Current Oncology Reports

, 16:403 | Cite as

Current Status of Molecular Biomarkers in Endometrial Cancer

Gynecologic Cancers (NS Reed, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Gynecologic Cancers

Abstract

In spite of the high and increasing incidence of endometrial cancer, our current models for prediction of prognosis and even more treatment response are suboptimal, and molecular biomarkers to assist clinical decision making are needed. In this review an overview is given of the currently known as well as promising prognostic and predictive biomarkers in endometrial carcinoma. Key clinical challenges, where use of molecular biomarkers can meet clinical needs, are highlighted. The current status for the presently most promising prognostic and predictive biomarkers in endometrial carcinoma is reviewed. DNA ploidy, p53 status, hormone receptor level, HER2, stathmin, L1 cell adhesion molecule expression and other biomarkers are discussed in relation to the scientific robustness of various essential steps in biomarker development and (current) clinical applicability for individualizing treatment strategies. Tumour heterogeneity and its consequences for biomarker assessment and the importance of developing standardised tests for implementation are discussed. To improve the development and clinical uptake of biomarkers, several strategies are proposed.

Keywords

Endometrial cancer Molecular biomarkers Prognostic biomarkers Predictive biomarkers Biomarker validation Clinical utility Gynaecologic cancer 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Wright JD, Barrena Medel NI, Sehouli J, Fujiwara K, Herzog TJ. Contemporary management of endometrial cancer. Lancet. 2012;379(9823):1352–60. doi:10.1016/S0140-6736(12)60442-5.PubMedGoogle Scholar
  2. 2.
    Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78. doi:10.1016/S0140-6736(08)60269-X.PubMedGoogle Scholar
  3. 3.
    Webb PM. Obesity and gynecologic cancer etiology and survival. In: 2013 educational book. Alexandria: American Society of Clinical Oncology; 2013. doi:10.1200/EdBook_AM.2013.33.e222.
  4. 4.
    Duong LM, Wilson RJ, Ajani UA, Singh SD, Eheman CR. Trends in endometrial cancer incidence rates in the United States, 1999-2006. J Womens Health. 2011;20(8):1157–63. doi:10.1089/jwh.2010.2529.Google Scholar
  5. 5.
    Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–85. doi:10.1200/JCO.2010.34.1578.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Salvesen HB, Haldorsen IS, Trovik J. Markers for individualised therapy in endometrial carcinoma. Lancet Oncol. 2012;13(8):e353–61. doi:10.1016/S1470-2045(12)70213-9.PubMedGoogle Scholar
  7. 7.
    Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10–7.PubMedGoogle Scholar
  8. 8.
    Dedes KJ, Wetterskog D, Ashworth A, Kaye SB, Reis-Filho JS. Emerging therapeutic targets in endometrial cancer. Nat Rev Clin Oncol. 2011;8(5):261–71. doi:10.1038/nrclinonc.2010.216.PubMedGoogle Scholar
  9. 9.
    Biomarkers Definitions Working G. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. doi:10.1067/mcp.2001.113989.Google Scholar
  10. 10.
    Trovik J, Mauland KK, Werner HM, Wik E, Helland H, Salvesen HB. Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective. Gynecol Oncol. 2012;125(2):381–7. doi:10.1016/j.ygyno.2012.01.050.PubMedGoogle Scholar
  11. 11.
    Pelikan HM, Trum JW, Bakers FC, Beets-Tan RG, Smits LJ, Kruitwagen RF. Diagnostic accuracy of preoperative tests for lymph node status in endometrial cancer: a systematic review. Cancer Imaging. 2013;13(3):314–22. doi:10.1102/1470-7330.2013.0032.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Yoon JH, Yoo SC, Kim WY, Chang SJ, Chang KH, Ryu HS. Para-aortic lymphadenectomy in the management of preoperative grade 1 endometrial cancer confined to the uterine corpus. Ann Surg Oncol. 2010;17(12):3234–40. doi:10.1245/s10434-010-1199-5.PubMedGoogle Scholar
  13. 13.
    Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100(23):1707–16. doi:10.1093/jnci/djn397.PubMedGoogle Scholar
  14. 14.
    group As, Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373(9658):125–36. doi:10.1016/S0140-6736(08)61766-3.PubMedGoogle Scholar
  15. 15.
