Advertisement

Intratumor Heterogeneity in Breast Cancer

  • Francisco Beca
  • Kornelia Polyak
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 882)

Abstract

Intratumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. Both genetic and epigenetic sources of intratumor heterogeneity are well recognized and several technologies have been developed for their characterization. With the technological advances in recent years, investigators are now elucidating intratumor heterogeneity at the single cell level and in situ. However, translating the accumulated knowledge about intratumor heterogeneity to clinical practice has been slow. We are certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies. Here we review some of the most important considerations related to intratumor heterogeneity. We discuss both genetic and epigenetic sources of intratumor heterogeneity and review experimental approaches that are commonly used to quantify it. We also discuss the impact of intratumor heterogeneity on cancer diagnosis and treatment and share our perspectives on the future of this field.

Keywords

Heterogeneity Breast cancer Evolution Selection Clonality Phenotype Therapy Resistance Progression 

References

  1. 1.
    Brown TM, Fee E (2006) Rudolf Carl Virchow: medical scientist, social reformer, role model. Am J Public Health 96(12):2104–2105. doi:10.2105/AJPH.2005.078436CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Young RH, Louis DN (2011) The Warrens and other pioneering clinician pathologists of the Massachusetts General Hospital during its early years: an appreciation on the 200th anniversary of the hospital founding. Mod Pathol 24(10):1285–1294. doi:10.1038/modpathol.2011.132CrossRefPubMedGoogle Scholar
  3. 3.
    Foote FW Jr, Stewart FW (1946) A histologic classification of carcinoma of the breast. Surgery 19:74–99PubMedGoogle Scholar
  4. 4.
    Fidler IJ, Kripke ML (1977) Metastasis results from preexisting variant cells within a malignant tumor. Science 197(4306):893–895CrossRefPubMedGoogle Scholar
  5. 5.
    Fidler IJ (1978) Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 38(9):2651–2660PubMedGoogle Scholar
  6. 6.
    Miller FR, Miller BE, Heppner GH (1983) Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability. Invasion Metastasis 3(1):22–31PubMedGoogle Scholar
  7. 7.
    Hawkins RA, Roberts MM, Forrest AP (1980) Oestrogen receptors and breast cancer: current status. Br J Surg 67(3):153–169CrossRefPubMedGoogle Scholar
  8. 8.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093CrossRefPubMedGoogle Scholar
  9. 9.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874. doi:10.1073/pnas.191367098CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Perou CM, Parker JS, Prat A, Ellis MJ, Bernard PS (2010) Clinical implementation of the intrinsic subtypes of breast cancer. Lancet Oncol 11(8):718–719; author reply 720–711. doi:10.1016/S1470-2045(10)70176-5CrossRefPubMedGoogle Scholar
  11. 11.
    Almendro V, Marusyk A, Polyak K (2013) Cellular heterogeneity and molecular evolution in cancer. Annu Rev Pathol 8:277–302. doi:10.1146/annurev-pathol-020712-163923CrossRefPubMedGoogle Scholar
  12. 12.
    Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12(5):323–334. doi:10.1038/nrc3261CrossRefPubMedGoogle Scholar
  13. 13.
    Wolman SR, Heppner GH (1992) Genetic heterogeneity in breast cancer. J Natl Cancer Inst 84(7):469–470CrossRefPubMedGoogle Scholar
  14. 14.
    Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117. doi:10.1038/nature09515CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    de Visser JA, Rozen DE (2006) Clonal interference and the periodic selection of new beneficial mutations in Escherichia coli. Genetics 172(4):2093–2100. doi:10.1534/genetics.105.052373CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194(4260):23–28CrossRefPubMedGoogle Scholar
  17. 17.
    Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K (2014) Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514(7520):54–58. doi:10.1038/nature13556CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ashworth A, Lord CJ, Reis-Filho JS (2011) Genetic interactions in cancer progression and treatment. Cell 145(1):30–38. doi:10.1016/j.cell.2011.03.020CrossRefPubMedGoogle Scholar
