. Juhl, K.A. David, Tissue ischemia time affects gene and protein expression patterns within minutes following surgical tumor excision. Biotechniques 36(6), 1030–7 (2004)

    CAS  PubMed  Google Scholar 

  43. N.S. Goldstein, S.M. Hewitt, C.R. Taylor, H. Yaziji, D.G. Hicks, Recommendations for improved standardization of immunohistochemistry. Appl. Immunohistochem. Mol. Morphol. 15(2), 124–33 (2007)

    Article  CAS  PubMed  Google Scholar 

  44. J.H. Williams, B.L. Mepham, D.H. Wright, Tissue preparation for immunocytochemistry. J. Clin. Pathol. 50(5), 422–8 (1997)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. D.A. Arber, Effect of prolonged formalin fixation on the immunohistochemical reactivity of breast markers. Appl. Immunohistochem. Mol. Morphol. 10(2), 183–6 (2002)

    PubMed  Google Scholar 

  46. M. Werner, A. Chott, A. Fabiano, H. Battifora, Effect of formalin tissue fixation and processing on immunohistochemistry. Am. J. Surg. Pathol. 24(7), 1016–9 (2000)

    Article  CAS  PubMed  Google Scholar 

  47. Z.P. Ren, J. Sallstrom, C. Sundstrom, M. Nister, Y. Olsson, Recovering DNA and optimizing PCR conditions from microdissected formalin-fixed and paraffin-embedded materials. Pathobiology 68(4–5), 215–7 (2000)

    Article  CAS  PubMed  Google Scholar 

  48. D. Groelz, L. Sobin, P. Branton, C. Compton, R. Wyrich, L. Rainen, Non-formalin fixative versus formalin-fixed tissue: a comparison of histology and RNA quality. Exp. Mol. Pathol. 94(1), 188–94 (2013)

    Article  CAS  PubMed  Google Scholar 

  49. L.A. Garraway, Concordance and discordance in tumor genomic profiling. J. Clin. Oncol. 30(24), 2937–9 (2012)

    Article  PubMed  Google Scholar 

  50. A. Maitra, I.I. Wistuba, A.F. Gazdar, Microdissection and the study of cancer pathways. Curr. Mol. Med. 1(1), 153–62 (2001)

    Article  CAS  PubMed  Google Scholar 

  51. Y. Otsuka, Y. Ichikawa, C. Kunisaki, G. Matsuda, H. Akiyama, M. Nomura, S. Togo, Y. Hayashizaki, H. Shimada, Correlating purity by microdissection with gene expression in gastric cancer tissue. Scand. J. Clin. Lab. Invest. 67(4), 367–79 (2007)

    Article  CAS  PubMed  Google Scholar 

  52. S. Pena-Llopis, J. Brugarolas, Simultaneous isolation of high-quality DNA, RNA, miRNA and proteins from tissues for genomic applications. Nat. Protoc. 8(11), 2240–55 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. C.J. Shukla, C.J. Pennington, A.C. Riddick, K.K. Sethia, R.Y. Ball, D.R. Edwards, Laser-capture microdissection in prostate cancer research: establishment and validation of a powerful tool for the assessment of tumour-stroma interactions. BJU Int. 101(6), 765–74 (2008)

    Article  PubMed  Google Scholar 

  54. K. Yoshihara, M. Shahmoradgoli, E. Martinez, R. Vegesna, H. Kim, W. Torres-Garcia, V. Trevino, H. Shen, P.W. Laird, D.A. Levine, S.L. Carter, G. Getz, K. Stemke-Hale, G.B. Mills, R.G. Verhaak, Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  55. Z. Hodi, J. Chakrabarti, A.H. Lee, J.E. Ronan, C.W. Elston, K.L. Cheung, J.F. Robertson, I.O. Ellis, The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. J. Clin. Pathol. 60(3), 299–302 (2007)

    Article  PubMed Central  PubMed  Google Scholar 

  56. N. McGranahan, R.A. Burrell, D. Endesfelder, M.R. Novelli, C. Swanton, Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep. 13(6), 528–38 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. R.A. Burrell, N. McGranahan, J. Bartek, C. Swanton, The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501(7467), 338–45 (2013)

    Article  CAS  PubMed  Google Scholar 

  58. R. Fisher, L. Pusztai, C. Swanton, Cancer heterogeneity: implications for targeted therapeutics. Br. J. Cancer 108(3), 479–85 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. J. Szollosi, M. Balazs, B.G. Feuerstein, C.C. Benz, F.M. Waldman, ERBB-2 (HER2/neu) gene copy number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer. Cancer Res. 55(22), 5400–7 (1995)