    May K, Bryant A, Dickinson HO, Kehoe S, Morrison J. Lymphadenectomy for the management of endometrial cancer. Cochrane Database Syst Rev. 2010;1, CD007585. doi:10.1002/14651858.CD007585.pub2.PubMedGoogle Scholar
  16. 16.
    Abu-Rustum NR, Alektiar K, Iasonos A, Lev G, Sonoda Y, Aghajanian C, et al. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol Oncol. 2006;103(2):714–8. doi:10.1016/j.ygyno.2006.03.055.PubMedGoogle Scholar
  17. 17.
    Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105(2):103–4.PubMedGoogle Scholar
  18. 18.
    Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, Soslow RA, Dao F, Sonoda Y, et al. Sentinel lymph node mapping for grade 1 endometrial cancer: is it the answer to the surgical staging dilemma? Gynecol Oncol. 2009;113(2):163–9. doi:10.1016/j.ygyno.2009.01.003.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Kim CH, Khoury-Collado F, Barber EL, Soslow RA, Makker V, Leitao Jr MM, et al. Sentinel lymph node mapping with pathologic ultrastaging: a valuable tool for assessing nodal metastasis in low-grade endometrial cancer with superficial myoinvasion. Gynecol Oncol. 2013;131(3):714–9. doi:10.1016/j.ygyno.2013.09.027.PubMedGoogle Scholar
  20. 20.
    Ballester M, Koskas M, Coutant C, Chereau E, Seror J, Rouzier R, et al. Does the use of the 2009 FIGO classification of endometrial cancer impact on indications of the sentinel node biopsy? BMC Cancer. 2010;10:465. doi:10.1186/1471-2407-10-465.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Mariani A, Sebo TJ, Katzmann JA, Roche PC, Keeney GL, Lesnick TG, et al. Endometrial cancer: can nodal status be predicted with curettage? Gynecol Oncol. 2005;96(3):594–600. doi:10.1016/j.ygyno.2004.11.030.PubMedGoogle Scholar
  22. 22.
    Steinbakk A, Malpica A, Slewa A, Skaland I, Gudlaugsson E, Janssen EA, et al. Biomarkers and microsatellite instability analysis of curettings can predict the behavior of FIGO stage I endometrial endometrioid adenocarcinoma. Mod Pathol. 2011;24(9):1262–71. doi:10.1038/modpathol.2011.75.PubMedGoogle Scholar
  23. 23.
    Trovik J, Wik E, Stefansson I, Carter SL, Beroukhim R, Oyan AM, et al. Stathmin is superior to AKT and phospho-AKT staining for the detection of phosphoinositide 3-kinase activation and aggressive endometrial cancer. Histopathology. 2010;57(4):641–6. doi:10.1111/j.1365-2559.2010.03661.x.PubMedGoogle Scholar
  24. 24.
    Trovik J, Wik E, Werner HM, Krakstad C, Helland H, Vandenput I, et al. Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial. Eur J Cancer. 2013;49(16):3431–41. doi:10.1016/j.ejca.2013.06.016.PubMedGoogle Scholar
  25. 25.
    Sood AK, Buller RE, Burger RA, Dawson JD, Sorosky JI, Berman M. Value of preoperative CA 125 level in the management of uterine cancer and prediction of clinical outcome. Obstet Gynecol. 1997;90(3):441–7.PubMedGoogle Scholar
  26. 26.
    Ambeba E, Linkov F. Advancements in the use of blood tests for cancer screening in women at high risk for endometrial and breast cancer. Future Oncol. 2011;7(12):1399–414. doi:10.2217/fon.11.127.PubMedGoogle Scholar
  27. 27.
    Antonsen SL, Hogdall E, Christensen IJ, Lydolph M, Tabor A, Loft Jakobsen A, et al. HE4 and CA125 levels in the preoperative assessment of endometrial cancer patients: a prospective multicenter study (ENDOMET). Acta Obstet Gynecol Scand. 2013;92(11):1313–22. doi:10.1111/aogs.12235.PubMedGoogle Scholar
  28. 28.