  19. 19.
    Jarosz DF, Taipale M, Lindquist S (2010) Protein homeostasis and the phenotypic manifestation of genetic diversity: principles and mechanisms. Annu Rev Genet 44:189–216. doi:10.1146/annurev.genet.40.110405.090412CrossRefPubMedGoogle Scholar
  20. 20.
    Sandhu R, Roll JD, Rivenbark AG, Coleman WB (2014) Dysregulation of the epigenome in human breast cancer: contributions of gene-specific DNA hypermethylation to breast cancer pathobiology and targeting the breast cancer methylome for improved therapy. Am J Pathol. doi:10.1016/j.ajpath.2014.12.003Google Scholar
  21. 21.
    Baylin SB (2005) DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2(Suppl 1):S4–S11. doi:10.1038/ncponc0354CrossRefPubMedGoogle Scholar
  22. 22.
    Fiegl H, Millinger S, Goebel G, Muller-Holzner E, Marth C, Laird PW, Widschwendter M (2006) Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res 66(1):29–33. doi:10.1158/0008-5472.CAN-05-2508CrossRefPubMedGoogle Scholar
  23. 23.
    Sunami E, Shinozaki M, Sim MS, Nguyen SL, Vu AT, Giuliano AE, Hoon DS (2008) Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res 10(3):R46. doi:10.1186/bcr2098CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Widschwendter M, Siegmund KD, Muller HM, Fiegl H, Marth C, Muller-Holzner E, Jones PA, Laird PW (2004) Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res 64(11):3807–3813. doi:10.1158/0008-5472.CAN-03-3852CrossRefPubMedGoogle Scholar
  25. 25.
    Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, Hong C, Fridlyand J, Costello JF, Tlsty TD (2006) Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem 281(34):24790–24802. doi:10.1074/jbc.M604175200CrossRefPubMedGoogle Scholar
  26. 26.
    Lehmann U, Langer F, Feist H, Glockner S, Hasemeier B, Kreipe H (2002) Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol 160(2):605–612. doi:10.1016/S0002-9440(10)64880-8CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pasquali L, Bedeir A, Ringquist S, Styche A, Bhargava R, Trucco G (2007) Quantification of CpG island methylation in progressive breast lesions from normal to invasive carcinoma. Cancer Lett 257(1):136–144. doi:10.1016/j.canlet.2007.07.010CrossRefPubMedGoogle Scholar
  28. 28.
    Dick JE (2008) Stem cell concepts renew cancer research. Blood 112(13):4793–4807. doi:10.1182/blood-2008-08-077941CrossRefPubMedGoogle Scholar
  29. 29.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737CrossRefPubMedGoogle Scholar
  30. 30.
    Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11(3):259–273. doi:10.1016/j.ccr.2007.01.013CrossRefPubMedGoogle Scholar
  31. 31.
    Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nat Med 17(3):313–319. doi:10.1038/nm.2304CrossRefPubMedGoogle Scholar
  32. 32.
    Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A 108(19):7950–7955. doi:10.1073/pnas.1102454108CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Balaban NQ, Merrin J, Chait R, Kowalik L, Leibler S (2004) Bacterial persistence as a phenotypic switch. Science 305(5690):1622–1625. doi:10.1126/science.1099390CrossRefPubMedGoogle Scholar
  34. 34.
    Raj A, Rifkin SA, Andersen E, van Oudenaarden A (2010) Variability in gene expression underlies incomplete penetrance. Nature 463(7283):913–918. doi:10.1038/nature08781CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Corre G, Stockholm D, Arnaud O, Kaneko G, Vinuelas J, Yamagata Y, Neildez-Nguyen TM, Kupiec JJ, Beslon G, Gandrillon O, Paldi A (2014) Stochastic fluctuations and distributed control of gene expression impact cellular memory. PloS One 9(12):e115574. doi:10.1371/journal.pone.0115574CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK (2009) Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459(7245):428–432. doi:10.1038/nature08012CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10(2):R25. doi:10.1186/bcr1982CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cancer Genome Atlas Network. (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. doi:10.1038/nature11412CrossRefGoogle Scholar
  39. 39.
    Ali HR, Rueda OM, Chin SF, Curtis C, Dunning MJ, Aparicio SA, Caldas C (2014) Genome-driven integrated classification of breast cancer validated in over 7,500 samples. Genome Biol 15(8):431. doi:10.1186/s13059-014-0431-1CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Group M, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352. doi:10.1038/nature10983PubMedPubMedCentralGoogle Scholar
