Biological characterisation of breast cancer by means of PET

  • Andreas K. Buck
  • Holger Schirrmeister
  • Torsten Mattfeldt
  • Sven N. Reske


Breast cancer is associated with increased glucose consumption and can therefore be visualised with the glucose analogue [18F]2-deoxy-2-fluoro-d-glucose (FDG) and positron emission tomography (PET). FDG uptake in the primary tumour can vary substantially, and specific tumour characteristics have been demonstrated to determine the degree of glucose metabolism. Factors with a major influence on FDG uptake in breast cancer comprise expression of glucose transporter Glut-1 and hexokinase I, number of viable tumour cells per volume, histological subtype, tumour grading, microvessel density and proliferative activity. Recently, an association between high FDG uptake and a worse prognosis was suggested. Several studies have been performed correlating FDG uptake with a variety of prognostic and molecular biomarkers as well as parameters predicting tumour response to therapy. However, a correlation with important clinical prognostic markers such as axillary lymph node status and size of the primary tumour, expression of oestrogen and progesterone receptors, proto-oncogene c-erbB-2 or VEGF could not be demonstrated. The lack of correlation with important markers of prognosis does not suggest that FDG uptake might be used as a prognostic criterion in breast cancer. Innovative radiotracers for specific imaging of tumoural perfusion ([15O]H2O), hormone receptor expression ([18F]FES), protein synthesis ([11C]methionine), proliferation rate ([18F]FLT) or bone mineralisation ([18F]fluoride) may provide additional information compared with that provided by FDG PET.


FDG uptake Breast cancer Molecular biomarkers Proliferation Prognosis 


  1. 1.
    Avril N, Dose J, Janicke F. Metabolic characterization of breast tumours with positron emission tomography using F-18 fluorodeoxyglucose. J Clin Oncol 1996; 14:1848–1857.PubMedGoogle Scholar
  2. 2.
    Avril N, Menzel M, Dose J, Schelling M, Weber W, Jänicke F, Nathrath W, Schwaiger M. Glucose metabolism of breast cancer assessed by18F-FDG PET: histologic and immunohistochemical tissue analysis. J Nucl Med 2001; 42:9–16.PubMedGoogle Scholar
  3. 3.
    Schirrmeister H, Kühn T, Guhlmann A, Santjohanser C, Hörster T, Nüssle K, Koretz K, Glatting G, Rieber A, Kreienberg R, Buck A, Reske SN. Fluorine-18 2-deoxy-2-fluoro-d-glucose PET in the preoperative staging of breast cancer: comparison with the standard staging procedures. Eur J Nucl Med 2001; 28:351–358.PubMedGoogle Scholar
  4. 4.
    Nicoletto MO, Donach M, De Nicolo A, Artioli G, Banna G, Monfardini S. BRCA-1 and BRCA-2 mutations as prognostic factors in clinical practice and genetic counselling. Cancer Treat Rev 2001; 27:295–304.CrossRefPubMedGoogle Scholar
  5. 5.
    Warburg O, Posener K, Negelein E. The metabolism of cancer cells. Biochem Zschr 1924; 152:129–169.Google Scholar
  6. 6.
    Dehdashti F, Mortimer J, Siegel B. Positron tomographic assessment of estrogen receptors in breast cancer: a comparison with FDG-PET and in vitro receptor assays. J Nucl Med 1995; 36:1766–1774.PubMedGoogle Scholar
  7. 7.
    Higashi K, Clavo AC, Wahl RL. Does FDG uptake measure proliferative activity of human cancer cells? In vitro comparison with DNA flow cytometry and tritiated thymidine uptake. J Nucl Med 1993; 34:414–419.PubMedGoogle Scholar
  8. 8.
    Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL. Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: I. Are inflammatory cells important? J Nucl Med 1995; 36:1854–1861.PubMedGoogle Scholar
  9. 9.
    Bos R, van Der Hoeven JJ, van Der Wall E, et al. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 2002; 20:379–387.PubMedGoogle Scholar
  10. 10.