    Staff AC, Trovik J, Eriksson AG, Wik E, Wollert KC, Kempf T, et al. Elevated plasma growth differentiation factor-15 correlates with lymph node metastases and poor survival in endometrial cancer. Clin Cancer Res. 2011;17(14):4825–33. doi:10.1158/1078-0432.CCR-11-0715.PubMedGoogle Scholar
  29. 29.
    Alcazar JL, Jurado M. Three-dimensional ultrasound for assessing women with gynecological cancer: a systematic review. Gynecol Oncol. 2011;120(3):340–6. doi:10.1016/j.ygyno.2010.10.023.PubMedGoogle Scholar
  30. 30.
    Haldorsen IS, Berg A, Werner HM, Magnussen IJ, Helland H, Salvesen OO, et al. Magnetic resonance imaging performs better than endocervical curettage for preoperative prediction of cervical stromal invasion in endometrial carcinomas. Gynecol Oncol. 2012;126(3):413–8. doi:10.1016/j.ygyno.2012.05.009.PubMedGoogle Scholar
  31. 31.
    Haldorsen IS, Salvesen HB. Staging of endometrial carcinomas with MRI using traditional and novel MRI techniques. Clin Radiol. 2012;67(1):2–12. doi:10.1016/j.crad.2011.02.018.PubMedGoogle Scholar
  32. 32.
    Antonsen SL, Jensen LN, Loft A, Berthelsen AK, Costa J, Tabor A, et al. MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancer - a multicenter prospective comparative study. Gynecol Oncol. 2013;128(2):300–8. doi:10.1016/j.ygyno.2012.11.025.PubMedGoogle Scholar
  33. 33.
    Engelsen IB, Stefansson IM, Akslen LA, Salvesen HB. GATA3 expression in estrogen receptor alpha-negative endometrial carcinomas identifies aggressive tumors with high proliferation and poor patient survival. Am J Obstet Gynecol. 2008;199(5):543.e1-7. doi:10.1016/j.ajog.2008.04.043.PubMedGoogle Scholar
  34. 34.
    Jongen V, Briet J, de Jong R, ten Hoor K, Boezen M, van der Zee A, et al. Expression of estrogen receptor-alpha and -beta and progesterone receptor-A and -B in a large cohort of patients with endometrioid endometrial cancer. Gynecol Oncol. 2009;112(3):537–42. doi:10.1016/j.ygyno.2008.10.032.PubMedGoogle Scholar
  35. 35.
    Engelsen IB, Stefansson I, Akslen LA, Salvesen HB. Pathologic expression of p53 or p16 in preoperative curettage specimens identifies high-risk endometrial carcinomas. Am J Obstet Gynecol. 2006;195(4):979–86. doi:10.1016/j.ajog.2006.02.045.PubMedGoogle Scholar
  36. 36.
    Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology. 2013;62(1):111–23. doi:10.1111/his.12053.PubMedGoogle Scholar
  37. 37.
    Garg K, Leitao Jr MM, Wynveen CA, Sica GL, Shia J, Shi W, et al. p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes. Mod Pathol. 2010;23(1):80–92. doi:10.1038/modpathol.2009.153.PubMedGoogle Scholar
  38. 38.
    Pradhan M, Davidson B, Abeler VM, Danielsen HE, Trope CG, Kristensen GB, et al. DNA ploidy may be a prognostic marker in stage I and II serous adenocarcinoma of the endometrium. Virchows Arch. 2012;461(3):291–8. doi:10.1007/s00428-012-1275-2.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Suehiro Y, Okada T, Okada T, Anno K, Okayama N, Ueno K, et al. Aneuploidy predicts outcome in patients with endometrial carcinoma and is related to lack of CDH13 hypermethylation. Clin Cancer Res. 2008;14(11):3354–61. doi:10.1158/1078-0432.CCR-07-4609.PubMedGoogle Scholar
  40. 40.
    Susini T, Amunni G, Molino C, Carriero C, Rapi S, Branconi F, et al. Ten-year results of a prospective study on the prognostic role of ploidy in endometrial carcinoma: dNA aneuploidy identifies high-risk cases among the so-called ‘low-risk’ patients with well and moderately differentiated tumors. Cancer. 2007;109(5):882–90. doi:10.1002/cncr.22465.PubMedGoogle Scholar
  41. 41.