  41. 41.
    Aparicio S, Caldas C (2013) The implications of clonal genome evolution for cancer medicine. N Engl J Med 368(9):842–851. doi:10.1056/NEJMra1204892CrossRefPubMedGoogle Scholar
  42. 42.
    Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, Laird PW, Onofrio RC, Winckler W, Weir BA, Beroukhim R, Pellman D, Levine DA, Lander ES, Meyerson M, Getz G (2012) Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 30(5):413–421. doi:10.1038/nbt.2203CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SW, Morin GB, Watson P, Gelmon K, Chia S, Chin SF, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399. doi:10.1038/nature10933PubMedGoogle Scholar
  44. 44.
    Navin N, Krasnitz A, Rodgers L, Cook K, Meth J, Kendall J, Riggs M, Eberling Y, Troge J, Grubor V, Levy D, Lundin P, Maner S, Zetterberg A, Hicks J, Wigler M (2010) Inferring tumor progression from genomic heterogeneity. Genome Res 20(1):68–80. doi:10.1101/gr.099622.109CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, Harris CC, McLellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang Q, Chen L, Lin L, Wendl MC, McMichael JF, Magrini VJ, Cook L, McGrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Lin L, Crowder R, Tao Y, Snider JE, Smith SM, Dukes AF, Sanderson GE, Pohl CS, Delehaunty KD, Fronick CC, Pape KA, Reed JS, Robinson JS, Hodges JS, Schierding W, Dees ND, Shen D, Locke DP, Wiechert ME, Eldred JM, Peck JB, Oberkfell BJ, Lolofie JT, Du F, Hawkins AE, O’Laughlin MD, Bernard KE, Cunningham M, Elliott G, Mason MD, Thompson DM Jr, Ivanovich JL, Goodfellow PJ, Perou CM, Weinstock GM, Aft R, Watson M, Ley TJ, Wilson RK, Mardis ER (2010) Genome remodelling in a Basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005. doi:10.1038/nature08989CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Martelotto LG, Ng CK, Piscuoglio S, Weigelt B, Reis-Filho JS (2014) Breast cancer intra-tumor heterogeneity. Breast Cancer Res 16(3):210CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94. doi:10.1038/nature09807CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wang Y, Waters J, Leung ML, Unruh A, Roh W, Shi X, Chen K, Scheet P, Vattathil S, Liang H, Multani A, Zhang H, Zhao R, Michor F, Meric-Bernstam F, Navin NE (2014) Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512(7513):155–160. doi:10.1038/nature13600CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Czyz ZT, Hoffmann M, Schlimok G, Polzer B, Klein CA (2014) Reliable single cell array CGH for clinical samples. PloS One 9(1):e85907. doi:10.1371/journal.pone.0085907CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Voet T, Kumar P, Van Loo P, Cooke SL, Marshall J, Lin ML, Zamani Esteki M, Van der Aa N, Mateiu L, McBride DJ, Bignell GR, McLaren S, Teague J, Butler A, Raine K, Stebbings LA, Quail MA, D’Hooghe T, Moreau Y, Futreal PA, Stratton MR, Vermeesch JR, Campbell PJ (2013) Single-cell paired-end genome sequencing reveals structural variation per cell cycle. Nucleic Acids Res 41(12):6119–6138. doi:10.1093/nar/gkt345CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bidard FC, Weigelt B, Reis-Filho JS (2013) Going with the flow: from circulating tumor cells to DNA. Sci Transl Med 5(207):207 ps214. doi:10.1126/scitranslmed.3006305CrossRefGoogle Scholar
  52. 52.
    Bagasra O (2007) Protocols for the in situ PCR-amplification and detection of mRNA and DNA sequences. Nat Protoc 2(11):2782–2795. doi:10.1038/nprot.2007.395CrossRefPubMedGoogle Scholar
  53. 53.
    Larsson C, Grundberg I, Soderberg O, Nilsson M (2010) In situ detection and genotyping of individual mRNA molecules. Nat Methods 7(5):395–397. doi:10.1038/nmeth.1448CrossRefPubMedGoogle Scholar
  54. 54.
    Weibrecht I, Lundin E, Kiflemariam S, Mignardi M, Grundberg I, Larsson C, Koos B, Nilsson M, Soderberg O (2013) In situ detection of individual mRNA molecules and protein complexes or post-translational modifications using padlock probes combined with the in situ proximity ligation assay. Nat Protoc 8(2):355–372. doi:10.1038/nprot.2013.006CrossRefPubMedGoogle Scholar
  55. 55.