    CAS  PubMed  Google Scholar 

  60. G.G. Chung, M.P. Zerkowski, S. Ghosh, R.L. Camp, D.L. Rimm, Quantitative analysis of estrogen receptor heterogeneity in breast cancer. Lab. Invest. 87(7), 662–9 (2007)

    Article  CAS  PubMed  Google Scholar 

  61. J. Tolles, Y. Bai, M. Baquero, L.N. Harris, D.L. Rimm, A.M. Molinaro, Optimal tumor sampling for immunostaining of biomarkers in breast carcinoma. Breast Cancer Res. 13(3), R51 (2011)

    Article  PubMed Central  PubMed  Google Scholar 

  62. A. Nassar, A. Radhakrishnan, I.A. Cabrero, G.A. Cotsonis, C. Cohen, Intratumoral heterogeneity of immunohistochemical marker expression in breast carcinoma: a tissue microarray-based study. Appl. Immunohistochem. Mol. Morphol. 18(5), 433–41 (2010)

    CAS  PubMed  Google Scholar 

  63. A. McLeer-Florin, S. Lantuejoul, Why technical aspects rather than biology explain cellular heterogeneity in ALK-positive non-small cell lung cancer. J Thorac Dis 4(3), 240–1 (2012)

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Z.Y. Chen, W.Z. Zhong, X.C. Zhang, J. Su, X.N. Yang, Z.H. Chen, J.J. Yang, Q. Zhou, H.H. Yan, S.J. An, H.J. Chen, B.Y. Jiang, T.S. Mok, Y.L. Wu, EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist 17(7), 978–85 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. K. Kalinsky, A. Heguy, U.K. Bhanot, S. Patil, M.E. Moynahan, PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression. Breast Cancer Res. Treat. 129(2), 635–43 (2011)

    Article  PubMed  Google Scholar 

  66. D.A. Landau, S.L. Carter, P. Stojanov, A. McKenna, K. Stevenson, M.S. Lawrence, C. Sougnez, C. Stewart, A. Sivachenko, L. Wang, Y. Wan, W. Zhang, S.A. Shukla, A. Vartanov, S.M. Fernandes, G. Saksena, K. Cibulskis, B. Tesar, S. Gabriel, N. Hacohen, M. Meyerson, E.S. Lander, D. Neuberg, J.R. Brown, G. Getz, C.J. Wu, Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152(4), 714–26 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. K. Anderson, C. Lutz, F.W. van Delft, C.M. Bateman, Y. Guo, S.M. Colman, H. Kempski, A.V. Moorman, I. Titley, J. Swansbury, L. Kearney, T. Enver, M. Greaves, Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469(7330), 356–61 (2011)

    Article  CAS  PubMed  Google Scholar 

  68. Z.P. Pavelic, L. Pavelic, E.E. Lower, M. Gapany, S. Gapany, E.A. Barker, H.D. Preisler, c-myc, c-erbB-2, and Ki-67 expression in normal breast tissue and in invasive and noninvasive breast carcinoma. Cancer Res. 52(9), 2597–602 (1992)

    CAS  PubMed  Google Scholar 

  69. G.L. Fota, A. Stepan, R.N. Ciurea, The evaluation of the immunoexpression of Her2/neu oncoprotein in ductal carcinoma in situ in association with invasive ductal carcinoma of the breast. Rom. J. Morphol. Embryol. 53(3 Suppl), 805–10 (2012)

    PubMed  Google Scholar 

  70. Y. Yatabe, A.C. Borczuk, C.A. Powell, Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer 74(1), 7–11 (2011)

    Article  PubMed Central  PubMed  Google Scholar 

  71. P. Zauber, S. Marotta, M. Sabbath-Solitare, KRAS gene mutations are more common in colorectal villous adenomas and in situ carcinomas than in carcinomas. Int J Mol Epidemiol Genet 4(1), 1–10 (2013)

    PubMed Central  CAS  PubMed  Google Scholar 

  72. A. Miron, M. Varadi, D. Carrasco, H. Li, L. Luongo, H.J. Kim, S.Y. Park, E.Y. Cho, G. Lewis, S. Kehoe, J.D. Iglehart, D. Dillon, D.C. Allred, L. Macconaill, R. Gelman, K. Polyak, PIK3CA mutations in in situ and invasive breast carcinomas. Cancer Res. 70(14), 5674–8 (2010)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. E. Amir, N. Miller, W. Geddie, O. Freedman, F. Kassam, C. Simmons, M. Oldfield, G. Dranitsaris, G. Tomlinson, A. Laupacis, I.F. Tannock, M. Clemons, Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J. Clin. Oncol. 30(6), 587–92 (2012)