    Wik E, Trovik J, Iversen OE, Engelsen IB, Stefansson IM, Vestrheim LC, et al. Deoxyribonucleic acid ploidy in endometrial carcinoma: a reproducible and valid prognostic marker in a routine diagnostic setting. Am J Obstet Gynecol. 2009;201(6):603.e1-7. doi:10.1016/j.ajog.2009.07.029.PubMedGoogle Scholar
  42. 42.
    Wik E, Raeder MB, Krakstad C, Trovik J, Birkeland E, Hoivik EA, et al. Lack of estrogen receptor-alpha is associated with epithelial-mesenchymal transition and PI3K alterations in endometrial carcinoma. Clin Cancer Res. 2013;19(5):1094–105. doi:10.1158/1078-0432.CCR-12-3039.PubMedGoogle Scholar
  43. 43.
    Mauland KK, Wik E, Salvesen HB. Clinical value of DNA content assessment in endometrial cancer. Cytom Part B. 2014;86(3):154–63. doi:10.1002/cyto.b.21164.Google Scholar
  44. 44.
    Risinger JI, Hayes K, Maxwell GL, Carney ME, Dodge RK, Barrett JC, et al. PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics. Clin Cancer Res. 1998;4(12):3005–10.PubMedGoogle Scholar
  45. 45.•
    Krakstad C, Trovik J, Wik E, Engelsen IB, Werner HM, Birkeland E, et al. Loss of GPER identifies new targets for therapy among a subgroup of ERalpha-positive endometrial cancer patients with poor outcome. Br J Cancer. 2012;106(10):1682–8. doi:10.1038/bjc.2012.91. Evaluation of hormone receptor status can potentially improve patient selection for endocrine treatment in endometrial cancer. This study shows that G-protein-coupled OR, an alternative OR, predicts poor survival in an OR-positive subgroup. The significant increase in biomarker loss from primary to metastatic disease may be important.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, Stefansson IM, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci U S A. 2009;106(12):4834–9. doi:10.1073/pnas.0806514106.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW. PIK3R1 (p85alpha) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 2011;71(12):4061–7. doi:10.1158/0008-5472.CAN-11-0549.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1(2):170–85. doi:10.1158/2159-8290.CD-11-0039.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. doi:10.1038/nature12113.Google Scholar
  50. 50.
    Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer. 2000;88(4):814–24.PubMedGoogle Scholar
  51. 51.
    Basil JB, Goodfellow PJ, Rader JS, Mutch DG, Herzog TJ. Clinical significance of microsatellite instability in endometrial carcinoma. Cancer. 2000;89(8):1758–64.PubMedGoogle Scholar
  52. 52.
    Catasus L, Gallardo A, Cuatrecasas M, Prat J. Concomitant PI3K-AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol. 2009;22(4):522–9. doi:10.1038/modpathol.2009.5.PubMedGoogle Scholar
  53. 53.
    Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, et al. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol. 2006;24(15):2376–85. doi:10.1200/JCO.2005.03.4827.PubMedGoogle Scholar
  54. 54.
    Tanaka Y, Terai Y, Kawaguchi H, Fujiwara S, Yoo S, Tsunetoh S, et al. Prognostic impact of EMT (epithelial-mesenchymal-transition)-related protein expression in endometrial cancer. Cancer Biol Ther. 2013;14(1):13–9. doi:10.4161/cbt.22625.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Yi TZ, Guo J, Zhou L, Chen X, Mi RR, Qu QX, et al. Prognostic value of E-cadherin expression and CDH1 promoter methylation in patients with endometrial carcinoma. Cancer Investig. 2011;29(1):86–92. doi:10.3109/07357907.2010.512603.Google Scholar
  56. 56.
    Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C, et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008;105(25):8713–7. doi:10.1073/pnas.0803379105.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, et al. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLoS One. 2012;7(2):e30801. doi:10.1371/journal.pone.0030801.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Birkeland E, Wik E, Mjos S, Hoivik EA, Trovik J, Werner HM, et al. KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer. Br J Cancer. 2012;107(12):1997–2004. doi:10.1038/bjc.2012.477.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Stefansson IM, Salvesen HB, Akslen LA. Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J Clin Oncol. 2004;22(7):1242–52. doi:10.1200/JCO.2004.09.034.PubMedGoogle Scholar
  60. 60.