    Gerdes MJ, Sevinsky CJ, Sood A, Adak S, Bello MO, Bordwell A, Can A, Corwin A, Dinn S, Filkins RJ, Hollman D, Kamath V, Kaanumalle S, Kenny K, Larsen M, Lazare M, Li Q, Lowes C, McCulloch CC, McDonough E, Montalto MC, Pang Z, Rittscher J, Santamaria-Pang A, Sarachan BD, Seel ML, Seppo A, Shaikh K, Sui Y, Zhang J, Ginty F (2013) Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue. Proc Natl Acad Sci U S A 110(29):11982–11987. doi:10.1073/pnas.1300136110CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Faratian D, Christiansen J, Gustavson M, Jones C, Scott C, Um I, Harrison DJ (2011) Heterogeneity mapping of protein expression in tumors using quantitative immunofluorescence. J Vis Exp (56):e3334. doi:10.3791/3334Google Scholar
  57. 57.
    Capodieci P, Magi-Galluzzi C, Moreira G Jr, Zeheb R, Loda M (1998) Automated in situ hybridization: diagnostic and research applications. Diagn Mol Pathol 7(2):69–75CrossRefPubMedGoogle Scholar
  58. 58.
    Park SY, Gonen M, Kim HJ, Michor F, Polyak K (2010) Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. J Clin Invest 120(2):636–644. doi:10.1172/JCI40724CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Almendro V, Cheng YK, Randles A, Itzkovitz S, Marusyk A, Ametller E, Gonzalez-Farre X, Munoz M, Russnes HG, Helland A, Rye IH, Borresen-Dale AL, Maruyama R, van Oudenaarden A, Dowsett M, Jones RL, Reis-Filho J, Gascon P, Gonen M, Michor F, Polyak K (2014) Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep 6(3):514–527. doi:10.1016/j.celrep.2013.12.041CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Almendro V, Kim HJ, Cheng YK, Gonen M, Itzkovitz S, Argani P, van Oudenaarden A, Sukumar S, Michor F, Polyak K (2014) Genetic and phenotypic diversity in breast tumor metastases. Cancer Res 74(5):1338–1348. doi:10.1158/0008-5472.CAN-13-2357-TCrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ikeda S, Takabe K, Inagaki M, Funakoshi N, Suzuki K (2007) Detection of gene point mutation in paraffin sections using in situ loop-mediated isothermal amplification. Pathol Int 57(9):594–599. doi:10.1111/j.1440–1827.2007.02144.xCrossRefPubMedGoogle Scholar
  62. 62.
    Low EO, Gibbins JR, Walker DM (2000) In situ detection of specific p53 mutations in cultured cells using the amplification refractory mutation system polymerase chain reaction. Diagn Mol Pathol 9(4):210–220CrossRefPubMedGoogle Scholar
  63. 63.
    Lowe LA, Kuehn MR (2000) Whole mount in situ hybridization to study gene expression during mouse development. Methods Mol Biol 137:125–137. doi:10.1385/1-59259-066-7:125PubMedGoogle Scholar
  64. 64.
    Jungmann R, Avendano MS, Woehrstein JB, Dai M, Shih WM, Yin P (2014) Multiplexed 3D cellular super-resolution imaging with DNA-PAINT and Exchange-PAINT. Nat Methods 11(3):313–318. doi:10.1038/nmeth.2835CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 134(6):907–922. doi:10.1043/1543-2165-134.6.907PubMedPubMedCentralGoogle Scholar
  66. 66.
    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892. doi:10.1056/NEJMoa1113205CrossRefPubMedGoogle Scholar
  67. 67.
    Allison KH, Dintzis SM, Schmidt RA (2011) Frequency of HER2 heterogeneity by fluorescence in situ hybridization according to CAP expert panel recommendations: time for a new look at how to report heterogeneity. Am J Clin Pathol 136(6):864–871. doi:10.1309/AJCPXTZSKBRIP07WCrossRefPubMedGoogle Scholar
  68. 68.
    Seol H, Lee HJ, Choi Y, Lee HE, Kim YJ, Kim JH, Kang E, Kim SW, Park SY (2012) Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol 25(7):938–948. doi:10.1038/modpathol.2012.36CrossRefPubMedGoogle Scholar
  69. 69.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2014) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138(2):241–256. doi:10.5858/arpa.2013-0953-SACrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Magurran AE (2004) Measuring biological diversity. Blackwell, MaldenGoogle Scholar
  71. 71.
    Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312. doi:nrc2627[pii]10.1038/nrc2627CrossRefPubMedGoogle Scholar
  72. 72.
    Collins VP, Loeffler RK, Tivey H (1956) Observations on growth rates of human tumors. Am J Roentgenol Radium Ther Nucl Med 76(5):988–1000PubMedGoogle Scholar
  73. 73.