    Kubota K, Matsuzawa T, Fujiwara T, et al. Differential diagnosis of lung tumor with positron emission tomography: a prospective study. J Nucl Med 1990; 31:1927–1932.PubMedGoogle Scholar
  11. 11.
    Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 1992; 33:1972–1980.PubMedGoogle Scholar
  12. 12.
    Maschauer S, Prante O, Hoffmann M, Deichen JT, Kuwert T. Characterization of18F-FDG uptake in human endothelial cells in vitro. J Nucl Med 2004; 45:455–460.PubMedGoogle Scholar
  13. 13.
    Reske SN, Grillenberger KG, Glatting G, et al. Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma. J Nucl Med 1997; 38:1344–1348.PubMedGoogle Scholar
  14. 14.
    Brown RS, Wahl RL. Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer 1993; 72:2979–2985.PubMedGoogle Scholar
  15. 15.
    Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL. Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. Cancer Res 1996; 56:2468–2471.PubMedGoogle Scholar
  16. 16.
    Caraco C, Aloj L, Chen LY, Chou JY, Eckelman WC. Cellular release of [18F]2-fluoro-2-deoxyglucose as a function of the glucose-6-phosphatase enzyme system. J Biol Chem 2000; 275:18489–18494.CrossRefPubMedGoogle Scholar
  17. 17.
    Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL. Intratumoral distribution of tritiated-FDG in breast carcinoma: correlation between Glut-1 expression and FDG uptake. J Nucl Med 1996; 37:1042–1047.PubMedGoogle Scholar
  18. 18.
    Aloj L, Caraco C, Jagoda E, Eckelman WC, Neumann RD. Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-d-glucose uptake in A431 and T47D cells in culture. Cancer Res 1999; 59:4709–4714.PubMedGoogle Scholar
  19. 19.
    Torizuka T, Zasadny KR, Recker B, Wahl RL. Untreated primary lung and breast cancers: correlation between F-18 FDG kinetic rate constants and findings of in vitro studies. Radiology 1998; 207:767–774.PubMedGoogle Scholar
  20. 20.
    Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 2001; 276:43407–43412.CrossRefPubMedGoogle Scholar
  21. 21.
    Brown RS, Goodman TM, Zasadny KR, Greenson JK, Wahl RL. Expression of hexokinase II and Glut-1 in untreated human breast cancer. Nucl Med Biol 2002; 29:443–453.CrossRefPubMedGoogle Scholar
  22. 22.
    Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med 1995; 36:1625–1632.PubMedGoogle Scholar
  23. 23.
    Burgman P, Odonoghue JA, Humm JL, Ling CC. Hypoxia-induced increase in FDG uptake in MCF7 cells. J Nucl Med 2001; 42:170–175.PubMedGoogle Scholar
  24. 24.
    Pedersen MW, Holm S, Lund EL, Hojgaard L, Kristjansen PE. Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. Neoplasia 2001; 3:80–87.CrossRefPubMedGoogle Scholar
  25. 25.
    Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001; 93:309–314.CrossRefPubMedGoogle Scholar
  26. 26.
    Semenza GL. Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 2000; 59:47–53.CrossRefPubMedGoogle Scholar
  27. 27.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86:353–364.PubMedGoogle Scholar
  28. 28.
    Oshida M, Uno K, Suzuki M, et al. Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2-deoxy-2-fluoro[18F]-d-glucose. Cancer 1998; 82:2227–2234.PubMedGoogle Scholar
  29. 29.
    Hasan J, Byers R, Jayson GC. Intra-tumoural microvessel density in human solid tumours. Br J Cancer 2002; 86:1566–1577.CrossRefPubMedGoogle Scholar
  30. 30.
    Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 1991; 324:1–8.PubMedGoogle Scholar
  31. 31.
    Masood S, Chiao J. Pathology of breast cancer. In: Taillefer R, Khalkhali I, Waxman AD, Biersack HJ, eds. Radionuclide imaging of the breast. New York: Dekker, 1998.Google Scholar
  32. 32.
    Buck A, Schirrmeister H, Kuhn T, Shen C, Kalker T, Kotzerke J, Dankerl A, Glatting G, Reske S, Mattfeldt T. FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters. Eur J Nucl Med Mol Imaging 2002; 29:1317–1323.CrossRefPubMedGoogle Scholar
  33. 33.