    Fadare O, Renshaw IL, Liang SX. Does the loss of ARID1A (BAF-250a) expression in endometrial clear cell carcinomas have any clinicopathologic significance? A pilot assessment. J Cancer. 2012;3:129–36. doi:10.7150/jca.4140.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Wiegand KC, Lee AF, Al-Agha OM, Chow C, Kalloger SE, Scott DW, et al. Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J Pathol. 2011;224(3):328–33. doi:10.1002/path.2911.PubMedGoogle Scholar
  62. 62.
    Werner HM, Berg A, Wik E, Birkeland E, Krakstad C, Kusonmano K, et al. ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas. Mod Pathol. 2013;26(3):428–34. doi:10.1038/modpathol.2012.174.PubMedGoogle Scholar
  63. 63.
    Trovik J, Wik E, Stefansson IM, Marcickiewicz J, Tingulstad S, Staff AC, et al. Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrial cancer. Clin Cancer Res. 2011;17(10):3368–77. doi:10.1158/1078-0432.CCR-10-2412.PubMedGoogle Scholar
  64. 64.•
    Zeimet AG, Reimer D, Huszar M, Winterhoff B, Puistola U, Azim SA, et al. L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. J Natl Cancer Inst. 2013;105(15):1142–50. doi:10.1093/jnci/djt144. Although only published recently and so far in only one study, L1 cell adhesion molecule seems a very promising prognostic biomarker that may help to select those type 1 stage 1 endometrial cancer patients who need adjuvant treatment. Validation studies, also focused on the biological rationale, are needed.PubMedGoogle Scholar
  65. 65.
    Brennan DJ, Hackethal A, Metcalf AM, Coward J, Ferguson K, Oehler MK, et al. Serum HE4 as a prognostic marker in endometrial cancer–a population based study. Gynecol Oncol. 2014;132(1):159–65. doi:10.1016/j.ygyno.2013.10.036.PubMedGoogle Scholar
  66. 66.
    Nicklin J, Janda M, Gebski V, Jobling T, Land R, Manolitsas T, et al. The utility of serum CA-125 in predicting extra-uterine disease in apparent early-stage endometrial cancer. Int J Cancer. 2012;131(4):885–90. doi:10.1002/ijc.26433.PubMedGoogle Scholar
  67. 67.
    Mutz-Dehbalaie I, Egle D, Fessler S, Hubalek M, Fiegl H, Marth C, et al. HE4 is an independent prognostic marker in endometrial cancer patients. Gynecol Oncol. 2012;126(2):186–91. doi:10.1016/j.ygyno.2012.04.022.PubMedGoogle Scholar
  68. 68.
    Zanotti L, Bignotti E, Calza S, Bandiera E, Ruggeri G, Galli C, et al. Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome. Clin Chem Lab Med. 2012;50(12):2189–98. doi:10.1515/cclm-2011-0757.PubMedGoogle Scholar
  69. 69.
    Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513–6.PubMedGoogle Scholar
  70. 70.
    Food and Drug Administration. Drugs. http://www.fda.gov/Drugs (2014).
  71. 71.
    DiMasi JA, Grabowski HG. Economics of new oncology drug development. J Clin Oncol. 2007;25(2):209–16. doi:10.1200/JCO.2006.09.0803.PubMedGoogle Scholar
  72. 72.
    Dellinger TH, Monk BJ. Systemic therapy for recurrent endometrial cancer: a review of North American trials. Expert Rev Anticancer Ther. 2009;9(7):905–16. doi:10.1586/era.09.54.PubMedGoogle Scholar
  73. 73.
    Hudis CA. Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39–51. doi:10.1056/NEJMra043186.PubMedGoogle Scholar
  74. 74.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer Jr CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84. doi:10.1056/NEJMoa052122.PubMedGoogle Scholar
  75. 75.
    Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175–81. doi:10.1200/JCO.2008.21.2514.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Lee Y, Shim HS, Park MS, Kim JH, Ha SJ, Kim SH, et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with advanced squamous cell lung carcinoma. Clin Cancer Res. 2012;18(6):1760–8. doi:10.1158/1078-0432.CCR-11-2582.PubMedGoogle Scholar
  77. 77.