    Steel GG, Lamerton LF (1966) The growth rate of human tumours. Br J Cancer 20(1):74–86CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Amir E, Miller N, Geddie W, Freedman O, Kassam F, Simmons C, Oldfield M, Dranitsaris G, Tomlinson G, Laupacis A, Tannock IF, Clemons M (2012) Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol 30(6):587–592. doi:10.1200/JCO.2010.33.5232CrossRefPubMedGoogle Scholar
  75. 75.
    Wilking U, Karlsson E, Skoog L, Hatschek T, Lidbrink E, Elmberger G, Johansson H, Lindstrom L, Bergh J (2011) HER2 status in a population-derived breast cancer cohort: discordances during tumor progression. Breast Cancer Res Treat 125(2):553–561. doi:10.1007/s10549-010-1029-2CrossRefPubMedGoogle Scholar
  76. 76.
    Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14(9):985–990. doi:10.1038/nm.1789CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, Antipova A, Lee C, McKernan K, De La VFM, Kinzler KW, Vogelstein B, Diaz LA Jr, Velculescu VE (2010) Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2(20):20ra14. doi:10.1126/scitranslmed.3000702CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, Dawson SJ, Piskorz AM, Jimenez-Linan M, Bentley D, Hadfield J, May AP, Caldas C, Brenton JD, Rosenfeld N (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4(136):136ra168. doi:10.1126/scitranslmed.3003726CrossRefGoogle Scholar
  79. 79.
    Martins D, Beca F, Schmitt F (2014) Metastatic breast cancer: mechanisms and opportunities for cytology. Cytopathology 25(4):225–230. doi:10.1111/cyt.12158CrossRefPubMedGoogle Scholar
  80. 80.
    Beca F, Schmitt F (2014) Growing indication for FNA to study and analyze tumor heterogeneity at metastatic sites. Cancer Cytopathol 122(7):504–511. doi:10.1002/cncy.21395CrossRefPubMedGoogle Scholar
  81. 81.
    Montagna E, Cancello G, Dellapasqua S, Munzone E, Colleoni M (2014) Metronomic therapy and breast cancer: a systematic review. Cancer Treat Rev 40(8):942–950. doi:10.1016/j.ctrv.2014.06.002CrossRefPubMedGoogle Scholar
  82. 82.
    Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de BF, Viale G, Goldhirsch A (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13(1):73–80Google Scholar
  83. 83.
    Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M (2006) Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 6:225. doi:10.1186/1471-2407-6-225CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Gatenby RA, Silva AS, Gillies RJ, Frieden BR (2009) Adaptive therapy. Cancer Res 69(11):4894–4903. doi:10.1158/0008-5472.CAN-08-3658CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Norton L, Simon R (1977) Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 61(7):1307–1317PubMedGoogle Scholar
  86. 86.
    Norton L, Simon R (1986) The Norton-Simon hypothesis revisited. Cancer Treat Rep 70(1):163–169PubMedGoogle Scholar
  87. 87.
    Janiszewska M, Beca F, Polyak K (2014) Tumor heterogeneity: the lernaean hydra of oncology? Oncology 28(9):781–782PubMedGoogle Scholar
  88. 88.
    Neckers L, Workman P (2012) Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 18(1):64–76. doi:10.1158/1078-0432.CCR-11-1000CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Jarosz DF, Lindquist S (2010) Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330(6012):1820–1824. doi:10.1126/science.1195487CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, D’Andrea G, Dickler M, Moynahan ME, Sugarman S, Ma W, Patil S, Norton L, Hannah AL, Hudis C (2011) HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 17(15):5132–5139. doi:10.1158/1078-0432.CCR-11-0072CrossRefPubMedGoogle Scholar
  91. 91.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339(6127):1546–1558. doi:10.1126/science.1235122CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Wilting RH, Dannenberg JH (2012) Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist Updat 15(1–2):21–38. doi:10.1016/j.drup.2012.01.008CrossRefPubMedGoogle Scholar

Copyright information

© Breast Cancer Research Foundation 2016

Authors and Affiliations

  1. 1.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  2. 2.Department of MedicineHarvard Medical SchoolBostonUSA
  3. 3.IPATIMUP—Institute of Molecular Pathology and Immunology of the University of PortoPortoPortugal
  4. 4.Department of MedicineBrigham and Women’s HospitalBostonUSA

Personalised recommendations