    Crippa F, Seregni E, Agresti R, Chiesa C, Pascali C, Bogni A, Decise D, De Sanctis V, Greco M, Daidone MG, Bombardieri E. Association between [18F]fluorodeoxy-glucose uptake and postoperative histopathology, hormone receptor status, thymidine labelling index and p53 in primary breast cancer: a preliminary observation. Eur J Nucl Med 1998; 25:1429–1434.PubMedGoogle Scholar
  34. 34.
    Avril N, Rose CA, Schelling M, Dose J, Kuhn W, Bense S, Weber W, Ziegler S, Graeff H, Schwaiger M. Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations. J Clin Oncol 2000; 18:3495–3502.PubMedGoogle Scholar
  35. 35.
    Hayes DF, Isaacs C, Stearns V. Prognostic factors in breast cancer: current and new predictors of metastasis. J Mammary Gland Biol Neoplasia 2001; 6:375–392.CrossRefPubMedGoogle Scholar
  36. 36.
    Loprinzi CL, Thome SD. Understanding the utility of adjuvant systemic therapy for primary breast cancer. J Clin Oncol 2001; 19:972–979.PubMedGoogle Scholar
  37. 37.
    MacGrogan G, Mauriac L, Durand M, Bonichon F, Trojani M, deMascarel I, Coindre J. Primary chemotherapy in breast invasive carcinoma: predictive value of the immunohistochemical detection of hormonal receptors, p53, c-erbB-2, MIB1, pS2 and GSTπ. Br J Cancer 1996; 74:1458–1465.PubMedGoogle Scholar
  38. 38.
    Dettmar P, Harbeck N, Thommsen C, Pache L, Ziffer P, Fizi K, Janicke F, Nathrath W, Schmitt M, Graeff H, Hofler H. Prognostic impact of proliferation-associated factors MIB1 (Ki-67) and S-phase in node-negative breast cancer. Br J Cancer 1997; 75:1525–1533.PubMedGoogle Scholar
  39. 39.
    Gebauer G, Fehm T, Merkle E, Jaeger W, Mitze M. Micrometastases in axillary lymph nodes and bone marrow of lymph node-negative breast cancer patients—prognostic relevance after 10 years. Anticancer Res 2003; 23:4319–4324.PubMedGoogle Scholar
  40. 40.
    den Bakker MA, van Weeszenberg A, de Kanter AY, Beverdam FH, Pritchard C, van der Kwast TH, Menke-Pluymers M. Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance. J Clin Pathol 2002; 55:932–935.CrossRefPubMedGoogle Scholar
  41. 41.
    Adler LP, Crowe JP, al-Kaisi NK, Sunshine JL. Evaluation of breast masses and axillary lymph nodes with [F-18] 2-deoxy-2-fluoro-d-glucose PET. Radiology 1993; 187:743–750.PubMedGoogle Scholar
  42. 42.
    Crowe JP Jr, Adler LP, Shenk RR, Sunshine J. Positron emission tomography and breast masses: comparison with clinical, mammographic, and pathological findings. Ann Surg Oncol 1994; 1:132–140.PubMedGoogle Scholar
  43. 43.
    Keshgegian A, Cnaan A. Proliferation markers in breast carcinoma. Am J Cell Pathol 1995; 5:42–49.Google Scholar
  44. 44.
    Barnard NJ, Hall PA, Lemoine NR. Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variables. J Pathol 1987; 152:287–295.PubMedGoogle Scholar
  45. 45.
    Barbareschi M. Prognostic value of immunohistochemical expression of p53 in breast carcinomas. A review of the literature involving over 9,000 patients. Appl Immunohistochem 1996; 4:106–116.Google Scholar
  46. 46.
    Alred D, Clatk G, Elledge R. Association of p53 protein expression with tumour cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst 1993; 85:200–206.PubMedGoogle Scholar
  47. 47.
    Overgaard J, Yilmaz M, Guldberg P, Hansen L, Alsner J. TP53 mutation is an independent prognostic marker for poor outcome in both node-negative and node-positive breast cancer. Acta Oncol 2000; 39:327–333.PubMedGoogle Scholar
  48. 48.