    Article  PubMed  Google Scholar 

  74. N. Niikura, J. Liu, N. Hayashi, E.A. Mittendorf, Y. Gong, S.L. Palla, Y. Tokuda, A.M. Gonzalez-Angulo, G.N. Hortobagyi, N.T. Ueno, Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J. Clin. Oncol. 30(6), 593–9 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  75. C. Xiao, Y. Gong, E.Y. Han, A.M. Gonzalez-Angulo, N. Sneige, Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment. Ann. Oncol. 22(7), 1547–53 (2011)

    Article  CAS  PubMed  Google Scholar 

  76. E.E. Lower, E. Glass, R. Blau, S. Harman, HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res. Treat. 113(2), 301–6 (2009)

    Article  CAS  PubMed  Google Scholar 

  77. A. Fabi, A. Di Benedetto, G. Metro, L. Perracchio, C. Nistico, F. Di Filippo, C. Ercolani, G. Ferretti, E. Melucci, S. Buglioni, I. Sperduti, P. Papaldo, F. Cognetti, M. Mottolese, HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care. Clin. Cancer Res. 17(7), 2055–64 (2011)

    Article  CAS  PubMed  Google Scholar 

  78. F. Penault-Llorca, R.A. Coudry, W.M. Hanna, R.Y. Osamura, J. Ruschoff, G. Viale, Experts’ opinion: recommendations for retesting breast cancer metastases for HER2 and hormone receptor status. Breast 22(2), 200–2 (2013)

    Article  PubMed  Google Scholar 

  79. A.M. Gonzalez-Angulo, J. Ferrer-Lozano, K. Stemke-Hale, A. Sahin, S. Liu, J.A. Barrera, O. Burgues, A.M. Lluch, H. Chen, G.N. Hortobagyi, G.B. Mills, F. Meric-Bernstam, PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol. Cancer Ther. 10(6), 1093–101 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. J. Dupont Jensen, A.V. Laenkholm, A. Knoop, M. Ewertz, R. Bandaru, W. Liu, W. Hackl, J.C. Barrett, and H. Gardner, PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin. Cancer Res. 17(4), 667–77 (2011)

    Article  CAS  PubMed  Google Scholar 

  81. M. Daneshmand, J.E. Hanson, M. Nabavi, J.F. Hilton, L. Vandermeer, F. Kanji, S.F. Dent, M. Clemons, I.A. Lorimer, Detection of PIK3CA mutations in breast cancer bone metastases. ISRN Oncol 2012, 492578 (2012)

    PubMed Central  PubMed  Google Scholar 

  82. E. Vakiani, M. Janakiraman, R. Shen, R. Sinha, Z. Zeng, J. Shia, A. Cercek, N. Kemeny, M. D’Angelica, A. Viale, A. Heguy, P. Paty, T.A. Chan, L.B. Saltz, M. Weiser, D.B. Solit, Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J. Clin. Oncol. 30(24), 2956–62 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. S.E. Baldus, K.L. Schaefer, R. Engers, D. Hartleb, N.H. Stoecklein, H.E. Gabbert, Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin. Cancer Res. 16(3), 790–9 (2010)

    Article  CAS  PubMed  Google Scholar 

  84. M. Deininger, E. Buchdunger, B.J. Druker, The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105(7), 2640–53 (2005)

    Article  CAS  PubMed  Google Scholar 

  85. B.E. Johnson, P.A. Janne, Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Cancer Res. 65(17), 7525–9 (2005)

    CAS  PubMed  Google Scholar 

  86. A.F. Gazdar, Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 28(Suppl 1), S24–31 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. N.P. Shah, J.M. Nicoll, B. Nagar, M.E. Gorre, R.L. Paquette, J. Kuriyan, C.L. Sawyers, 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(2), 117–25 (2002)

    Article  CAS  PubMed  Google Scholar 

  88. B. Liegl, I. Kepten, C. Le, M. Zhu, G.D. Demetri, M.C. Heinrich, C.D. Fletcher, C.L. Corless, J.A. Fletcher, Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J. Pathol. 216(1), 64–74 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. K.Y. Su, H.Y. Chen, K.C. Li, M.L. Kuo, J.C. Yang, W.K. Chan, B.C. Ho, G.C. Chang, J.Y. Shih, S.L. Yu, P.C. Yang, Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J. Clin. Oncol. 30(4), 433–40 (2012)