    Vandenput I, Trovik J, Leunen K, Wik E, Stefansson I, Akslen L, et al. Evolution in endometrial cancer: evidence from an immunohistochemical study. Int J Gynecol Cancer. 2011;21(2):316–22. doi:10.1097/IGC.0b013e31820575f5.PubMedGoogle Scholar
  78. 78.
    Decruze SB, Green JA. Hormone therapy in advanced and recurrent endometrial cancer: a systematic review. Int J Gynecol Cancer. 2007;17(5):964–78. doi:10.1111/j.1525-1438.2007.00897.x.PubMedGoogle Scholar
  79. 79.•
    Mackay HJ, Eisenhauer EA, Kamel-Reid S, Tsao M, Clarke B, Karakasis K, et al. Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer. 2013. doi:10.1002/cncr.28414. No combination of biomarkers was found to be predictive of mammalian target of rapamycin inhibitor activity in this study using archival tissue from nearly 100 women with recurrent endometrial cancer. The authors call for caution in enriching trials for patients with certain biomarker characteristics.PubMedGoogle Scholar
  80. 80.
    Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012;30(8):777–82. doi:10.1200/JCO.2011.36.1196.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Werner HM, Trovik J, Halle MK, Wik E, Akslen LA, Birkeland E, et al. Stathmin protein level, a potential predictive marker for taxane treatment response in endometrial cancer. PLoS One. 2014;9(2):e90141. doi:10.1371/journal.pone.0090141.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Meyer LA, Slomovitz BM, Djordjevic B, Westin SN, Iglesias DA, Munsell MF, et al. The search continues: looking for predictive biomarkers for response to Mammalian target of rapamycin inhibition in endometrial cancer. Int Gynecol Cancer. 2014;24(4):713–7. doi:10.1097/IGC.0000000000000118.Google Scholar
  83. 83.
    Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116(1):15–20. doi:10.1016/j.ygyno.2009.09.025.PubMedCentralPubMedGoogle Scholar
  84. 84.
    National Institutes of Health. NCT01237067. 2014. http://clinicaltrials.gov/show/NCT01237067. Accessed Apr 2014.
  85. 85.
    Nout RA, Bosse T, Creutzberg CL, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, et al. Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K-AKT, Wnt/β-catenin and P53 pathway activation. Gynecol Oncol. 2012;126(3):466–73. doi:10.1016/j.ygyno.2012.05.012.PubMedGoogle Scholar
  86. 86.
    Alkushi A, Clarke BA, Akbari M, Makretsov N, Lim P, Miller D, et al. Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data. Mod Pathol. 2007;20(11):1156–65. doi:10.1038/modpathol.3800950.PubMedGoogle Scholar
  87. 87.
    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. doi:10.1056/NEJMoa1113205.PubMedGoogle Scholar
  88. 88.
    Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 2012;72(19):4875–82. doi:10.1158/0008-5472.CAN-12-2217.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Buza N, Hui P. Marked heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma. Genes Chromosomes Cancer. 2013. doi:10.1002/gcc.22113.PubMedGoogle Scholar
  90. 90.
    Soslow RA, Wethington SL, Cesari M, Chiappetta D, Olvera N, Shia J, et al. Clinicopathologic analysis of matched primary and recurrent endometrial carcinoma. Am J Surg Pathol. 2012;36(12):1771–81. doi:10.1097/PAS.0b013e318273591a.PubMedGoogle Scholar
  91. 91.
    Thompson AM, Jordan LB, Quinlan P, Anderson E, Skene A, Dewar JA, et al. Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS). Breast Cancer Res. 2010;12(6):R92. doi:10.1186/bcr2771.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Arslan C, Sari E, Aksoy S, Altundag K. Variation in hormone receptor and HER-2 status between primary and metastatic breast cancer: review of the literature. Expert Opin Ther Targets. 2011;15(1):21–30. doi:10.1517/14656566.2011.537260.PubMedGoogle Scholar
  93. 93.
    Khasraw M, Brogi E, Seidman AD. The need to examine metastatic tissue at the time of progression of breast cancer: is re-biopsy a necessity or a luxury? Curr Oncol Rep. 2011;13(1):17–25. doi:10.1007/s11912-010-0137-9.PubMedGoogle Scholar
  94. 94.