    Pich A, Margaria E, Chiusa L. Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival. J Clin Oncol 2000; 18:2948–2956.PubMedGoogle Scholar
  49. 49.
    Rudolph P, Alm P, Olsson H, Heidebrecht H, Ferno M, Baldetorp B, Parwaresch R. Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer. Hum Pathol 2001; 32:311–319.PubMedGoogle Scholar
  50. 50.
    Beaney RP, Lammertsma AA, Jones T, McKenzie CG, Halnan KE. Positron emission tomography for in-vivo measurement of regional blood flow, oxygen utilisation, and blood volume in patients with breast carcinoma. Lancet 1984; 1:131–134.PubMedGoogle Scholar
  51. 51.
    Wilson CB, Lammertsma AA, McKenzie CG, Sikora K, Jones T. Measurements of blood flow and exchanging water space in breast tumors using positron emission tomography: a rapid and noninvasive dynamic method. Cancer Res 1992; 52:1592–1597.PubMedGoogle Scholar
  52. 52.
    Zasadny KR, Tatsumi M, Wahl RL. FDG metabolism and uptake versus blood flow in women with untreated primary breast cancers. Eur J Nucl Med Mol Imaging 2003; 30:274–280.PubMedGoogle Scholar
  53. 53.
    McGuire AH, Dehdashti F, Siegel BA, Lyss AP, Brodack JW, Mathias CJ, Mintun MA, Katzenellenbogen JA, Welch MJ. Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma. J Nucl Med 1991; 32:1526–1531.PubMedGoogle Scholar
  54. 54.
    Mortimer JE, Dehdashti F, Siegel BA, Trinkaus K, Katzenellenbogen JA, Welch MJ. Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol 2001; 19:2797–2803.PubMedGoogle Scholar
  55. 55.
    Leskinen-Kallio S, Nagren K, Lehikoinen P, Ruotsalainen U, Joensuu H. Uptake of11C-methionine in breast cancer studied by PET. An association with the size of S-phase fraction. Br J Cancer 1991; 64:1121–1124.PubMedGoogle Scholar
  56. 56.
    Jansson T, Westlin JE, Ahlstrom H, Lilja A, Langstrom B, Bergh J. Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: a method for early therapy evaluation? J Clin Oncol 1995; 13:1470–1477.PubMedGoogle Scholar
  57. 57.
    Buck AK, Schirrmeister H, Hetzel M, Von Der Heide M, Halter G, Glatting G, Mattfeldt T, Liewald F, Reske SN, Neumaier B. 3-deoxy-3-[18F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res 2002; 62:3331–3334.PubMedGoogle Scholar
  58. 58.
    Cobben DC, van der Laan BF, Hoekstra HJ, Jager PL, Willemsen AT, Vaalburg W, Suurmeijer AJ, Elsinga PH. Detection of mammary, laryngeal and soft tissue tumors with FLT-PET. J Nucl Med 2002; 43:P278.Google Scholar
  59. 59.
    Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer 1987; 55:61–66.PubMedGoogle Scholar
  60. 60.
    Schirrmeister H, Guhlmann A, Kotzerke J, Santjohanser C, Kuhn T, Kreienberg R, Messer P, Nussle K, Elsner K, Glatting G, Trager H, Neumaier B, Diederichs C, Reske SN. Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography. J Clin Oncol 1999; 17:2381–2389.PubMedGoogle Scholar
  61. 61.
    Yamashita K, Koyama H, Inaji H. Prognostic significance of bone metastasis from breast cancer. Clin Orthop Related Res 1995; 312:89–94.Google Scholar
  62. 62.
    Cook GJ, Houston S, Rubens R, Maisey MN, Fogelman I. Detection of bone metastases in breast cancer by FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol 1998; 16:3375–3379.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Andreas K. Buck
    • 1
  • Holger Schirrmeister
    • 1
  • Torsten Mattfeldt
    • 2
  • Sven N. Reske
    • 1
  1. 1.Department of Nuclear MedicineUniversity Hospital UlmUlmGermany
  2. 2.Department of PathologyUniversity Hospital UlmGermany

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