    Article  CAS  PubMed  Google Scholar 

  90. W. Pao, J. Chmielecki, Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Cancer 10(11), 760–74 (2010)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. M.F. Rimawi, I.A. Mayer, A. Forero, R. Nanda, M.P. Goetz, A.A. Rodriguez, A.C. Pavlick, T. Wang, S.G. Hilsenbeck, C. Gutierrez, R. Schiff, C.K. Osborne, J.C. Chang, Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J. Clin. Oncol. 31(14), 1726–31 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. P.C. Roche, V.J. Suman, R.B. Jenkins, N.E. Davidson, S. Martino, P.A. Kaufman, F.K. Addo, B. Murphy, J.N. Ingle, E.A. Perez, Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J. Natl. Cancer Inst. 94(11), 855–7 (2002)

    Article  PubMed  Google Scholar 

  93. E.A. Perez, V.J. Suman, N.E. Davidson, S. Martino, P.A. Kaufman, W.L. Lingle, P.J. Flynn, J.N. Ingle, D. Visscher, R.B. Jenkins, HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J. Clin. Oncol. 24(19), 3032–8 (2006)

    Article  PubMed  Google Scholar 

  94. McCullough, A.E., P. Dell’orto, M.M. Reinholz, R.D. Gelber, A.C. Dueck, L. Russo, R.B. Jenkins, S. Andrighetto, B. Chen, C. Jackisch, M. Untch, E.A. Perez, M.J. Piccart-Gebhart, and G. Viale, Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study. Breast Cancer Res Treat, 2014

  95. M. Mengel, R. von Wasielewski, B. Wiese, T. Rudiger, H.K. Muller-Hermelink, H. Kreipe, Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. J. Pathol. 198(3), 292–9 (2002)

    Article  PubMed  Google Scholar 

  96. Polley, M.Y., S.C. Leung, L.M. McShane, D. Gao, J.C. Hugh, M.G. Mastropasqua, G. Viale, L.A. Zabaglo, F. Penault-Llorca, J.M. Bartlett, A.M. Gown, W.F. Symmans, T. Piper, E. Mehl, R.A. Enos, D.F. Hayes, M. Dowsett, and T.O. Nielsen, An International Ki67 Reproducibility Study. J Natl Cancer Inst, 2013

  97. Geretti, E.P., V; Onsum, M; et al., Quantification of HER2 expression at the single cell level and HER2 intratumoral heterogeneity of breast cancer tissue samples using automated image analysis. Cancer Res, 2012(72).

  98. Wickham T, F.K., A phase I study of MM-302, a HER2- targeted liposomal doxorubicin, in patients with advanced, HER2-positive breast cancer. Cancer Res 2012. 72

  99. B.R. Leyland-Jones, C.B. Ambrosone, J. Bartlett, M.J. Ellis, R.A. Enos, A. Raji, M.R. Pins, J.A. Zujewski, S.M. Hewitt, J.F. Forbes, M. Abramovitz, S. Braga, F. Cardoso, N. Harbeck, C. Denkert, S.D. Jewell, Recommendations for collection and handling of specimens from group breast cancer clinical trials. J. Clin. Oncol. 26(34), 5638–44 (2008)

    Article  PubMed Central  PubMed  Google Scholar 

  100. S. Loi, W.F. Symmans, J.M. Bartlett, D. Fumagalli, L. Van’t Veer, J.F. Forbes, P. Bedard, C. Denkert, J. Zujewski, G. Viale, L. Pusztai, L.J. Esserman, B.R. Leyland-Jones, Proposals for uniform collection of biospecimens from neoadjuvant breast cancer clinical trials: timing and specimen types. Lancet Oncol. 12(12), 1162–8 (2011)

    Article  PubMed  Google Scholar 

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  1. Molecular Oncology Laboratory, Vall d’Hebron Institute of Oncology, Passeig Vall d’Hebron, 119-129, Barcelona, Spain

    Ludmila Prudkin & Paolo Nuciforo

  2. Universitat Autònoma de Barcelona, Barcelona, Spain

    Paolo Nuciforo

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Prudkin, L., Nuciforo, P. Obstacles to precision oncology: confronting current factors affecting the successful introduction of biomarkers to the clinic. Cell Oncol. 38, 39–48 (2015). https://doi.org/10.1007/s13402-014-0192-6

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