    Simmons C, Miller N, Geddie W, Gianfelice D, Oldfield M, Dranitsaris G, et al. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol. 2009;20(9):1499–504. doi:10.1093/annonc/mdp028.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–312. doi:10.1200/JCO.2007.14.2364.PubMedGoogle Scholar
  96. 96.
    Lindstrom LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol. 2012;30(21):2601–8. doi:10.1200/JCO.2011.37.2482.PubMedGoogle Scholar
  97. 97.
    Amir E, Clemons M, Purdie CA, Miller N, Quinlan P, Geddie W, et al. Tissue confirmation of disease recurrence in breast cancer patients: pooled analysis of multi-centre, multi-disciplinary prospective studies. Cancer Treat Rev. 2012;38(6):708–14. doi:10.1016/j.ctrv.2011.11.006.PubMedGoogle Scholar
  98. 98.
    Amir E, Miller N, Geddie W, Freedman O, Kassam F, Simmons C, et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol. 2012;30(6):587–92. doi:10.1200/JCO.2010.33.5232.PubMedGoogle Scholar
  99. 99.
    Parkinson DR, McCormack RT, Keating SM, Gutman SI, Hamilton SR, Mansfield EA, et al. Evidence of clinical utility: an unmet need in molecular diagnostics for patients with cancer. Clin Cancer Res. 2014;20(6):1428–44. doi:10.1158/1078-0432.CCR-13-2961.PubMedGoogle Scholar
  100. 100.
    Simon R, Roychowdhury S. Implementing personalized cancer genomics in clinical trials. Nat Rev Drug Discov. 2013;12(5):358–69. doi:10.1038/nrd3979.PubMedGoogle Scholar
  101. 101.
    Dancey JE, Dobbin KK, Groshen S, Jessup JM, Hruszkewycz AH, Koehler M, et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res. 2010;16(6):1745–55. doi:10.1158/1078-0432.CCR-09-2167.PubMedGoogle Scholar
  102. 102.
    Duffy MJ, Crown J. Companion biomarkers: paving the pathway to personalized treatment for cancer. Clin Chem. 2013;59(10):1447–56. doi:10.1373/clinchem.2012.200477.PubMedGoogle Scholar
  103. 103.
    Ioannidis JP, Panagiotou OA. Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA. 2011;305(21):2200–10. doi:10.1001/jama.2011.713.PubMedGoogle Scholar
  104. 104.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97(16):1180–4. doi:10.1093/jnci/dji237.PubMedGoogle Scholar
  105. 105.
    Werner HM, Mills GB, Ram PT. Cancer systems biology: a peek into the future of patient care? Nat Rev Clin Oncol. 2014;11(3):167–76. doi:10.1038/nrclinonc.2014.6.PubMedGoogle Scholar
  106. 106.•
    Haldorsen IS, Stefansson I, Gruner R, Husby JA, Magnussen IJ, Werner HM, et al. Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas. Br J Cancer. 2014;110(1):107–14. doi:10.1038/bjc.2013.694. Functional imaging results exemplify the potential of advanced imaging to non-invasively and preoperatively identify a patient group with aggressive disease and poor survival. The results are well correlated with known immunohistochemistry parameters reflecting microvascular proliferation.PubMedGoogle Scholar
  107. 107.
    Sleijfer S, Bogaerts J, Siu LL. Designing transformative clinical trials in the cancer genome era. J Clin Oncol. 2013;31(15):1834–41. doi:10.1200/JCO.2012.45.3639.PubMedGoogle Scholar
  108. 108.
    de Bono JS, Ashworth A. Translating cancer research into targeted therapeutics. Nature. 2010;467(7315):543–9. doi:10.1038/nature09339.PubMedGoogle Scholar
  109. 109.
    Schilsky RL, Doroshow JH, Leblanc M, Conley BA. Development and use of integral assays in clinical trials. Clin Cancer Res. 2012;18(6):1540–6. doi:10.1158/1078-0432.CCR-11-2202.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Clinical ScienceUniversity of BergenBergenNorway
  2. 2.Womens’ ClinicHaukeland University HospitalBergenNorway

Personalised recommendations